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Wettergren Y, Rolny P, Lindegren H, Odin E, Rotter Sopasakis V, Keane S, Ejeskär K. Increased MLH1, MGMT, and p16INK4a methylation levels in colon mucosa potentially useful as early risk marker of colon cancer. Mol Cell Oncol 2025; 12:2503069. [PMID: 40357388 PMCID: PMC12068326 DOI: 10.1080/23723556.2025.2503069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/30/2025] [Accepted: 05/01/2025] [Indexed: 05/15/2025]
Abstract
The genes MutL Homolog 1 (MLH1), O6-methylguanine-DNA methyltransferase (MGMT), and cyclin-dependent kinase inhibitor p16INK4a are commonly downregulated by hypermethylation in colorectal cancer. Long interspersed nucleotide element 1 (LINE-1) can be used as marker for global hypomethylation. This study compared MLH1, MGMT, p16INK4a, and LINE-1 methylation with gene expression in colon tumors, matched non-cancerous mucosa, and control mucosa to identify signs of premalignancy. Tissues were obtained from 20 colon cancer patients and 40 controls. CpG site methylation was quantified by pyrosequencing, expression by qPCR, and MSI/KRAS status by fragment analysis and droplet digital PCR. MLH1, MGMT, and p16INK4a methylation was increasingly higher in control mucosa, non-cancerous mucosa, and tumors. MLH1 expression was lower in tumors compared to non-cancerous mucosa but higher compared to control mucosa. Tumoral LINE-1 methylation correlated negatively with MLH1 (r = -0.51, p = .021) and p16INK4a (r = -0.55, p = .012) methylation, but positively (r = 0.74, p = .0002) with MLH1 expression. A p16INK4a SNP (rs3814960 C>T) was associated with methylation, expression, and MSI/KRAS status. Aberrant methylation of tumor suppressor genes in colon mucosa could be an early cancer risk marker. Control mucosa is a more reliable reference than non-cancerous mucosa when identifying premalignant changes. Extended studies will evaluate the possible association between rs3814960 and cancer susceptibility. Trial registration: NCT03072641.
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Affiliation(s)
- Yvonne Wettergren
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Peter Rolny
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Medicine, Division of Gastroenterology and Hepatology, Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - Helena Lindegren
- Department of Medicine, Division of Gastroenterology and Hepatology, Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - Elisabeth Odin
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Victoria Rotter Sopasakis
- Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Simon Keane
- Translational Medicine, School of Health Sciences, University of Skövde, Skövde, Sweden
| | - Katarina Ejeskär
- Translational Medicine, School of Health Sciences, University of Skövde, Skövde, Sweden
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Brinkman MT, Crofts S, Green H. The use of nutrigenomics and nutritional biomarkers with standard care of long-term recurrent metastatic rectal cancer: a case report. Front Oncol 2024; 14:1451675. [PMID: 39687889 PMCID: PMC11646835 DOI: 10.3389/fonc.2024.1451675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 11/07/2024] [Indexed: 12/18/2024] Open
Abstract
Introduction Distant metastases following standard treatment for locally advanced rectal cancer (LARC) are typically associated with poor disease-free survival. We report on a 52-year-old Australian male of Dutch ancestry with no family history of colorectal cancer or significant medical history who experienced bleeding per rectum for several months prior to a colonoscopy in July 2010. He was subsequently diagnosed with Stage IIb LARC. Case presentation Despite treatment with curative intent, a distant recurrence to his left lung was detected in May 2012, upstaging him to Stage IV rectal cancer. He had repeated distant metastatic recurrences over the next 8 years, and treatment included multiple surgeries, chemotherapies, radiation treatments, a "watch and wait" period of 20 months, and personalised dietary management. Genetic and nutrigenomic testing identified that the case had KRAS and MTHFR mutations. As part of his dietary management, the case also had his levels of folate, vitamin B12, and vitamin D regularly monitored because of his genetic predisposition and history of deficiency for these key nutrients. Apart from changes in his CEA levels, sudden increases in the patient's folate levels, inconsistent with dietary exposures preceded detection of each new distant recurrence, with significant decreases in the levels at the next follow-up measurement. Conclusion A multimodal approach to this patient's management appeared to contribute to his long-term survival of nearly 10 years from the initial diagnosis. Multidisciplinary management, including the use of additional biomarkers, may enhance survival rates in other similar cases with advanced disease resistant to differing therapies, and with potentially poor prognosis.
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Affiliation(s)
- Maree T. Brinkman
- Department of Clinical Studies and Nutritional Epidemiology, Nutrition Biomed Research Institute, Melbourne, VIC, Australia
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Ogino S, Ugai T. The global epidemic of early-onset cancer: nature, nurture, or both? Ann Oncol 2024; 35:1071-1073. [PMID: 39293513 PMCID: PMC11624085 DOI: 10.1016/j.annonc.2024.08.2336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Accepted: 08/26/2024] [Indexed: 09/20/2024] Open
Affiliation(s)
- S Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston; Broad Institute of MIT and Harvard, Cambridge; Cancer Immunology Program, Dana-Farber Harvard Cancer Center, Boston; Division of Nutrition, Harvard Medical School, Boston, USA; Tokyo Medical and Dental University (Institute of Science Tokyo), Tokyo, Japan.
| | - T Ugai
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston
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Zinkeng A, Taylor FL, Cheong SH, Song H, Merchant JL. Early Onset Colorectal Cancer: Molecular Underpinnings Accelerating Occurrence. Cell Mol Gastroenterol Hepatol 2024; 19:101425. [PMID: 39510499 PMCID: PMC11731505 DOI: 10.1016/j.jcmgh.2024.101425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 10/28/2024] [Accepted: 10/28/2024] [Indexed: 11/15/2024]
Abstract
The onset of colorectal cancer (CRC) in patients younger than 50 continues to rapidly increase. This study highlights the epidemiologic changes, risk factors, clinical characteristics, and molecular profiles prevalent in early onset CRC patients, and identifies key areas for future research. It has been noted that only a small fraction of early onset CRC cases is attributed to known hereditary mutations and fit the canonical pathway of late-onset colorectal cancer development. To highlight this, we review the genetic and epigenetic modifications specific to early onset CRC. We also discuss the synergetic effect of single-nucleotide polymorphisms and environmental factors on the early onset of CRC. Additionally, we discuss the potential of noninvasive biomarker assays to enhance early detection, screening, diagnosis, and prognostic outcome predictions.
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Affiliation(s)
- Atehkeng Zinkeng
- Medical Scientist Training Program, University of Arizona College of Medicine, Tucson, Arizona
| | | | | | | | - Juanita L Merchant
- Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona.
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Aglago EK, Qu C, Harlid S, Phipps AI, Steinfelder RS, Ogino S, Thomas CE, Hsu L, Toland AE, Brenner H, Berndt SI, Buchanan DD, Campbell PT, Cao Y, Chan AT, Drew DA, Figueiredo JC, French AJ, Gallinger S, Georgeson P, Giannakis M, Goode EL, Gruber SB, Gunter MJ, Harrison TA, Hoffmeister M, Huang WY, Hullar MA, Huyghe JR, Jenkins MA, Lynch BM, Moreno V, Murphy N, Newton CC, Nowak JA, Obón-Santacana M, Sun W, Ugai T, Um CY, Zaidi SH, Tsilidis KK, van Guelpen B, Peters U. Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing. Am J Clin Nutr 2024; 120:664-673. [PMID: 39025327 PMCID: PMC11393398 DOI: 10.1016/j.ajcnut.2024.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 07/06/2024] [Accepted: 07/15/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer. OBJECTIVE We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing. DESIGN Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-β, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors. RESULTS We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways. CONCLUSIONS Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation.
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Affiliation(s)
- Elom K Aglago
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom.
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States; Department of Epidemiology, University of Washington, Seattle, WA, United States
| | - Robert S Steinfelder
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Claire E Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States; Department of Biostatistics, University of Washington, Seattle, WA, United States
| | - Amanda E Toland
- Department of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia; University of Melbourne Centre for Cancer Research, The University of Melbourne, Parkville, VIC, Australia; Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Peter T Campbell
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Yin Cao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, United States; Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO, United States; Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
| | - Andrew T Chan
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Broad Institute of MIT and Harvard, Cambridge, MA, United States; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
| | - David A Drew
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States; Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Amy J French
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Peter Georgeson
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia; University of Melbourne Centre for Cancer Research, The University of Melbourne, Parkville, VIC, Australia
| | - Marios Giannakis
- Broad Institute of MIT and Harvard, Cambridge, MA, United States; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Ellen L Goode
- Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, United States
| | - Stephen B Gruber
- Department of Medical Oncology & Therapeutics Research and Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, United States
| | - Marc J Gunter
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Wen-Yi Huang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Meredith Aj Hullar
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
| | - Brigid M Lynch
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia
| | - Victor Moreno
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain; ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Department of Clinical Sciences, Faculty of Medicine and health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | | | - Jonathan A Nowak
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Mireia Obón-Santacana
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain; ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Wei Sun
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Tomotaka Ugai
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Caroline Y Um
- Department of Population Science, American Cancer Society, Atlanta, Georgia
| | - Syed H Zaidi
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Konstantinos K Tsilidis
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Greece
| | - Bethany van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States; Department of Epidemiology, University of Washington, Seattle, WA, United States
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Laskar RS, Qu C, Huyghe JR, Harrison T, Hayes RB, Cao Y, Campbell PT, Steinfelder R, Talukdar FR, Brenner H, Ogino S, Brendt S, Bishop DT, Buchanan DD, Chan AT, Cotterchio M, Gruber SB, Gsur A, van Guelpen B, Jenkins MA, Keku TO, Lynch BM, Le Marchand L, Martin RM, McCarthy K, Moreno V, Pearlman R, Song M, Tsilidis KK, Vodička P, Woods MO, Wu K, Hsu L, Gunter MJ, Peters U, Murphy N. Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer. Ann Oncol 2024; 35:523-536. [PMID: 38408508 PMCID: PMC11213623 DOI: 10.1016/j.annonc.2024.02.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 01/30/2024] [Accepted: 02/20/2024] [Indexed: 02/28/2024] Open
Abstract
BACKGROUND The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.
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Affiliation(s)
- R S Laskar
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France; Early Cancer Institute, Department of Oncology, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
| | - C Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle
| | - J R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle
| | - T Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle
| | - R B Hayes
- Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York
| | - Y Cao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis; Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis; Alvin J. Siteman Cancer Center, St Louis
| | - P T Campbell
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, USA
| | - R Steinfelder
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle
| | - F R Talukdar
- Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - H Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - S Ogino
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston; Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston
| | - S Brendt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, USA
| | - D T Bishop
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
| | - D D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia
| | - A T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, USA
| | - M Cotterchio
- Ontario Health (Cancer Care Ontario), Toronto; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | - S B Gruber
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, USA
| | - A Gsur
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - B van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - M A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - T O Keku
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, USA
| | - B M Lynch
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne; Physical Activity Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
| | | | - R M Martin
- Medical Research Council (MRC) Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol; National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol
| | - K McCarthy
- Department of Colorectal Surgery, North Bristol NHS Trust, Bristol, UK
| | - V Moreno
- Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona; CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - R Pearlman
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus
| | - M Song
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, USA
| | - K K Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - P Vodička
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - M O Woods
- Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada
| | - K Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, USA
| | - L Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle
| | - M J Gunter
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - U Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle; Department of Epidemiology, University of Washington, Seattle, USA
| | - N Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
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Inciuraite R, Steponaitiene R, Raudze O, Kulokiene U, Kiudelis V, Lukosevicius R, Ugenskiene R, Adamonis K, Kiudelis G, Jonaitis LV, Kupcinskas J, Skieceviciene J. Prolonged culturing of colonic epithelial organoids derived from healthy individuals and ulcerative colitis patients results in the decrease of LINE-1 methylation level. Sci Rep 2024; 14:4456. [PMID: 38396014 PMCID: PMC10891043 DOI: 10.1038/s41598-024-55076-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 02/19/2024] [Indexed: 02/25/2024] Open
Abstract
Patient-derived human intestinal organoids are becoming an indispensable tool for the research of digestive system in health and disease. However, very little is still known about the long-term culturing effect on global genomic methylation level in colonic epithelial organoids derived from healthy individuals as well as active and quiescent ulcerative colitis (UC) patients. In this study, we aimed to evaluate the epigenetic stability of these organoids by assessing the methylation level of LINE-1 during prolonged culturing. We found that LINE-1 region of both healthy control and UC patient colon tissues as well as corresponding epithelial organoids is highly methylated (exceeding 60%). We also showed that long-term culturing of colonic epithelial organoids generated from stem cells of healthy and diseased (both active and quiescent UC) individuals results in decrease of LINE-1 (up to 8%) methylation level, when compared to tissue of origin and short-term cultures. Moreover, we revealed that LINE-1 methylation level in sub-cultured organoids decreases at different pace depending on the patient diagnosis (healthy control, active or quiescent UC). Therefore, we propose LINE-1 as a potential and convenient biomarker for reliable assessment of global methylation status of patient-derived intestinal epithelial organoids in routine testing of ex vivo cultures.
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Affiliation(s)
- Ruta Inciuraite
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
| | - Ruta Steponaitiene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
| | - Odeta Raudze
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
| | - Ugne Kulokiene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
| | - Vytautas Kiudelis
- Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
| | - Rokas Lukosevicius
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
| | - Rasa Ugenskiene
- Department of Genetics and Molecular Medicine, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
| | - Kestutis Adamonis
- Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
| | - Gediminas Kiudelis
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
- Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
| | - Laimas Virginijus Jonaitis
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
- Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
| | - Juozas Kupcinskas
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
- Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, A. Mickeviciaus St. 9, 44307, Kaunas, Lithuania.
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8
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Liu J, Huang B, Ding F, Li Y. Environment factors, DNA methylation, and cancer. ENVIRONMENTAL GEOCHEMISTRY AND HEALTH 2023; 45:7543-7568. [PMID: 37715840 DOI: 10.1007/s10653-023-01749-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 08/30/2023] [Indexed: 09/18/2023]
Abstract
Today, the rapid development of science and technology and the rapid change in economy and society are changing the way of life of human beings and affecting the natural, living, working, and internal environment on which human beings depend. At the same time, the global incidence of cancer has increased significantly yearly, and cancer has become the number one killer that threatens human health. Studies have shown that diet, living habits, residential environment, mental and psychological factors, intestinal flora, genetics, social factors, and viral and non-viral infections are closely related to human cancer. However, the molecular mechanisms of the environment and cancer development remain to be further explored. In recent years, DNA methylation has become a key hub and bridge for environmental and cancer research. Some environmental factors can alter the hyper/hypomethylation of human cancer suppressor gene promoters, proto-oncogene promoters, and the whole genome, causing low/high expression or gene mutation of related genes, thereby exerting oncogenic or anticancer effects. It is expected to develop early warning markers of cancer environment based on DNA methylation, thereby providing new methods for early detection of cancers, diagnosis, and targeted therapy. This review systematically expounds on the internal mechanism of environmental factors affecting cancer by changing DNA methylation, aiming to help establish the concept of cancer prevention and improve people's health.
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Affiliation(s)
- Jie Liu
- Department of General Surgery, Second Hospital of Lanzhou University, Lan Zhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lan Zhou, China
| | - Binjie Huang
- Department of General Surgery, Second Hospital of Lanzhou University, Lan Zhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lan Zhou, China
| | - Feifei Ding
- Department of General Surgery, Second Hospital of Lanzhou University, Lan Zhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lan Zhou, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lan Zhou, China.
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lan Zhou, China.
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9
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Lai J, Guo M, Wang D, Liu K, Hu D, Li J. Association Between Vitamin B6 and the Risk of Colorectal Cancer: A Meta-analysis of Observational Studies. Nutr Cancer 2023; 75:1281-1294. [PMID: 36961108 DOI: 10.1080/01635581.2023.2191823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 02/07/2023] [Accepted: 03/12/2023] [Indexed: 03/25/2023]
Abstract
OBJECTIVE This meta-analysis aimed to assess the association between vitamin B6 intake, blood PLP levels, and the risk of colorectal cancer. METHODS The databases PubMed, Cochrane Library and Embase databases were comprehensively searched for cohort studies or case-control studies. The odds ratio (OR) and 95% confidence interval (CI) were extracted from each eligible study, and the statistical software Stata was used to perform statistical merging. RESULTS Twenty-eight studies (20 cohort studies, 8 case-control studies) were included in our meta-analysis. The combined OR for the association between colorectal cancer risk and vitamin B6 intake was 0.80 (95% CI: 0.68-0.94), while the combined OR between blood PLP levels and colorectal cancer risk was 0.54 (95% CI: 0.35-0.84). In addition, the subgroup analysis revealed that vitamin B6 could reduce the risk of colorectal cancer in women [vitamin B6 intake OR = 0.79, 95% CI (0.65-0.96); blood PLP levels OR = 0.41, 95% CI (0.30-0.57)] and also reduce the risk of colon cancer in men and women [vitamin B6 intake OR = 0.76, 95% CI (0.64-0.91); blood PLP levels OR = 0.56, 95% CI (0.42-0.73)]. CONCLUSION In this meta-analysis, vitamin B6 intake and blood PLP levels were inversely associated with colorectal cancer risk.
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Affiliation(s)
- Jianxiong Lai
- Department of General Surgery, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
| | - Mingqiao Guo
- Department of General Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Dongmei Wang
- Department of General Surgery, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
| | - Kuan Liu
- Department of General Surgery, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
| | - Dengmin Hu
- Department of General Surgery, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
| | - Jian Li
- Department of General Surgery, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
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10
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Boughanem H, Kompella P, Tinahones FJ, Macias-Gonzalez M. An overview of vitamins as epidrugs for colorectal cancer prevention. Nutr Rev 2023; 81:455-479. [PMID: 36018754 DOI: 10.1093/nutrit/nuac065] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Gene expression altering epigenomic modifications such as DNA methylation, histone modification, and chromosome remodeling is crucial to regulating many biological processes. Several lifestyle factors, such as diet and natural, bioactive food compounds, such as vitamins, modify epigenetic patterns. However, epigenetic dysregulation can increase the risk of many diseases, including cancer. Various studies have provided supporting and contrasting evidence on the relationship between vitamins and cancer risk. Though there is a gap in knowledge about whether dietary vitamins can induce epigenetic modifications in the context of colorectal cancer (CRC), the possibility of using them as epidrugs for CRC treatment is being explored. This is promising because such studies might be informative about the most effective way to use vitamins in combination with DNA methyltransferase inhibitors and other approved therapies to prevent and treat CRC. This review summarizes the available epidemiological and observational studies involving dietary, circulating levels, and supplementation of vitamins and their relationship with CRC risk. Additionally, using available in vitro, in vivo, and human observational studies, the role of vitamins as potential epigenetic modifiers in CRC is discussed. This review is focused on the action of vitamins as modifiers of DNA methylation because aberrant DNA methylation, together with genetic alterations, can induce the initiation and progression of CRC. Although this review presents some studies with promising results, studies with better study designs are necessary. A thorough understanding of the underlying molecular mechanisms of vitamin-mediated epigenetic regulation of CRC genes can help identify effective therapeutic targets for CRC prevention and treatment.
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Affiliation(s)
- Hatim Boughanem
- are with the Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga, Spain.,are with the Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Pallavi Kompella
- are with the Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga, Spain.,is with the Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA
| | - Francisco J Tinahones
- are with the Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga, Spain.,are with the Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel Macias-Gonzalez
- are with the Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga, Spain.,are with the Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
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11
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Chávez-Hidalgo LP, Martín-Fernández-de-Labastida S, M de Pancorbo M, Arroyo-Izaga M. Influence of methyl donor nutrients as epigenetic regulators in colorectal cancer: A systematic review of observational studies. World J Gastroenterol 2023; 29:1219-1234. [PMID: 36926668 PMCID: PMC10011952 DOI: 10.3748/wjg.v29.i7.1219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/26/2022] [Accepted: 02/14/2023] [Indexed: 02/21/2023] Open
Abstract
BACKGROUND Dietary methyl donors might influence DNA methylation during carcinogenesis of colorectal cancer (CRC). However, whether the influence of methyl donor intake is modified by polymorphisms in such epigenetic regulators is still unclear.
AIM To improve the current understanding of the molecular basis of CRC.
METHODS A literature search in the Medline database, Reference Citation Analysis (https://www.referencecitationanalysis.com/), and manual reference screening were performed to identify observational studies published from inception to May 2022.
RESULTS A total of fourteen case-control studies and five cohort studies were identified. These studies included information on dietary methyl donors, dietary components that potentially modulate the bioavailability of methyl groups, genetic variants of methyl metabolizing enzymes, and/or markers of CpG island methylator phenotype and/or microsatellite instability, and their possible interactions on CRC risk.
CONCLUSION Several studies have suggested interactions between methylenetetrahydrofolate reductase polymorphisms, methyl donor nutrients (such as folate) and alcohol on CRC risk. Moreover, vitamin B6, niacin, and alcohol may affect CRC risk through not only genetic but also epigenetic regulation. Identification of specific mechanisms in these interactions associated with CRC may assist in developing targeted prevention strategies for individuals at the highest risk of developing CRC.
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Affiliation(s)
- Lourdes Pilar Chávez-Hidalgo
- Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
| | - Silvia Martín-Fernández-de-Labastida
- Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
| | - Marian M de Pancorbo
- Department of Z. and Cellular Biology A., University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
- BIOMICs Research Group, MICROFLUIDICs and BIOMICs Cluster UPV/EHU, Lascaray Research Center, University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
| | - Marta Arroyo-Izaga
- Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
- BIOMICs Research Group, MICROFLUIDICs and BIOMICs Cluster UPV/EHU, Lascaray Research Center, University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
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12
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Liu X, Chen J, Li J, Zeng Z, Jiang X, Gao Y, Huang Z, Wu Q, Gong Y, Xie C. Integrated analysis reveals common DNA methylation patterns of alcohol-associated cancers: A pan-cancer analysis. Front Genet 2023; 14:1032683. [PMID: 36861126 PMCID: PMC9968750 DOI: 10.3389/fgene.2023.1032683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 01/24/2023] [Indexed: 02/16/2023] Open
Abstract
Background: The role of alcohol in carcinogenesis has received increasing attention in recent years. Evidence shows its impacts on various aspects, including epigenetics alteration. The DNA methylation patterns underlying alcohol-associated cancers are not fully understood. Methods: We investigated the aberrant DNA methylation patterns in four alcohol-associated cancers based on the Illumina HumanMethylation450 BeadChip. Pearson coefficient correlations were identified between differential methylated CpG probes and annotated genes. Transcriptional factor motifs were enriched and clustered using MEME Suite, and a regulatory network was constructed. Results: In each cancer, differential methylated probes (DMPs) were identified, and 172 hypermethylated and 21 hypomethylated pan-cancer DMPs (PDMPs) were examined further. Annotated genes significantly regulated by PDMPs were investigated and enriched in transcriptional misregulation in cancers. The CpG island chr19:58220189-58220517 was hypermethylated in all four cancers and silenced in the transcription factor ZNF154. Various biological effects were exerted by 33 hypermethylated and seven hypomethylated transcriptional factor motifs grouped into five clusters. Eleven pan-cancer DMPs were identified to be associated with clinical outcomes in the four alcohol-associated cancers, which might provide a potential point of view for clinical outcome prediction. Conclusion: This study provides an integrated insight into DNA methylation patterns in alcohol-associated cancers and reveals the corresponding features, influences, and potential mechanisms.
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Affiliation(s)
- Xingyu Liu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jiarui Chen
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jiali Li
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zihang Zeng
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xueping Jiang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yanping Gao
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhengrong Huang
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
- Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qiuji Wu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yan Gong
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
- Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Conghua Xie
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
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13
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Erichsen L, Thimm C, Santourlidis S. Methyl Group Metabolism in Differentiation, Aging, and Cancer. Int J Mol Sci 2022; 23:8378. [PMID: 35955511 PMCID: PMC9369357 DOI: 10.3390/ijms23158378] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 07/21/2022] [Accepted: 07/26/2022] [Indexed: 12/04/2022] Open
Abstract
Methyl group metabolism belongs to a relatively understudied field of research. Its importance lies in the fact that methyl group metabolic pathways are crucial for the successful conversion of dietary nutrients into the basic building blocks to carry out any cellular methylation reaction. Methyl groups play essential roles in numerous cellular functions such as DNA methylation, nucleotide- and protein biosynthesis. Especially, DNA methylation is responsible for organizing the genome into transcriptionally silent and active regions. Ultimately, it is this proper annotation that determines the quality of expression patterns required to ensure and shape the phenotypic integrity and function of a highly specialized cell type. Life is characterized by constantly changing environmental conditions, which are addressed by changes in DNA methylation. This relationship is increasingly coming into focus as it is of fundamental importance for differentiation, aging, and cancer. The stability and permanence of these metabolic processes, fueling the supplementation of methyl groups, seem to be important criteria to prevent deficiencies and erosion of the methylome. Alterations in the metabolic processes can lead to epigenetic and genetic perturbations, causative for diverse disorders, accelerated aging, and various age-related diseases. In recent decades, the intake of methyl group compounds has changed significantly due to, e.g., environmental pollution and food additives. Based on the current knowledge, this review provides a brief overview of the highly interconnected relationship between nutrition, metabolism, changes in epigenetic modifications, cancer, and aging. One goal is to provide an impetus to additionally investigate changes in DNA methylation as a possible consequence of an impaired methyl group metabolism.
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Affiliation(s)
- Lars Erichsen
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany;
| | - Chantelle Thimm
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany;
| | - Simeon Santourlidis
- Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany;
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14
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Fatemi N, Tierling S, Es HA, Varkiani M, Nazemalhosseini Mojarad E, Asadzadeh Aghdaei H, Walter J, Totonchi M. DNA Methylation Biomarkers in Colorectal Cancer: Clinical Applications for Precision Medicine. Int J Cancer 2022; 151:2068-2081. [PMID: 35730647 DOI: 10.1002/ijc.34186] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/29/2022] [Accepted: 06/08/2022] [Indexed: 11/06/2022]
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer death worldwide that is attributed to gradual long-term accumulation of both genetic and epigenetic changes. To reduce the mortality rate of CRC and to improve treatment efficacy, it will be important to develop accurate noninvasive diagnostic tests for screening, acute, and personalized diagnosis. Epigenetic changes such as DNA methylation play an important role in the development and progression of CRC. Over the last decade, a panel of DNA methylation markers has been reported showing a high accuracy and reproducibility in various semi-invasive or noninvasive biosamples. Research to obtain comprehensive panels of markers allowing a highly sensitive and differentiating diagnosis of CRC is ongoing. Moreover, the epigenetic alterations for cancer therapy, as a precision medicine strategy will increase their therapeutic potential over time. Here, we discuss the current state of DNA methylation-based biomarkers and their impact on CRC diagnosis. We emphasize the need to further identify and stratify methylation-biomarkers and to develop robust and effective detection methods that are applicable for a routine clinical setting of CRC diagnostics particularly at the early stage of the disease.
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Affiliation(s)
- Nayeralsadat Fatemi
- Basic & Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology & Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sascha Tierling
- Department of Genetics/Epigenetics, Faculty NT, Life Sciences, Saarland University, Saarbrücken, Germany
| | | | - Maryam Varkiani
- Department of Molecular Genetics, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
| | - Ehsan Nazemalhosseini Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic & Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology & Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jörn Walter
- Department of Genetics/Epigenetics, Faculty NT, Life Sciences, Saarland University, Saarbrücken, Germany
| | - Mehdi Totonchi
- Basic & Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology & Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
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15
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Szigeti KA, Kalmár A, Galamb O, Valcz G, Barták BK, Nagy ZB, Zsigrai S, Felletár I, V Patai Á, Micsik T, Papp M, Márkus E, Tulassay Z, Igaz P, Takács I, Molnár B. Global DNA hypomethylation of colorectal tumours detected in tissue and liquid biopsies may be related to decreased methyl-donor content. BMC Cancer 2022; 22:605. [PMID: 35655145 PMCID: PMC9164347 DOI: 10.1186/s12885-022-09659-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 05/03/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hypomethylation of long interspersed nuclear element 1 (LINE-1) is characteristic of various cancer types, including colorectal cancer (CRC). Malfunction of several factors or alteration of methyl-donor molecules' (folic acid and S-adenosylmethionine) availability can contribute to DNA methylation changes. Detection of epigenetic alterations in liquid biopsies can assist in the early recognition of CRC. Following the investigations of a Hungarian colon tissue sample set, our goal was to examine the LINE-1 methylation of blood samples along the colorectal adenoma-carcinoma sequence and in inflammatory bowel disease. Moreover, we aimed to explore the possible underlying mechanisms of global DNA hypomethylation formation on a multi-level aspect. METHODS LINE-1 methylation of colon tissue (n = 183) and plasma (n = 48) samples of healthy controls and patients with colorectal tumours were examined with bisulfite pyrosequencing. To investigate mRNA expression, microarray analysis results were reanalysed in silico (n = 60). Immunohistochemistry staining was used to validate DNA methyltransferases (DNMTs) and folate receptor beta (FOLR2) expression along with the determination of methyl-donor molecules' in situ level (n = 40). RESULTS Significantly decreased LINE-1 methylation level was observed in line with cancer progression both in tissue (adenoma: 72.7 ± 4.8%, and CRC: 69.7 ± 7.6% vs. normal: 77.5 ± 1.7%, p ≤ 0.01) and liquid biopsies (adenoma: 80.0 ± 1.7%, and CRC: 79.8 ± 1.3% vs. normal: 82.0 ± 2.0%, p ≤ 0.01). However, no significant changes were recognized in inflammatory bowel disease cases. According to in silico analysis of microarray data, altered mRNA levels of several DNA methylation-related enzymes were detected in tumours vs. healthy biopsies, namely one-carbon metabolism-related genes-which met our analysing criteria-showed upregulation, while FOLR2 was downregulated. Using immunohistochemistry, DNMTs, and FOLR2 expression were confirmed. Moreover, significantly diminished folic acid and S-adenosylmethionine levels were observed in parallel with decreasing 5-methylcytosine staining in tumours compared to normal adjacent to tumour tissues (p ≤ 0.05). CONCLUSION Our results suggest that LINE-1 hypomethylation may have a distinguishing value in precancerous stages compared to healthy samples in liquid biopsies. Furthermore, the reduction of global DNA methylation level could be linked to reduced methyl-donor availability with the contribution of decreased FOLR2 expression.
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Affiliation(s)
- Krisztina A Szigeti
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary.
| | - Alexandra Kalmár
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
- Molecular Medicine Research Group, Eötvös Loránd Research Network, 1083, Budapest, Hungary
| | - Orsolya Galamb
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
- Molecular Medicine Research Group, Eötvös Loránd Research Network, 1083, Budapest, Hungary
| | - Gábor Valcz
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
- Molecular Medicine Research Group, Eötvös Loránd Research Network, 1083, Budapest, Hungary
| | - Barbara K Barták
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
| | - Zsófia B Nagy
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
| | - Sára Zsigrai
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
| | - Ildikó Felletár
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
| | - Árpád V Patai
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, 1082, Budapest, Hungary
- Interdisciplinary Gastroenterology (IGA) Working Group, Semmelweis University, 1082, Budapest, Hungary
| | - Tamás Micsik
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085, Budapest, Hungary
| | - Márton Papp
- Centre for Bioinformatics, University of Veterinary Medicine Budapest, 1078, Budapest, Hungary
| | - Eszter Márkus
- Department of Anaesthesia and Intensive Care, Pest County Flor Ferenc Hospital, 2143, Kistarcsa, Hungary
| | - Zsolt Tulassay
- Molecular Medicine Research Group, Eötvös Loránd Research Network, 1083, Budapest, Hungary
- Department of Internal Medicine and Hematology, Faculty of Medicine, Semmelweis University, 1088, Budapest, Hungary
| | - Peter Igaz
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
- Molecular Medicine Research Group, Eötvös Loránd Research Network, 1083, Budapest, Hungary
- Department of Endocrinology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
| | - István Takács
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
| | - Béla Molnár
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083, Budapest, Hungary
- Molecular Medicine Research Group, Eötvös Loránd Research Network, 1083, Budapest, Hungary
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16
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Li R, Ugai T, Xu L, Zucker D, Ogino S, Wang M. Utility of Continuous Disease Subtyping Systems for Improved Evaluation of Etiologic Heterogeneity. Cancers (Basel) 2022; 14:1811. [PMID: 35406583 PMCID: PMC8997600 DOI: 10.3390/cancers14071811] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/26/2022] [Accepted: 03/31/2022] [Indexed: 12/04/2022] Open
Abstract
Molecular pathologic diagnosis is important in clinical (oncology) practice. Integration of molecular pathology into epidemiological methods (i.e., molecular pathological epidemiology) allows for investigating the distinct etiology of disease subtypes based on biomarker analyses, thereby contributing to precision medicine and prevention. However, existing approaches for investigating etiological heterogeneity deal with categorical subtypes. We aimed to fully leverage continuous measures available in most biomarker readouts (gene/protein expression levels, signaling pathway activation, immune cell counts, microbiome/microbial abundance in tumor microenvironment, etc.). We present a cause-specific Cox proportional hazards regression model for evaluating how the exposure-disease subtype association changes across continuous subtyping biomarker levels. Utilizing two longitudinal observational prospective cohort studies, we investigated how the association of alcohol intake (a risk factor) with colorectal cancer incidence differed across the continuous values of tumor epigenetic DNA methylation at long interspersed nucleotide element-1 (LINE-1). The heterogeneous alcohol effect was modeled using different functions of the LINE-1 marker to demonstrate the method's flexibility. This real-world proof-of-principle computational application demonstrates how the new method enables visualizing the trend of the exposure effect over continuous marker levels. The utilization of continuous biomarker data without categorization for investigating etiological heterogeneity can advance our understanding of biological and pathogenic mechanisms.
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Affiliation(s)
- Ruitong Li
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; (R.L.); (S.O.)
| | - Tomotaka Ugai
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Lantian Xu
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
| | - David Zucker
- Department of Statistics and Data Science, Hebrew University, Jerusalem 91905, Israel;
| | - Shuji Ogino
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; (R.L.); (S.O.)
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA 02115, USA
| | - Molin Wang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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The Role of Diet and Lifestyle in Early-Onset Colorectal Cancer: A Systematic Review. Cancers (Basel) 2021; 13:cancers13235933. [PMID: 34885046 PMCID: PMC8657307 DOI: 10.3390/cancers13235933] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/16/2021] [Accepted: 11/24/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary This systematic review sifted through the exogenous dietary and lifestyle risk factors associated with early-onset colorectal cancer, going through the putative involvement of these exogenous risk factors in epigenetic and microbiota modifications. Given the burden of early-onset colorectal cancer and its globally increasing trend with scant literature on its pathogenesis, we believe it would be of benefit to highlight the importance of further systematic and large studies. Indeed, dietary and lifestyle modification could complement colorectal screening for early-onset colorectal cancer prevention. Abstract The incidence of early-onset colorectal cancer, defined as colorectal cancer occurring in young adults under the age of 50, is increasing globally. Knowledge of the etiological factors in young adults is far from complete. Questionable eoCRCs’ exogenous factors are represented by processed meat, sugary drinks, alcohol, Western dietary pattern, overweight and obesity, physical inactivity, and smoking, though with heterogeneous results. Therefore, we performed a systematic review to summarize the current evidence on the role of diet and lifestyle as eoCRC risk factors. We systematically searched PubMed, Scopus, and EMBASE up to July 2021, for original studies evaluating diet, alcohol, physical activity, BMI, and smoking in eoCRC and included twenty-six studies. Indeed, the exogenous factors could represent modifiable key factors, whose recognition could establish areas of future interventions through public health strategies for eoCRC primary prevention. Additionally, we discussed the role of additional non-modifiable risk factors, and of epigenetic regulation and microbiota as mediators of the eoCRC triggered by diet and lifestyle.
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Sikavi DR, Nguyen LH, Haruki K, Ugai T, Ma W, Wang DD, Thompson KN, Yan Y, Branck T, Wilkinson JE, Akimoto N, Zhong R, Lau MC, Mima K, Kosumi K, Morikawa T, Rimm EB, Garrett WS, Izard J, Cao Y, Song M, Huttenhower C, Ogino S, Chan AT. The Sulfur Microbial Diet and Risk of Colorectal Cancer by Molecular Subtypes and Intratumoral Microbial Species in Adult Men. Clin Transl Gastroenterol 2021; 12:e00338. [PMID: 34333506 PMCID: PMC8323793 DOI: 10.14309/ctg.0000000000000338] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 03/05/2021] [Indexed: 01/22/2023] Open
Abstract
INTRODUCTION We recently described the sulfur microbial diet, a pattern of intake associated with increased gut sulfur-metabolizing bacteria and incidence of distal colorectal cancer (CRC). We assessed whether this risk differed by CRC molecular subtypes or presence of intratumoral microbes involved in CRC pathogenesis (Fusobacterium nucleatum and Bifidobacterium spp.). METHODS We performed Cox proportional hazards modeling to examine the association between the sulfur microbial diet and incidence of overall and distal CRC by molecular and microbial subtype in the Health Professionals Follow-Up Study (1986-2012). RESULTS We documented 1,264 incident CRC cases among 48,246 men, approximately 40% of whom had available tissue data. After accounting for multiple hypothesis testing, the relationship between the sulfur microbial diet and CRC incidence did not differ by subtype. However, there was a suggestion of an association by prostaglandin synthase 2 (PTGS2) status with a multivariable adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.31 (95% confidence interval: 0.99-1.74, Ptrend = 0.07, Pheterogeneity = 0.04) for PTGS2-high CRC. The association of the sulfur microbial diet with distal CRC seemed to differ by the presence of intratumoral Bifidobacterium spp. with an adjusted hazard ratio for highest vs lowest tertile of sulfur microbial diet scores of 1.65 (95% confidence interval: 1.14-2.39, Ptrend = 0.01, Pheterogeneity = 0.03) for Bifidobacterium-negative distal CRC. We observed no apparent heterogeneity by other tested molecular markers. DISCUSSION Greater long-term adherence to the sulfur microbial diet could be associated with PTGS2-high and Bifidobacterium-negative distal CRC in men. Additional studies are needed to further characterize the role of gut microbial sulfur metabolism and CRC.
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Affiliation(s)
- Daniel R. Sikavi
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Long H. Nguyen
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Koichiro Haruki
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Tomotaka Ugai
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Wenjie Ma
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Dong D. Wang
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Kelsey N. Thompson
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Yan Yan
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Tobyn Branck
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Jeremy E. Wilkinson
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Naohiko Akimoto
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Rong Zhong
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Mai Chan Lau
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Kosuke Mima
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Keisuke Kosumi
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Teppei Morikawa
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Eric B. Rimm
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Wendy S. Garrett
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Jacques Izard
- Department of Food Science and Technology, University of Nebraska, Lincoln, Nebraska, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Yin Cao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, Missouri, USA
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri, USA
| | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Curtis Huttenhower
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, Massachusetts, USA
| | - Andrew T. Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
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Canever L, Varela R, Mastella GA, Damázio LS, Valvassori SS, Quevedo JL, Zugno AI. Effects of maternal folic acid supplementation on nuclear methyltransferase activity of adult rats subjected to an animal model of schizophrenia. Int J Dev Neurosci 2021; 81:461-467. [PMID: 33786893 DOI: 10.1002/jdn.10109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 11/09/2022] Open
Abstract
INTRODUCTION Schizophrenia is considered one of the most disabling and severe human diseases worldwide. The etiology of schizophrenia is thought to be multifactorial and evidence suggests that DNA methylation can play an important role in underlying pivotal neurobiological alterations of this disorder. Some studies have demonstrated the effects of dietary supplementation as an alternative approach to the prevention of schizophrenia, including folic acid. However, no study has ever investigated the role of such supplementation in altering the DNA methylation system in the context of schizophrenia. OBJECTIVES The present study aims to investigate the effects of maternal folic acid supplementation at different doses on nuclear methyltransferase activity of adult rat offspring subjected to an animal model schizophrenia induced by ketamine. METHODS Adult female Wistar rats, (60 days old) received folic acid-deficient diet, control diet, or control diet plus folic acid supplementation (at 5, 10, or 50 mg/kg) during pregnancy and lactation. After reaching adulthood (60 days), the male offspring of these dams were subjected to the animal model of schizophrenia induced by 7 days of ketamine intraperitoneal injection (25 mg/kg). After the 7-day protocol, the activity of nuclear methyltransferase was evaluated in the brains of the offspring. RESULTS Maternal folic acid supplementation at 50 mg/kg increased methyltransferase activity in the frontal cortex, while 10 mg/kg increased methyltransferase activity in the hippocampus. In the striatum of offspring treated with ketamine, maternal deficient diet, control diet, and folic acid supplementation at 5 mg/kg decreased methyltransferase activity compared to the control group. The folic acid supplementation at 10 and 50 mg/kg reversed this ketamine effect. CONCLUSIONS Maternal FA deficiency could be related to schizophrenia pathophysiology, while FA supplementation could present a protective effect since it demonstrated persistent effects in epigenetic parameters in adult offspring.
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Affiliation(s)
- Lara Canever
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, Brazil
| | - Roger Varela
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, Brazil
| | - Gustavo A Mastella
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, Brazil
| | - Louyse S Damázio
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, Brazil
| | - Samira S Valvassori
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, Brazil
| | - João L Quevedo
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, Brazil.,Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.,Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.,Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Alexandra I Zugno
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, Brazil
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20
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Soundararajan S, Agrawal A, Purushottam M, Anand SD, Shankarappa B, Sharma P, Jain S, Murthy P. Changes in DNA methylation persist over time in males with severe alcohol use disorder-A longitudinal follow-up study. Am J Med Genet B Neuropsychiatr Genet 2021; 186:183-192. [PMID: 33491855 DOI: 10.1002/ajmg.b.32833] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 12/31/2020] [Accepted: 01/08/2021] [Indexed: 12/25/2022]
Abstract
Treatment strategies for alcohol use disorder (AUD) aim for abstinence or harm reduction. While deranged biochemical parameters reverse with alcohol abstinence, whether molecular changes at the epigenetic level reverse is not clearly understood. We investigated whether the reduction from high alcohol use reflects DNA methylation at the gene-specific and global level. In subjects seeking treatment for severe AUD, we assessed gene-specific (aldehyde dehydrogenase [ALDH2]/methylene tetrahydrofolate reductase [MTHFR]) and global (long interspersed elements [LINE-1]) methylation across three-time points (baseline, after detoxification and at an early remission period of 3 months), in peripheral blood leukocytes. We observed that both gene-specific and global DNA methylation did not change over time, irrespective of the drinking status at 3 months (52% abstained from alcohol). Further, we also compared DNA methylation in AUD subjects with healthy controls. At baseline, there was a significantly higher gene-specific DNA methylation (ALDH2: p < .001 and MTHFR: p = .001) and a significant lower global methylation (LINE-1: p = .014) in AUD as compared to controls. Our results suggest that epigenetic changes at the DNA methylation level associated with severe AUD persist for at least 3 months of treatment.
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Affiliation(s)
- Soundarya Soundararajan
- Department of Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.,Centre for Addiction Medicine, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.,Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Arpana Agrawal
- Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Meera Purushottam
- Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.,Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Shravanthi Daphne Anand
- Centre for Addiction Medicine, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Bhagyalakshmi Shankarappa
- Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Priyamvada Sharma
- Centre for Addiction Medicine, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.,Department of Clinical Pharmacology and Neurotoxicology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Sanjeev Jain
- Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.,Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Pratima Murthy
- Centre for Addiction Medicine, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.,Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
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21
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Zeggar HR, How-Kit A, Daunay A, Bettaieb I, Sahbatou M, Rahal K, Adouni O, Gammoudi A, Douik H, Deleuze JF, Kharrat M. Tumor DNA hypomethylation of LINE-1 is associated with low tumor grade of breast cancer in Tunisian patients. Oncol Lett 2020; 20:1999-2006. [PMID: 32724446 PMCID: PMC7377197 DOI: 10.3892/ol.2020.11745] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 05/19/2020] [Indexed: 12/24/2022] Open
Abstract
DNA hypomethylation of long interspersed repetitive DNA retrotransposon (LINE-1) and Alu repeats elements of short interspersed elements family (SINEs) is an early event in carcinogenesis that causes transcriptional activation and leads to chromosomal instability. In the current study, DNA methylation levels of LINE-1 and Alu repeats were analyzed in tumoral tissues of invasive breast cancer in a Tunisian cohort and its association with the clinicopathological features of patients was defined. DNA methylation of LINE-1 and Alu repeats were analyzed using pyrosequencing in 61 invasive breast cancers. Median values observed for DNA methylation of LINE-1 and Alu repeats were considered as the cut-off (59.81 and 18.49%, respectively). The results of the current study demonstrated a positive correlation between DNA methylation levels of LINE-1 and Alu repeats (rho=0.284; P<0.03). DNA hypomethylation of LINE-1 was also indicated to be associated with low grade (P=0.023). To the best of our knowledge, the current study is the first study regarding DNA methylation of LINE-1 and Alu repeats element in breast cancer of the Tunisian population. The results of the current study suggest that, since hypomethylation of LINE-1 is associated with low grade, it could be used as a biomarker for prognosis for patients with breast cancer.
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Affiliation(s)
- Hayet Radia Zeggar
- University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES10 Human Genetics Laboratory, 1007 Tunis, Tunisia
| | - Alexandre How-Kit
- Laboratoire de Génomique, Fondation Jean Dausset-CEPH, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France
| | - Antoine Daunay
- Laboratoire de Génomique, Fondation Jean Dausset-CEPH, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France
| | - Ilhem Bettaieb
- Department of Immunohistocytology, Salah Azaïz Cancer Institute, 1006 Tunis, Tunisia
| | - Mourad Sahbatou
- Laboratoire de Biostatistique, Fondation Jean Dausset-CEPH, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France
| | - Khaled Rahal
- Service de Chirurgie Carcinologique, Institut Salah Azaiz de Tunis, 1006 Tunis, Tunisia
| | - Olfa Adouni
- Department of Immunohistocytology, Salah Azaïz Cancer Institute, 1006 Tunis, Tunisia
| | - Amor Gammoudi
- Department of Immunohistocytology, Salah Azaïz Cancer Institute, 1006 Tunis, Tunisia
| | - Hayet Douik
- University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES10 Human Genetics Laboratory, 1007 Tunis, Tunisia
| | - Jean-François Deleuze
- Laboratoire de Génomique, Fondation Jean Dausset-CEPH, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France
- Centre National de Recherche en Génomique Humaine, CEA, Le Commissariat à l'énergie atomique et aux énergies alternatives-Institut François Jacob, 92265 Evry, France
| | - Maher Kharrat
- University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES10 Human Genetics Laboratory, 1007 Tunis, Tunisia
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22
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Maugeri A, Barchitta M. How Dietary Factors Affect DNA Methylation: Lesson from Epidemiological Studies. MEDICINA (KAUNAS, LITHUANIA) 2020; 56:E374. [PMID: 32722411 PMCID: PMC7466216 DOI: 10.3390/medicina56080374] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 07/22/2020] [Accepted: 07/23/2020] [Indexed: 02/06/2023]
Abstract
Over the past decades, DNA methylation has been proposed as a molecular mechanism underlying the positive or negative effects of diet on human health. Despite the number of studies on this topic is rapidly increasing, the relationship between dietary factors, changes in DNA methylation and health outcomes remains unclear. In this review, we summarize the literature from observational studies (cross-sectional, retrospective, or prospective) which examined the association of dietary factors (nutrients, foods, and dietary patterns) with DNA methylation markers among diseased or healthy people during the lifetime. Next, we discuss the methodological pitfalls by examining strengths and limitations of published studies. Finally, we close with a discussion on future challenges of this field of research, raising the need for large-size prospective studies evaluating the association between diet and DNA methylation in health and diseases for appropriate public health strategies.
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Affiliation(s)
- Andrea Maugeri
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, 95123 Catania, Italy;
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23
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Wang L, Lo CH, He X, Hang D, Wang M, Wu K, Chan AT, Ogino S, Giovannucci EL, Song M. Risk Factor Profiles Differ for Cancers of Different Regions of the Colorectum. Gastroenterology 2020; 159:241-256.e13. [PMID: 32247020 PMCID: PMC7387153 DOI: 10.1053/j.gastro.2020.03.054] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/11/2020] [Accepted: 03/23/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS The molecular features of colorectal tumors differ with their anatomic location. Colorectal tumors are usually classified as proximal or distal. We collected data from 3 cohorts to identify demographic, clinical, anthropometric, lifestyle, and dietary risk factors for colorectal cancer (CRC) at 7 anatomic subsites. We examined whether the associations differ among refined subsites and whether there are trends in associations from cecum to rectum. METHODS We collected data from the Nurses' Health Study, Nurses' Health Study 2, and Health Professionals Follow-up Study (45,351 men and 178,016 women, followed for a median 23 years) on 24 risk factors in relation to risk of cancer in cecum, ascending colon, transverse colon, descending colon, sigmoid colon, rectosigmoid junction, and rectum. Hazard ratios were estimated using Cox proportional hazards regression. We tested for linear and nonlinear trends in associations with CRC among subsites and within proximal colon, distal colon, and rectum. RESULTS We documented 3058 cases of CRC (474 in cecum, 633 in ascending colon, 250 in transverse colon, 221 in descending colon, 750 in sigmoid colon, 202 in rectosigmoid junction, and 528 in rectum). The positive associations with cancer risk decreased, from cecum to rectum, for age and family history of CRC. In contrast, the inverse associations with cancer risk increased, from cecum to rectum, for endoscopic screening and intake of whole grains, cereal fiber, and processed red meat. There was a significant nonlinear trend in the association between CRC and female sex, with hazard ratios ranging from 1.73 for ascending colon cancer to 0.54 for sigmoid colon cancer. For proximal colon cancers, the association with alcohol consumption and smoking before age 30 years increased from the cecum to transverse colon. For distal colon cancers, the positive association with waist circumference in men was greater for descending vs sigmoid colon cancer. CONCLUSIONS In an analysis of 3058 cases of CRC, we found that risk factor profiles differed for cancers along the colorectum. Proximal vs distal classifications are not sufficient to encompass the regional variations in colorectal tumor features and risk factors.
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Affiliation(s)
- Liang Wang
- Center of Gastrointestinal Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Chun-Han Lo
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Xiaosheng He
- Department of Colorectal Surgery, the Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China
| | - Dong Hang
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, P.R. China
| | - Molin Wang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Shuji Ogino
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Edward L Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Mingyang Song
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Díaz-Hirashi Z, Gao T, Verdeguer F. Metabolic Reprogramming and Signaling to Chromatin Modifications in Tumorigenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1219:225-241. [PMID: 32130702 DOI: 10.1007/978-3-030-34025-4_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Cellular proliferation relies on a high energetic status, replenished through nutrient intake, that leads to the production of biosynthetic material. A communication between the energetic levels and the control of gene expression is essential to engage in cell division. Multiple nutrient and metabolic sensing mechanisms in cells control transcriptional responses through cell signaling cascades that activate specific transcription factors associated with a concomitant regulation of the chromatin state. In addition to this canonical axis, gene expression could be directly influenced by the fluctuation of specific key intermediary metabolites of central metabolic pathways which are also donors or cofactors of histone and DNA modifications. This alternative axis represents a more direct connection between nutrients and the epigenome function. Cancer cells are highly energetically demanding to sustain proliferation. To reach their energetic demands, cancer cells rewire metabolic pathways. Recent discoveries show that perturbations of metabolic pathways in cancer cells have a direct impact on the epigenome. In this chapter, the interaction between metabolic driven changes of transcriptional programs in the context of tumorigenesis will be discussed.
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Affiliation(s)
- Zyanya Díaz-Hirashi
- Department of Molecular Mechanisms of Disease, University of Zürich, Zürich, Switzerland
| | - Tian Gao
- Department of Molecular Mechanisms of Disease, University of Zürich, Zürich, Switzerland
| | - Francisco Verdeguer
- Department of Molecular Mechanisms of Disease, University of Zürich, Zürich, Switzerland.
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25
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Low folate status, and MTHFR 677C > T and MTR 2756A > G polymorphisms associated with colorectal cancer risk in Thais: a case-control study. Nutr Res 2019; 72:80-91. [DOI: 10.1016/j.nutres.2019.10.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 10/17/2019] [Accepted: 10/22/2019] [Indexed: 12/30/2022]
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Birkett N, Al-Zoughool M, Bird M, Baan RA, Zielinski J, Krewski D. Overview of biological mechanisms of human carcinogens. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2019; 22:288-359. [PMID: 31631808 DOI: 10.1080/10937404.2019.1643539] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
This review summarizes the carcinogenic mechanisms for 109 Group 1 human carcinogens identified as causes of human cancer through Volume 106 of the IARC Monographs. The International Agency for Research on Cancer (IARC) evaluates human, experimental and mechanistic evidence on agents suspected of inducing cancer in humans, using a well-established weight of evidence approach. The monographs provide detailed mechanistic information about all carcinogens. Carcinogens with closely similar mechanisms of action (e.g. agents emitting alpha particles) were combined into groups for the review. A narrative synopsis of the mechanistic profiles for the 86 carcinogens or carcinogen groups is presented, based primarily on information in the IARC monographs, supplemented with a non-systematic review. Most carcinogens included a genotoxic mechanism.
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Affiliation(s)
- Nicholas Birkett
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Mustafa Al-Zoughool
- Department of Community and Environmental Health, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Michael Bird
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Robert A Baan
- International Agency for Research on Cancer, Lyon, France
| | - Jan Zielinski
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Daniel Krewski
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
- Risk Sciences International, Ottawa, Canada
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27
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Zhang W, Li M, Sun F, Xu X, Zhang Z, Liu J, Sun X, Zhang A, Shen Y, Xu J, Miao M, Wu B, Yuan Y, Huang X, Shi H, Du J. Association of Sperm Methylation at LINE-1, Four Candidate Genes, and Nicotine/Alcohol Exposure With the Risk of Infertility. Front Genet 2019; 10:1001. [PMID: 31681430 PMCID: PMC6813923 DOI: 10.3389/fgene.2019.01001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 09/20/2019] [Indexed: 12/15/2022] Open
Abstract
In this study, we examined whether smoking and drinking affect sperm quality and the DNA methylation of the repetitive element LINE-1, MEST, P16, H19, and GNAS in sperm. Semen samples were obtained from 143 male residents in a minority-inhabited district of Guizhou province in southwest China. Quantitative DNA methylation analysis of the samples was performed using MassARRAY EpiTYPER assays. Sperm motility was significantly lower in both the nicotine-exposed (P = 0.0064) and the nicotine- and alcohol-exposed (P = 0.0008) groups. Follicle-stimulating hormone (FSH) levels were higher in the nicotine-exposed group (P = 0.0026). The repetitive element LINE-1 was hypermethylated in the three exposed groups, while P16 was hypomethylated in the alcohol and both the alcohol and nicotine exposure groups. Our results also show that alcohol and nicotine exposure altered sperm cell quality, which may be related to the methylation levels of MEST and GNAS. In addition, MEST, GNAS, and the repetitive element LINE1 methylation was significantly associated with the concentration of sperm as well as FSH and luteinizing hormone levels.
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Affiliation(s)
- Wenjing Zhang
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China.,Reproductive Medical Center, Changhai Hospital of Shanghai, Shanghai, China
| | - Min Li
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Feng Sun
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xuting Xu
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Zhejiang, China
| | - Zhaofeng Zhang
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Junwei Liu
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Xiaowei Sun
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Aiping Zhang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Yupei Shen
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Jianhua Xu
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Maohua Miao
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Bin Wu
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Yao Yuan
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Xianliang Huang
- Shanghai Institute of Planned Parenthood Research Hospital, Shanghai, China
| | - Huijuan Shi
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
| | - Jing Du
- NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, China
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28
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Mandaviya PR, Joehanes R, Brody J, Castillo-Fernandez JE, Dekkers KF, Do AN, Graff M, Hänninen IK, Tanaka T, de Jonge EAL, Kiefte-de Jong JC, Absher DM, Aslibekyan S, de Rijke YB, Fornage M, Hernandez DG, Hurme MA, Ikram MA, Jacques PF, Justice AE, Kiel DP, Lemaitre RN, Mendelson MM, Mikkilä V, Moore AZ, Pallister T, Raitakari OT, Schalkwijk CG, Sha J, Slagboom EPE, Smith CE, Stehouwer CDA, Tsai PC, Uitterlinden AG, van der Kallen CJH, van Heemst D, Arnett DK, Bandinelli S, Bell JT, Heijmans BT, Lehtimäki T, Levy D, North KE, Sotoodehnia N, van Greevenbroek MMJ, van Meurs JBJ, Heil SG. Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals. Am J Clin Nutr 2019; 110:437-450. [PMID: 31165884 PMCID: PMC6669135 DOI: 10.1093/ajcn/nqz031] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 12/12/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans. OBJECTIVE The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes. METHODS A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes. RESULTS The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs. CONCLUSIONS We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies.
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Affiliation(s)
- Pooja R Mandaviya
- Department of Internal Medicine
- Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Roby Joehanes
- Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
- Broad Institute of MIT & Harvard, Cambridge, MA
- Framingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Framingham, MA
| | - Jennifer Brody
- Department of Medicine, University of Washington, Seattle, WA
| | | | - Koen F Dekkers
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Anh N Do
- Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Mariaelisa Graff
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC
| | - Ismo K Hänninen
- Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center–Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Pirkanmaa, Finland
| | - Toshiko Tanaka
- Translational Gerontology Branch, National Institute on Aging, Baltimore, MD
| | - Ester A L de Jonge
- Department of Internal Medicine
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jessica C Kiefte-de Jong
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
- Faculty of Governance and Global Affairs, Leiden University College, The Hague, The Netherlands
| | | | - Stella Aslibekyan
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL
| | - Yolanda B de Rijke
- Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Myriam Fornage
- Brown Foundation Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX
| | - Dena G Hernandez
- Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD
| | - Mikko A Hurme
- Department of Microbiology and Immunology, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Pirkanmaa, Finland
| | - M Arfan Ikram
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Paul F Jacques
- USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA
- Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA
| | - Anne E Justice
- Biomedical and Translational Informatics, Geisinger Health, Danville, PA
| | - Douglas P Kiel
- Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
- Broad Institute of MIT & Harvard, Cambridge, MA
| | | | - Michael M Mendelson
- Framingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Framingham, MA
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | - Vera Mikkilä
- Division of Nutrition, Department of Food and Environmental Sciences, Helsinki, Uusimaa, Finland
| | - Ann Z Moore
- Translational Gerontology Branch, National Institute on Aging, Baltimore, MD
| | - Tess Pallister
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Olli T Raitakari
- Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Southwest Finland, Finland
| | - Casper G Schalkwijk
- Department of Internal Medicine, Maastricht University Medical Centre and CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
| | - Jin Sha
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Eline P E Slagboom
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Caren E Smith
- USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA
| | - Coen D A Stehouwer
- Department of Internal Medicine, Maastricht University Medical Centre and CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
| | - Pei-Chien Tsai
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
- Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan
| | | | - Carla J H van der Kallen
- Department of Internal Medicine, Maastricht University Medical Centre and CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
| | - Diana van Heemst
- Department of Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Donna K Arnett
- College of Public Health, University of Kentucky, Lexington, KY
| | | | - Jordana T Bell
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Bastiaan T Heijmans
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center–Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Pirkanmaa, Finland
| | - Daniel Levy
- Framingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Framingham, MA
| | - Kari E North
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC
| | | | - Marleen M J van Greevenbroek
- Department of Internal Medicine, Maastricht University Medical Centre and CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
| | | | - Sandra G Heil
- Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
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Zeng JD, Wu WKK, Wang HY, Li XX. Serine and one-carbon metabolism, a bridge that links mTOR signaling and DNA methylation in cancer. Pharmacol Res 2019; 149:104352. [PMID: 31323332 DOI: 10.1016/j.phrs.2019.104352] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 07/10/2019] [Accepted: 07/11/2019] [Indexed: 12/24/2022]
Abstract
Mammalian / mechanistic target of rapamycin (mTOR) is a critical sensor of environmental cues that regulates cellular macromolecule synthesis and metabolism in eukaryotes. DNA methylation is the most well-studied epigenetic modification that is capable of regulating gene transcription and affecting genome stability. Both dysregulation of mTOR signaling and DNA methylation patterns have been shown to be closely linked to tumor progression and serve as promising targets for cancer therapy. Although their respective roles in tumorigenesis have been extensively studied, whether molecular interplay exists between them is still largely unknown. In this review, we provide a brief overview of mTOR signaling, DNA methylation as well as related serine and one-carbon metabolism, one of the most critical aspects of metabolic reprogramming in cancer. Based on the latest understanding regarding the regulation of metabolic processes by mTOR signaling as well as interaction between metabolism and epigenetics, we further discuss how serine and one-carbon metabolism may serve as a bridge that links mTOR signaling and DNA methylation to promote tumor growth. Elucidating their relationship may provide novel insight for cancer therapy in the future.
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Affiliation(s)
- Ju-Deng Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation center for Cancer Medicine, Sun Yat-sen University cancer center, Guangzhou, Guangdong, China; Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China
| | - William K K Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Digestive diseases, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Hui-Yun Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation center for Cancer Medicine, Sun Yat-sen University cancer center, Guangzhou, Guangdong, China.
| | - Xiao-Xing Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation center for Cancer Medicine, Sun Yat-sen University cancer center, Guangzhou, Guangdong, China.
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30
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Association between serum 25-hydroxyvitamin D and global DNA methylation in visceral adipose tissue from colorectal cancer patients. BMC Cancer 2019; 19:93. [PMID: 30665376 PMCID: PMC6341579 DOI: 10.1186/s12885-018-5226-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 12/16/2018] [Indexed: 12/17/2022] Open
Abstract
Background Visceral adipose tissue (VAT) has been identified as the essential fat depot for pathogenetic theories that associateobesity and colon cancer. LINE-1 hypomethylation has been mostly detected in tumor colon tissue, but less is known about the epigenetic pattern in surrounding tissues. The aim was to analyze for the first time the potential relationship between serum vitamin D, obesity and global methylation (LINE-1) in the visceral adipose tissue (VAT) from patients with and without colorectal cancer. Methods A total of 55 patients with colorectal cancer and 35 control subjects participated in the study. LINE-1 DNA methylation in VAT was measured by pyrosequencing. Serum 25(OH)D levels were determined by ELISA. Results Cancer patients had lower levels of LINE-1 methylation in VAT compared with the control group. In the subjects with colorectal cancer, LINE-1 DNA methylation levels were associated positively with vitamin D levels (r = 0,463; p < 0.001) and negatively with BMI (r = − 0.334, p = 0.01) and HOMA insulin resistance index (r = − 0.348, p = 0.01). Serum vitamin D was the main variable explaining the LINE-1% variance in the cancer group (β = 0.460, p < 0.001). In a multivariate analysis, subjects with higher LINE-1 methylation values had lower risk of developing colorectal cancer (OR = 0.53; IC95% =0.28–0.99) compared with the control group. Conclusions We showed for the first time an association between LINE-1 DNA methylation in VAT and vitamin D levels in subjects with colorectal cancer, highlighting the importance of VAT from cancer patients, which could be modified epigenetically compared to healthy subjects.
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31
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Hsi E, Wang YS, Huang CW, Yu ML, Juo SHH, Liang CL. Genome-wide DNA hypermethylation and homocysteine increase a risk for myopia. Int J Ophthalmol 2019; 12:38-45. [PMID: 30662838 PMCID: PMC6326929 DOI: 10.18240/ijo.2019.01.06] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 11/27/2018] [Indexed: 01/04/2023] Open
Abstract
AIM To test for the association between genome-wide methylation and myopia in human and mice. METHODS Long interspersed nucleotide element 1 (LINE-1) methylation levels were used to surrogate genome-wide methylation level. We first tested for the association between high myopia (<-6 D) and LINE-1 methylation in leukocytes in 220 cases and 220 control subjects. Secondly, we validated the results of LINE-1 methylation in eyes from the form deprivation myopia (FDM) mice. Furthermore, we calculated the correlation of LINE-1 methylation levels between leukocyte DNA and ocular DNA in the mice. We also tested whether dopamine can alter LINE-1 methylation levels. RESULTS The LINE-1 methylation level was significantly higher in the myopic human subjects than controls. The upper and middle tertiles of the methylation levels increased an approximately 2-fold (P≤0.002) risk for myopia than the lower tertile. Similarly, FDM mice had high LINE-1 methylation levels in the leukocyte, retina and sclera, and furthermore the methylation levels detected from these three tissues were significantly correlated. Immunohistochemical staining revealed higher levels of homocysteine and methionine in the rodent myopic eyes than normal eyes. Dopamine treatment to the cells reduced both LINE-1 methylation and DNA methyltransferase levels. CONCLUSION LINE-1 hypermethylation may be associated with high myopia in human and mice. Homocysteine and methionine are accumulated in myopic eyes, which may provide excess methyl group for genome-wide methylation.
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Affiliation(s)
- Edward Hsi
- Centre for Myopia and Eye Disease, Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
- Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yung-Song Wang
- Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Institute of Fisheries Science, National Taiwan University, Taipei 106, Taiwan
| | - Chia-Wei Huang
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Suh-Hang Hank Juo
- Centre for Myopia and Eye Disease, Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
- Institute of New Drug Development, China Medical University, 91 Hsueh-Shih Road, Taichung 404, Taiwan
- Drug Development Center, China Medical University 404, Taiwan
| | - Chung-Ling Liang
- Department of Ophthalmology, Asia University Hospital, Taichung 413, Taiwan
- Department of Optometry, College of Medical and Health Science, Asia University, Taichung 413, Taiwan
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32
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Miranda-Gonçalves V, Lameirinhas A, Henrique R, Jerónimo C. Metabolism and Epigenetic Interplay in Cancer: Regulation and Putative Therapeutic Targets. Front Genet 2018; 9:427. [PMID: 30356832 PMCID: PMC6190739 DOI: 10.3389/fgene.2018.00427] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 09/10/2018] [Indexed: 12/31/2022] Open
Abstract
Alterations in the epigenome and metabolism affect molecular rewiring of cancer cells facilitating cancer development and progression. Modulation of histone and DNA modification enzymes occurs owing to metabolic reprogramming driven by oncogenes and expression of metabolism-associated genes is, in turn, epigenetically regulated, promoting the well-known metabolic reprogramming of cancer cells and, consequently, altering the metabolome. Thus, several malignant traits are supported by the interplay between metabolomics and epigenetics, promoting neoplastic transformation. In this review we emphasize the importance of tumour metabolites in the activity of most chromatin-modifying enzymes and implication in neoplastic transformation. Furthermore, candidate targets deriving from metabolism of cancer cells and altered epigenetic factors is emphasized, focusing on compounds that counteract the epigenomic-metabolic interplay in cancer.
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Affiliation(s)
- Vera Miranda-Gonçalves
- Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal
| | - Ana Lameirinhas
- Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal.,Master in Oncology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Rui Henrique
- Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto, Porto, Portugal.,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal.,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
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Gogna P, O'Sullivan DE, King WD. The effect of inflammation-related lifestyle exposures and interactions with gene variants on long interspersed nuclear element-1 DNA methylation. Epigenomics 2018; 10:785-796. [PMID: 29888958 DOI: 10.2217/epi-2017-0164] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To examine the relationship between inflammation-related lifestyle factors and long interspersed nuclear element-1 (LINE-1) DNA methylation, and test for interaction by gene variants involved in one-carbon metabolism. PATIENTS & METHODS The study population consisted of 280 individuals undergoing colonoscopy screening. Multivariable linear regression was employed to examine associations of physical activity, BMI and NSAID use with LINE-1 DNA methylation and interactions with MTR and MTHFR gene variants. RESULTS The highest quartile of physical activity compared with the lowest was associated with higher LINE-1 DNA methylation (p = 0.005). Long-term NSAID use and a normal BMI were associated with increased LINE-1 DNA methylation among individuals with the variant MTR allele (p = 0.02; p = 0.03). CONCLUSION This study provides evidence that inflammation-related exposures may influence LINE-1 DNA methylation.
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Affiliation(s)
- Priyanka Gogna
- Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canada
| | - Dylan E O'Sullivan
- Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canada
| | - Will D King
- Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canada
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Relationship between LINE-1 methylation pattern and pesticide exposure in urban sprayers. Food Chem Toxicol 2018; 113:125-133. [DOI: 10.1016/j.fct.2018.01.035] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 12/29/2017] [Accepted: 01/22/2018] [Indexed: 10/18/2022]
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Wu D, Yang H, Winham SJ, Natanzon Y, Koestler DC, Luo T, Fridley BL, Goode EL, Zhang Y, Cui Y. Mediation analysis of alcohol consumption, DNA methylation, and epithelial ovarian cancer. J Hum Genet 2018; 63:339-348. [PMID: 29321518 DOI: 10.1038/s10038-017-0385-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 10/23/2017] [Accepted: 10/24/2017] [Indexed: 01/12/2023]
Abstract
Epigenetic factors and consumption of alcohol, which suppresses DNA methylation, may influence the development and progression of epithelial ovarian cancer (EOC). However, there is a lack of understanding whether these factors interact to affect the EOC risk. In this study, we aimed to gain insight into this relationship by identifying leukocyte-derived DNA methylation markers acting as potential mediators of alcohol-associated EOC. We implemented a causal inference test (CIT) and the VanderWeele and Vansteelandt multiple mediator model to examine CpG sites that mediate the association between alcohol consumption and EOC risk. We modified one step of the CIT by adopting a high-dimensional inference procedure. The data were based on 196 cases and 202 age-matched controls from the Mayo Clinic Ovarian Cancer Case-Control Study. Implementation of the CIT test revealed two CpG sites (cg09358725, cg11016563), which represent potential mediators of the relationship between alcohol consumption and EOC case-control status. Implementation of the VanderWeele and Vansteelandt multiple mediator model further revealed that these two CpGs were the key mediators. Decreased methylation at both CpGs was more common in cases who drank alcohol at the time of enrollment vs. those who did not. cg11016563 resides in TRPC6 which has been previously shown to be overexpressed in EOC. These findings suggest two CpGs may serve as novel biomarkers for EOC susceptibility.
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Affiliation(s)
- Dongyan Wu
- Division of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, 030001, China.,Department of Medical Affairs, Yanqing Hospital of Peking University Third Hospital, Beijing, 102100, China
| | - Haitao Yang
- Division of Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, 050017, China
| | - Stacey J Winham
- Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Yanina Natanzon
- Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Devin C Koestler
- Department of Biostatistics, The University of Kansas Medical center, Kansas City, KS, 66160, USA
| | - Tiane Luo
- Division of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Brooke L Fridley
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, 33612, USA
| | - Ellen L Goode
- Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Yanbo Zhang
- Division of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Yuehua Cui
- Division of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, 030001, China. .,Department of Statistics and Probability, Michigan State University, East Lansing, MI, 48824, USA.
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Abstract
Chronic, heavy alcohol consumption is associated with serious negative health effects, including the development of several cancer types. One of the pathways affected by alcohol toxicity is the one-carbon metabolism. The alcohol-induced impairment of this metabolic pathway results in epigenetic changes associated with cancer development. These epigenetic changes are induced by folate deficiency and by products of the ethanol metabolism. The changes induced by long-term heavy ethanol consumption result in elevations of homocysteine and S-adenosyl-homocysteine (SAH) and reductions in S-adenosylmethionine (SAM) and antioxidant glutathione (GSH) levels, leading to abnormal promoter gene hypermethylation, global hypomethylation, and metabolic insufficiency of antioxidant defense mechanisms. In addition, reactive oxygen species (ROS) generated during the ethanol metabolism induce alterations in DNA methylation patterns that play a critical role in cancer development. Specific epigenetic changes in esophageal, hepatic, and colorectal cancers have been detected in blood samples and proposed to be used clinically as epigenetic biomarkers for diagnosis and prognosis of these cancers. Also, genetic variants of genes involved in one-carbon metabolism and ethanol metabolism were found to modulate the relationship between alcohol-induced epigenetic changes and cancer risk. Furthermore, alcohol metabolism products have been associated with an increase in NADH levels, which lead to histone modifications and changes in gene expression that in turn influence cancer susceptibility. Chronic excessive use of alcohol also affects selected members of the family of microRNAs, and as miRNAs could act as epigenetic regulators, this may play an important role in carcinogenesis. In conclusion, targeting alcohol-induced epigenetic changes in several cancer types could make available clinical tools for the diagnosis, prognosis, and treatment of these cancers, with an important role in precision medicine.
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Lifestyle, Diet, and Colorectal Cancer Risk According to (Epi)genetic Instability: Current Evidence and Future Directions of Molecular Pathological Epidemiology. CURRENT COLORECTAL CANCER REPORTS 2017; 13:455-469. [PMID: 29249914 PMCID: PMC5725509 DOI: 10.1007/s11888-017-0395-0] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Purpose of Review In this review, we describe molecular pathological epidemiology (MPE) studies from around the world that have studied diet and/or lifestyle factors in relation to molecular markers of (epi)genetic pathways in colorectal cancer (CRC), and explore future perspectives in this realm of research. The main focus of this review is diet and lifestyle factors for which there is evidence for an association with CRC as identified by the World Cancer Research Fund reports. In addition, we review promising hypotheses, that warrant consideration in future studies. Recent Findings Associations between molecular characteristics of CRC have been published in relation to smoking, alcohol consumption; body mass index (BMI); waist:hip ratio; adult attained height; physical activity; early life energy restriction; dietary acrylamide, fiber, fat, methyl donors, omega 3 fatty acids; meat, including total protein, processed meat, and heme iron; and fruit and vegetable intake. Summary MPE studies help identify where associations between diet, lifestyle, and CRC risk may otherwise be masked and also shed light on how timing of exposure can influence etiology. Sample size is often an issue, but this may be addressed in the future by pooling data.
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Moazzen S, Dolatkhah R, Tabrizi JS, Shaarbafi J, Alizadeh BZ, de Bock GH, Dastgiri S. Folic acid intake and folate status and colorectal cancer risk: A systematic review and meta-analysis. Clin Nutr 2017; 37:1926-1934. [PMID: 29132834 DOI: 10.1016/j.clnu.2017.10.010] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 10/12/2017] [Accepted: 10/14/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS To evaluate the controversies among the studies assessing the association between folic acid intake or folate status and colorectal cancer risk. METHODS PubMed, Cochrane library and references of related articles were searched from January 2000 to September 2016. Studies on folic acid intake or folate status and colorectal cancer or adenoma risk were included. Full text review was conducted for potentially eligible studies. Quality assessment was performed. Random-effects meta-analysis was used to estimate risk ratio and 95% Confidence Intervals. Analysis was conducted by Comprehensive Meta-Analysis software. RESULTS Folic acid supplement intake showed no significant effect on colorectal cancer risk in meta-analysis of randomized controlled trials, RR: 1.07 (95% CI: 0.86-1.43). The effect on risk was not significant in cohort studies either; RR = 0.96 (95% CI: 0.76-1.21). However, there was significant reduced colorectal cancer risk in total folate intake in cohort studies; 0.71 (95% CI: 0.59-0.86). Odds Ratio was also significantly reduced in case control studies; 0.77 (95% CI: 0.62-0.95). Nevertheless once folate status was measured as Red Blood Cell folate content, no significant effect on colorectal cancer risk was observed; 1.05 (95% CI: 0.85-1.30). CONCLUSION The differences in bioavailability and metabolism of synthetic folic acid and natural dietary folate as well as variation in the baseline characteristics of subjects and various methods of folate status assessment might be the main reasons for these controversies. Findings of present study highlight the importance of individualized folic acid supplement intake given the fact that the beneficiary effects of long term folic acid supplementation is not confirmed.
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Affiliation(s)
- Sara Moazzen
- Health Service Management Research Center, Tabriz University of Medical Sciences, Tabriz 51666114731, Iran; Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands.
| | - Roya Dolatkhah
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz 51666114731, Iran.
| | - Jafar Sadegh Tabrizi
- Health Service Management Research Center, Tabriz University of Medical Sciences, Tabriz 51666114731, Iran.
| | | | - Behrooz Z Alizadeh
- Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands; The Liver and Gastrointestinal Disease Research Center, Tabriz University of Medical Sciences, Tabriz 51666114731, Iran.
| | - Geertruida H de Bock
- Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands.
| | - Saeed Dastgiri
- School of Medicine, Health Service Management Research Center, Tabriz University of Medical Sciences, Tabriz 51666114731, Iran.
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Choi YJ, Lee DH, Han KD, Kim HS, Yoon H, Shin CM, Park YS, Kim N. The relationship between drinking alcohol and esophageal, gastric or colorectal cancer: A nationwide population-based cohort study of South Korea. PLoS One 2017; 12:e0185778. [PMID: 28973012 PMCID: PMC5626486 DOI: 10.1371/journal.pone.0185778] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 09/19/2017] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Epidemiologic findings of low-volume alcohol consumption in relation to gastrointestinal cancers including gastric cancer are inconsistent. METHODS The association between alcohol intake and esophageal, gastric and colorectal cancer risk was examined in a population-based prospective cohort of 23,323,730 adults in Korea who had undergone a biennial evaluation provided by the National Health Insurance Corporation between the years 2009 and 2012. After median 5.4 years of follow-up, 9,171 esophageal, 135,382 gastric and 154,970 colorectal cancer cases were identified. Cox regression models were used to estimate hazard ratios (HR) and corresponding 95% confidence intervals (95% CI). RESULTS Light drinking as well as moderate to heavy alcohol consumption significantly increased the risks of the three gastrointestinal cancers (HR 1.51; 95% CI, 1.43-1.60; HR 1.08; 95% CI, 1.06-1.09; HR 1.12; 95% CI, 1.11-1.14) compared with non-drinkers after adjusting for age, sex, smoking, exercise, income, body mass index, and diabetes. The synergistically increased cancer risk between excessive amount of alcohol consumption and currently smoking or underweight individuals was observed only in the esophageal cancers. CONCLUSIONS Light drinking including even one alcoholic drink a day is associated with increased risks of esophageal, gastric and colorectal cancer.
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Affiliation(s)
- Yoon Jin Choi
- Department of Internal Medicine and Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Dong Ho Lee
- Department of Internal Medicine and Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Kyung-Do Han
- Department of Biostatistics, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Hyun Soo Kim
- Department of Internal Medicine and Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Hyuk Yoon
- Department of Internal Medicine and Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Cheol Min Shin
- Department of Internal Medicine and Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Young Soo Park
- Department of Internal Medicine and Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Nayoung Kim
- Department of Internal Medicine and Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
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Kupcinskas J, Steponaitiene R, Langner C, Smailyte G, Skieceviciene J, Kupcinskas L, Malfertheiner P, Link A. LINE-1 hypomethylation is not a common event in preneoplastic stages of gastric carcinogenesis. Sci Rep 2017; 7:4828. [PMID: 28684753 PMCID: PMC5500474 DOI: 10.1038/s41598-017-05143-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 05/16/2017] [Indexed: 02/07/2023] Open
Abstract
LINE-1 hypomethylation is widely accepted as marker for global genomic DNA hypomethylation, which is a frequent event in cancer. The aim of the study was to evaluate LINE-1 methylation status at different stages of gastric carcinogenesis and evaluate its prognostic potential in clinical settings. LINE-1 methylation was analyzed in 267 tissue samples by bisulfite pyrosequencing including primary colorectal cancer tissues (T-CRC) with corresponding adjacent colon mucosa (N-CRC), gastric cancer tissues (T-GC) with corresponding gastric mucosa (N-GC), normal gastric tissues (N), chronic non-atrophic and atrophic gastritis (CG). LINE-1 methylation level was lower in both T-GC and T-CRC when compared to paired adjacent tissues. No difference was observed for LINE-1 methylation status between patients with normal gastric mucosa, CG and N-GC. LINE-1 methylation in T-GC but not N-GC tended to correlate with age. Subgroup stratification analysis did not reveal significant differences in LINE-1 methylation status according to tumor stage, anatomical location, histological subtype, differentiation grade. We observed similar overall survival data between patients with high or low LINE-1 levels. In summary, LINE-1 hypomethylation is a characteristic feature in GC but not very common in early preneoplastic stages of gastric carcinogenesis. Prognostic role of LINE-1 hypomethylation in GC patients could not be confirmed in this cohort.
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Affiliation(s)
- Juozas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Ruta Steponaitiene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Cosima Langner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Giedre Smailyte
- Lithuanian Cancer Registry, National Cancer Institute, Vilnius, Lithuania
- Centre for Demographic Research, Vytautas Magnus University, Kaunas, Lithuania
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Limas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
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Delgado-Morales R, Agís-Balboa RC, Esteller M, Berdasco M. Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders. Clin Epigenetics 2017; 9:67. [PMID: 28670349 PMCID: PMC5493012 DOI: 10.1186/s13148-017-0365-z] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 06/11/2017] [Indexed: 12/26/2022] Open
Abstract
Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer's disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed.
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Affiliation(s)
- Raúl Delgado-Morales
- Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Biomedical Research Institute (IDIBELL), 3rd Floor, Hospital Duran i Reynals, Av. Gran Via 199-203, 08908L'Hospitalet, Barcelona, Catalonia Spain.,Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands
| | - Roberto Carlos Agís-Balboa
- Psychiatric Diseases Research Group, Galicia Sur Health Research Institute, Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, CIBERSAM, Vigo, Spain
| | - Manel Esteller
- Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Biomedical Research Institute (IDIBELL), 3rd Floor, Hospital Duran i Reynals, Av. Gran Via 199-203, 08908L'Hospitalet, Barcelona, Catalonia Spain.,Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - María Berdasco
- Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Biomedical Research Institute (IDIBELL), 3rd Floor, Hospital Duran i Reynals, Av. Gran Via 199-203, 08908L'Hospitalet, Barcelona, Catalonia Spain
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Jia K, Wang R, Tian J. Vitamin B6Intake and the Risk of Colorectal Cancer: A Meta-Analysis of Prospective Cohort Studies. Nutr Cancer 2017; 69:723-731. [PMID: 28569561 DOI: 10.1080/01635581.2017.1324633] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Kai Jia
- Department of Nutrition, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Rong Wang
- Department of Nutrition, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jingfeng Tian
- Department of Nutrition, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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Furlan C, Polesel J, Barzan L, Franchin G, Sulfaro S, Romeo S, Colizzi F, Rizzo A, Baggio V, Giacomarra V, Dei Tos AP, Boscolo-Rizzo P, Vaccher E, Dolcetti R, Sigalotti L, Fratta E. Prognostic significance of LINE-1 hypomethylation in oropharyngeal squamous cell carcinoma. Clin Epigenetics 2017; 9:58. [PMID: 28572862 PMCID: PMC5450111 DOI: 10.1186/s13148-017-0357-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 05/18/2017] [Indexed: 01/13/2023] Open
Abstract
Background Inclusion of new biomarkers to improve a personalized treatment approach for oropharyngeal squamous cell carcinoma (OPSCC) is urgently needed. Hypomethylation of the Long interspersed nucleotide element-1 (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was found to be associated with a poor prognosis in several cancers. At present, no studies have investigated the influence of LINE-1 methylation levels on OPSCC relapse. The main goal of this study was the evaluation of the prognostic value of LINE-1 methylation status in predicting early tumor relapse in locally advanced OPSCC. Methods We retrospectively reviewed a cohort of 77 patients with stage III–IVB OPSCC. Methylation of LINE-1 repetitive sequences was evaluated by real-time quantitative methylation-specific PCR in formalin-fixed paraffin-embedded tissues. The prognostic relevance of LINE-1 methylation was assessed by comparing patients who relapsed within 2 years from the end of treatment (cases) with those who did not (controls). Results were validated in an independent cohort of 33 patients with OPSCC. Results With respect to early OPSCC relapse, the mean LINE-1 methylation level was significantly lower in relapsed cases than in control group (p < 0.01). Interestingly, LINE-1 methylation was lower in relapsed cases than in controls in both HPV16-negative and HPV16-positive OPSCC patients, even if statistical significance was reached only for the former group (p = 0.01). LINE-1 methylation levels were also significantly reduced in relapsed cases with respect to the controls in OPSCC current smokers (p = 0.02). Consistently, in HPV16-negative current smokers, OPSCC relapse was significantly associated with decreased levels of LINE-1 methylation (p = 0.02). Using logistic regression model, we found that patients with hypomethylated LINE-1 were associated with a 3.5 higher risk of early relapse than hypermethylated ones (OR = 3.51; 95% CI 1.03–12.00). Adjustment for potential confounders did not substantially change the risk magnitude. Results from the validation cohort confirmed the lower LINE-1 methylation in patients who early relapsed compared to relapse-free patients. Conclusions LINE-1 hypomethylation is associated with higher risk of early relapse in stage III–IVB OPSCC. Further validation in a prospective study is needed for its application in daily clinical practice.
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Affiliation(s)
- Carlo Furlan
- Division of Radiotherapy, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN Italy
| | - Jerry Polesel
- Unit of Cancer Epidemiology, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN Italy
| | - Luigi Barzan
- Department of Surgery, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN Italy
| | - Giovanni Franchin
- Division of Radiotherapy, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN Italy
| | - Sandro Sulfaro
- Division of Pathology, General Hospital "S. Maria degli Angeli", Pordenone, Italy
| | - Salvatore Romeo
- Department of Pathology, San Donà di Piave Hospital, San Donà di Piave, Italy
| | - Francesca Colizzi
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN Italy
| | - Aurora Rizzo
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN Italy
| | - Vittorio Baggio
- Department of Radiation Oncology, Treviso Regional Hospital, Treviso, Italy
| | - Vittorio Giacomarra
- Unit of Otolaryngology, General Hospital "S. Maria degli Angeli", Pordenone, Italy
| | | | - Paolo Boscolo-Rizzo
- Department of Neurosciences, ENT Clinic and Regional Center for Head and Neck Cancer, Treviso Regional Hospital, University of Padua, Treviso, Italy
| | - Emanuela Vaccher
- Division of Medical Oncology A, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN Italy
| | - Riccardo Dolcetti
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN Italy.,Translational Research Institute, The University of Queensland Diamantina Institute, Brisbane, Australia
| | - Luca Sigalotti
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN Italy.,Institute of Clinical Pathology, University Hospital of Udine, Udine, Italy
| | - Elisabetta Fratta
- Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN Italy
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Abstract
Alterations in the epigenome and metabolism both affect molecular rewiring in cancer cells and facilitate cancer development and progression. However, recent evidence suggests the existence of important bidirectional regulatory mechanisms between metabolic remodelling and the epigenome (specifically methylation and acetylation of histones) in cancer. Most chromatin-modifying enzymes require substrates or cofactors that are intermediates of cell metabolism. Such metabolites, and often the enzymes that produce them, can transfer into the nucleus, directly linking metabolism to nuclear transcription. We discuss how metabolic remodelling can contribute to tumour epigenetic alterations, thereby affecting cancer cell differentiation, proliferation and/or apoptosis, as well as therapeutic responses.
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Affiliation(s)
- Adam Kinnaird
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
- Division of Urology, Department of Surgery, University of Alberta, Edmonton, Alberta T6G 2R7, Canada
| | - Steven Zhao
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Kathryn E Wellen
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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Plasma Folate and Vitamin B12 Levels in Patients with Hepatocellular Carcinoma. Int J Mol Sci 2016; 17:ijms17071032. [PMID: 27376276 PMCID: PMC4964408 DOI: 10.3390/ijms17071032] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Revised: 06/16/2016] [Accepted: 06/23/2016] [Indexed: 12/14/2022] Open
Abstract
Folate and vitamin B12 involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 levels with HCC in a case-control study on 312 HCC patients and 325 cancer-free controls. Plasma concentrations of folate and vitamin B12 in all the subjects were measured by electrochemiluminescence immunoassay. Meanwhile, the information of HCC patients' clinical characteristics including tumor-node-metastasis (TNM) stage, tumor size and tumor markers were collected. The patients of HCC had significantly lower folate levels than those of controls; there was no significant difference in the mean of plasma vitamin B12 levels. We also observed an inverse association between the levels of plasma folate and HCC: the adjusted odds ratios (OR) (95% confidence intervals (CI)) of HCC from the highest to lowest quartile of folate were 0.30 (0.15-0.60), 0.33 (0.17-0.65), and 0.19 (0.09-0.38). Compared to the subjects in the lowest quartile of plasma vitamin B12, only the subjects in the highest quartile of vitamin B12 exhibited a significant positive relationship with HCC, the adjusted OR was 2.01 (95% CI, 1.02-3.98). HCC patients with Stage III and IV or bigger tumor size had lower folate and higher vitamin B12 levels. There was no significant difference in the mean plasma folate levels of the HCC cases in tumor markers status (AFP, CEA and CA19-9 levels), whereas patients with higher CEA or CA19-9 levels retained significantly more plasma vitamin B12 than those with normal-CEA or CA19-9 level. In conclusion, plasma folate and vitamin B12 levels could be associated with HCC, and might be used as predictors of clinical characteristics of HCC patients. However, further prospective studies are essential to confirm the observed results.
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The Impact of External Factors on the Epigenome: In Utero and over Lifetime. BIOMED RESEARCH INTERNATIONAL 2016; 2016:2568635. [PMID: 27294112 PMCID: PMC4887632 DOI: 10.1155/2016/2568635] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 04/12/2016] [Accepted: 04/26/2016] [Indexed: 01/07/2023]
Abstract
Epigenetic marks change during fetal development, adult life, and aging. Some changes play an important role in the establishment and regulation of gene programs, but others seem to occur without any apparent physiological role. An important future challenge in the field of epigenetics will be to describe how the environment affects both of these types of epigenetic change and to learn if interaction between them can determine healthy and disease phenotypes during lifetime. Here we discuss how chemical and physical environmental stressors, diet, life habits, and pharmacological treatments can affect the epigenome during lifetime and the possible impact of these epigenetic changes on pathophysiological processes.
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Wang M, Spiegelman D, Kuchiba A, Lochhead P, Kim S, Chan AT, Poole EM, Tamimi R, Tworoger SS, Giovannucci E, Rosner B, Ogino S. Statistical methods for studying disease subtype heterogeneity. Stat Med 2015; 35:782-800. [PMID: 26619806 DOI: 10.1002/sim.6793] [Citation(s) in RCA: 234] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 09/08/2015] [Accepted: 10/13/2015] [Indexed: 12/31/2022]
Abstract
A fundamental goal of epidemiologic research is to investigate the relationship between exposures and disease risk. Cases of the disease are often considered a single outcome and assumed to share a common etiology. However, evidence indicates that many human diseases arise and evolve through a range of heterogeneous molecular pathologic processes, influenced by diverse exposures. Pathogenic heterogeneity has been considered in various neoplasms such as colorectal, lung, prostate, and breast cancers, leukemia and lymphoma, and non-neoplastic diseases, including obesity, type II diabetes, glaucoma, stroke, cardiovascular disease, autism, and autoimmune disease. In this article, we discuss analytic options for studying disease subtype heterogeneity, emphasizing methods for evaluating whether the association of a potential risk factor with disease varies by disease subtype. Methods are described for scenarios where disease subtypes are categorical and ordinal and for cohort studies, matched and unmatched case-control studies, and case-case study designs. For illustration, we apply the methods to a molecular pathological epidemiology study of alcohol intake and colon cancer risk by tumor LINE-1 methylation subtypes. User-friendly software to implement the methods is publicly available.
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Affiliation(s)
- Molin Wang
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A
| | - Donna Spiegelman
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.,Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A
| | - Aya Kuchiba
- Department of Biostatistics, National Cancer Center, Tokyo, Japan
| | - Paul Lochhead
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, U.S.A
| | - Sehee Kim
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, U.S.A
| | - Andrew T Chan
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A.,Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, U.S.A
| | - Elizabeth M Poole
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A
| | - Rulla Tamimi
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A
| | - Shelley S Tworoger
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A
| | - Edward Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A
| | - Bernard Rosner
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A
| | - Shuji Ogino
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, U.S.A.,Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, U.S.A
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Lochhead P, Nishihara R, Qian ZR, Mima K, Cao Y, Sukawa Y, Kim SA, Inamura K, Zhang X, Wu K, Giovannucci E, Meyerhardt JA, Chan AT, Fuchs CS, Ogino S. Postdiagnostic intake of one-carbon nutrients and alcohol in relation to colorectal cancer survival. Am J Clin Nutr 2015; 102:1134-41. [PMID: 26423386 PMCID: PMC4625593 DOI: 10.3945/ajcn.115.115162] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 08/24/2015] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Observational data have suggested that intakes of nutrients involved in one-carbon metabolism are inversely associated with risk of colorectal carcinoma and adenomas. In contrast, results from some preclinical studies and cardiovascular and chemoprevention trials have raised concerns that high folate intake may promote carcinogenesis by facilitating the progression of established neoplasia. OBJECTIVE We tested the hypothesis that higher total folate intake (including food folate and folic acid from fortified foods and supplements) or other one-carbon nutrient intakes might be associated with poorer survival after a diagnosis of colorectal cancer. DESIGN We used rectal and colon cancer cases within the following 2 US prospective cohort studies: the Nurses' Health Study and the Health Professionals Follow-Up Study. Biennial questionnaires were used to gather information on medical history and lifestyle factors, including smoking and alcohol consumption. B-vitamin and methionine intakes were derived from food-frequency questionnaires. Data on tumor molecular characteristics (including microsatellite instability, CpG island methylator phenotype, KRAS, BRAF, and PIK3CA mutations, and long interspersed nucleotide element 1 methylation level) were available for a subset of cases. We assessed colorectal cancer-specific mortality according to postdiagnostic intakes of one-carbon nutrients with the use of multivariable Cox proportional hazards regression models. RESULTS In 1550 stage I-III colorectal cancer cases with a median follow-up of 14.9 y, we documented 641 deaths including 176 colorectal cancer-specific deaths. No statistically significant associations were observed between postdiagnostic intakes of folate or other one-carbon nutrients and colorectal cancer-specific mortality (multivariate P-trend ≥ 0.21). In an exploratory molecular pathologic epidemiology survival analysis, there was no significant interaction between one-carbon nutrients or alcohol and any of the tumor molecular biomarkers examined. CONCLUSIONS Higher postdiagnostic intakes of one-carbon nutrients are not associated with the prognosis in stage I-III colorectal cancer. Our findings do not support the hypothesis that higher folate intake after colorectal cancer diagnosis might increase risk of cancer-related death.
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Affiliation(s)
- Paul Lochhead
- Gastrointestinal Research Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom;
| | - Reiko Nishihara
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Zhi Rong Qian
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Kosuke Mima
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Yin Cao
- Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA; and
| | - Yasutaka Sukawa
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Sun A Kim
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Kentaro Inamura
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Xuehong Zhang
- Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA; and
| | - Kana Wu
- Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA; and
| | | | - Jeffrey A Meyerhardt
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital, Boston, MA; Channing Division of Network Medicine, Department of Medicine, and
| | - Charles S Fuchs
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Channing Division of Network Medicine, Department of Medicine, and
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Department of Pathology, Brigham and Women's Hospital, Boston, MA
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Ferrari A, de Carvalho AM, Steluti J, Teixeira J, Marchioni DML, Aguiar S. Folate and nutrients involved in the 1-carbon cycle in the pretreatment of patients for colorectal cancer. Nutrients 2015; 7:4318-35. [PMID: 26043032 PMCID: PMC4488786 DOI: 10.3390/nu7064318] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 05/08/2015] [Indexed: 12/31/2022] Open
Abstract
To assess the ingestion of folate and nutrients involved in the 1-carbon cycle in non-treated patients with colorectal adenocarcinoma in a reference center for oncology in southeastern Brazil. In total, 195 new cases with colorectal adenocarcinoma completed a clinical evaluation questionnaire and a Food Frequency Questionnaire (FFQ). Blood samples from 161 patients were drawn for the assessment of serum folate. A moderate correlation was found between serum concentrations of folate, folate intake and the dietary folate equivalent (DFE) of synthetic supplements. Mulatto or black male patients with a primary educational level had a higher intake of dietary folate. Of patients obtaining folate from the diet alone or from dietary supplements, 11.00% and 0.10%, respectively, had intake below the recommended level. Of the patients using dietary supplements, 35% to 50% showed high levels of folic acid intake. There was a prevalence of inadequacy for vitamins B2, B6 and B12, ranging from 12.10% to 20.18%, while 13.76% to 22.55% of patients were likely to have adequate choline intake. The considerable percentage of patients with folate intake above the recommended levels deserves attention because of the harmful effects that this nutrient may have in the presence of established neoplastic lesions.
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Affiliation(s)
- Ariana Ferrari
- Department of Pelvic Surgery, A.C. Camargo Cancer Center, Rua Professor Antônio Prudente, 211, Liberdade, São Paulo (SP) CEP 01509-010, Brazil.
| | - Aline Martins de Carvalho
- Department of Nutrition, School of Public Health, University of São Paulo, Av. Dr. Arnaldo 715, Consolação, São Paulo (SP) CEP 01246-904, Brazil.
| | - Josiane Steluti
- Department of Nutrition, School of Public Health, University of São Paulo, Av. Dr. Arnaldo 715, Consolação, São Paulo (SP) CEP 01246-904, Brazil.
| | - Juliana Teixeira
- Department of Nutrition, School of Public Health, University of São Paulo, Av. Dr. Arnaldo 715, Consolação, São Paulo (SP) CEP 01246-904, Brazil.
| | - Dirce Maria Lobo Marchioni
- Department of Nutrition, School of Public Health, University of São Paulo, Av. Dr. Arnaldo 715, Consolação, São Paulo (SP) CEP 01246-904, Brazil.
| | - Samuel Aguiar
- Department of Pelvic Surgery, A.C. Camargo Cancer Center, Rua Professor Antônio Prudente, 211, Liberdade, São Paulo (SP) CEP 01509-010, Brazil.
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50
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Begg CB, Orlow I, Zabor EC, Arora A, Sharma A, Seshan VE, Bernstein JL. Identifying Etiologically Distinct Sub-Types of Cancer: A Demonstration Project Involving Breast Cancer. Cancer Med 2015; 4:1432-9. [PMID: 25974664 PMCID: PMC4567028 DOI: 10.1002/cam4.456] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 03/03/2015] [Accepted: 03/04/2015] [Indexed: 12/19/2022] Open
Abstract
With the advent of increasingly detailed molecular portraits of tumor specimens, much attention has been directed toward identifying clinically distinct subtypes of cancer. Subtyping of tumors can also be accomplished with the goal of identifying distinct etiologies. We demonstrate the use of new methodologies to identify genes that distinguish etiologically heterogeneous subtypes of breast cancer using data from the case-control Cancer and Steroid Hormone Study. Tumor specimens were evaluated using a breast cancer expression panel of 196 genes. Using a statistical measure that distinguishes the degree of etiologic heterogeneity in tumor subtypes, each gene is ranked on the basis of its ability to distinguish etiologically distinct subtypes. This is accomplished independently using case-control comparisons and by examining the concordance odds ratios in double primaries. The estrogen receptor gene, and others in this pathway with expression levels that correlated strongly with estrogen receptor levels, demonstrate high degrees of etiologic heterogeneity in both methods. Our results are consistent with a growing literature that confirms the distinct etiologies of breast cancers classified on the basis of estrogen receptor expression levels. This proof-of-principle project demonstrates the viability of new strategies to identify genomic features that distinguish subtypes of cancer from an etiologic perspective.
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Affiliation(s)
- Colin B Begg
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, New York
| | - Irene Orlow
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, New York
| | - Emily C Zabor
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, New York
| | - Arshi Arora
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, New York
| | - Ajay Sharma
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, New York
| | - Venkatraman E Seshan
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, New York
| | - Jonine L Bernstein
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, New York
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