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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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Fang A, Ugai T, Gurjao C, Zhong R, Liu Z, Zhang X, Wang P, Nowak J, Wang M, Giannakis M, Ogino S, Zhang X, Giovannucci E. Alcohol and colorectal cancer risk, subclassified by mutational signatures of DNA mismatch repair deficiency. J Natl Cancer Inst 2024; 116:1255-1263. [PMID: 38574386 PMCID: PMC11308185 DOI: 10.1093/jnci/djae078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 03/05/2024] [Accepted: 03/27/2024] [Indexed: 04/06/2024] Open
Abstract
BACKGROUND We examined whether the association between alcohol consumption and colorectal cancer (CRC) incidence was stronger for tumors with higher contributions of defective mismatch repair (dMMR)-related tumor mutational signatures. METHODS We used data from 227 916 men and women who participated in the Nurses' Health Study (1980-2016), the Nurses' Health Study II (1991-2017), and the Health Professionals Follow-Up Study (1986-2016). Dietary data were collected every 4 years through validated food frequency questionnaires. Relative contributions of 2 defective mismatch repair-related tumor mutational signatures with single-based substitutions (c-dMMRa/SBS15 and c-dMMRb/SBS26) were quantified using whole-exome sequencing data in a subset of incident CRC patients. Duplication-method Cox proportional hazards regression models were used to assess the association between alcohol consumption and the risk of CRC subtypes according to different contributions of the tumor mutational signatures. All statistical tests were 2-sided. RESULTS We documented 825 incident CRC patients with available tumor mutational signature data over 26 to 36 years of follow-up. The association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of c-dMMRb/SBS26 (Ptrend = .02 for heterogeneity) compared with tumors with lower contributions of this tumor mutational signature. Compared with nondrinkers, drinkers who imbibed 15 g/d or more of alcohol had a high risk of c-dMMRb/SBS26-high CRC (multivariable-adjusted hazard ratio = 2.43, 95% confidence interval = 1.55 to 3.82) but not c-dMMRb/SBS26-low CRC (multivariable-adjusted hazard ratio = 0.86, 95% confidence interval = 0.57 to 1.28) or c-dMMRb/SBS26-moderate CRC (multivariable-adjusted hazard ratio = 1.14, 95% confidence interval = 0.76 to 1.71). No significant differential associations were observed for c-dMMRa/SBS15 (Ptrend = .41 for heterogeneity). CONCLUSIONS High alcohol consumption was associated with an increased incidence of CRC containing higher contributions of c-dMMRb/SBS26, suggesting that alcohol consumption may be involved in colorectal carcinogenesis through the DNA mismatch repair pathway.
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Affiliation(s)
- Aiping Fang
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Tomotaka Ugai
- Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Carino Gurjao
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Rong Zhong
- Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhenhua Liu
- Department of Nutrition, School of Public Health & Health Sciences, University of Massachusetts Amherst, Amherst, MA, USA
- Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA
| | - Xinyuan Zhang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Peilu Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Institute of Nutrition, Fudan University, Shanghai, China
| | - Jonathan Nowak
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Molin Wang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Marios Giannakis
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Shuji Ogino
- Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Xuehong Zhang
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Edward Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Fu H, He J, Li C, Deng Z, Chang H. Folate intake and risk of colorectal cancer: a systematic review and up-to-date meta-analysis of prospective studies. Eur J Cancer Prev 2023; 32:103-112. [PMID: 35579178 DOI: 10.1097/cej.0000000000000744] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
PURPOSE Colorectal cancer is one of the most commonly diagnosed and deadly cancers worldwide. Epidemiological studies on the relationship between folate intake and the risk of colorectal cancer have reported inconsistent findings since folate fortification in the USA. For this situation, we conducted a large number of data analyses to study the relationship between folate intake and colorectal cancer risk. METHODS PubMed and EMBASE databases were used to search the literature systematically. Eligible studies were reviewed and meta-analyzed to assess the relationship. RESULTS A total of 24 cohort studies involving 37 280 patients and 6 165 894 individuals were included. The results showed that high folate intake was associated with a reduced risk of colorectal cancer. The combined relative risk (RR) for the highest intake compared with the lowest was 0.88 [95% confidence interval (CI), 0.83-0.92, P = 10 -4 ). Further studies indicated that the increase of folate intake may decrease the risk of colorectal cancer in people with medium or high alcohol consumption (RR = 0.97, 95% CI: 0.96-0.99, P = 0.008; RR = 0.95, 95% CI: 0.92-0.98, P = 0.003), but not in non-drinkers (RR = 1.00, 95% CI: 0.98-1.02, P = 0.827). Next, high folate intake may decrease the risk of colon cancer (RR = 0.86, 95% CI: 0.81-0.92, P = 10 -4 ) but not rectal cancer (RR = 0.92, 95% CI: 0.84-1.02, P = 0.112). Additionally, the result that high folate intake may decrease the risk of colorectal cancer was observed in the USA and Europe but not in other regions. CONCLUSION High folate intake may be protective against colon cancer, particularly in people with middle or high alcohol consumption, but it still needs to be further confirmed.
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Affiliation(s)
- Hongjuan Fu
- College of Food Science, Southwest University, Chongqing, China
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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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Wang YY, Li L, Liu XJ, Miao QF, Li Y, Zhang MR, Zhen YS. Development of a novel multi-functional integrated bioconjugate that effectively targets K-Ras mutant pancreatic cancer. J Pharm Anal 2021; 12:232-242. [PMID: 35582405 PMCID: PMC9091918 DOI: 10.1016/j.jpha.2021.07.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 06/17/2021] [Accepted: 07/02/2021] [Indexed: 12/16/2022] Open
Abstract
Folate receptor (FR) overexpression occurs in a variety of cancers, including pancreatic cancer. In addition, enhanced macropinocytosis exists in K-Ras mutant pancreatic cancer. Furthermore, the occurrence of intensive desmoplasia causes a hypoxic microenvironment in pancreatic cancer. In this study, a novel FR-directed, macropinocytosis-enhanced, and highly cytotoxic bioconjugate folate (F)-human serum albumin (HSA)-apoprotein of lidamycin (LDP)-active enediyne (AE) derived from lidamycin was designed and prepared. F-HSA-LDP-AE consisted of four moieties: F, HSA, LDP, and AE. F-HSA-LDP presented high binding efficiency with the FR and pancreatic cancer cells. Its uptake in wild-type cells was more extensive than in K-Ras mutant-type cells. By in vivo optical imaging, F-HSA-LDP displayed prominent tumor-specific biodistribution in pancreatic cancer xenograft-bearing mice, showing clear and lasting tumor localization for 360 h. In the MTT assay, F-HSA-LDP-AE demonstrated potent cytotoxicity in three types of pancreatic cancer cell lines. It also induced apoptosis and caused G2/M cell cycle arrest. F-HSA-LDP-AE markedly suppressed the tumor growth of AsPc-1 pancreatic cancer xenografts in athymic mice. At well-tolerated doses of 0.5 and 1 mg/kg, (i.v., twice), the inhibition rates were 91.2% and 94.8%, respectively (P<0.01). The results of this study indicate that the F-HSA-LDP multi-functional bioconjugate might be effective for treating K-Ras mutant pancreatic cancer.
We designed and generated a folate receptor-targeted and macropinocytosis-enhanced recombinant protein conjugate. F-HSA-LDP displayed highly specific biodistribution and long-lasting tumor accumulation in pancreatic cancer cells. F-HSA-LDP-AE induced apoptosis and G2/M cell cycle arrest and markedly suppressed the growth of pancreatic cancer cells.
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El Asri A, Zarrouq B, El Kinany K, Bouguenouch L, Ouldim K, El Rhazi K. Associations between nutritional factors and KRAS mutations in colorectal cancer: a systematic review. BMC Cancer 2020; 20:696. [PMID: 32723394 PMCID: PMC7388532 DOI: 10.1186/s12885-020-07189-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 07/16/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Between 30 and 50% of colon tumors have mutations in the Kirsten-ras (KRAS) gene, which have a large nutritional attributable risk. Despite its high frequency in colorectal cancer (CRC), data to support specific associations between KRAS mutations in CRC and diet are sparse. Here, we conducted a systematic review to summarize the current epidemiological evidence on the association between various dietary factors and KRAS mutations. METHODS PubMed, Science Direct, and Cochrane databases were searched for relevant studies published until December 31, 2019, using inclusion and exclusion criteria in accordance with PRISMA guidelines. We analyzed the studies to find associations between nutritional factors and CRC tumors with KRAS mutations in humans. RESULTS We identified 28 relevant studies to include in this systematic review. In-depth analyses showed unclear associations between nutritional factors and KRAS mutations in CRC. Most epidemiological studies in the same nutrient or food often reported conflicting and/or inconclusive findings, whereas for some dietary factors, the results were homogeneous. CONCLUSIONS Further research using a more robust prospective cohort study is needed to lend more credence to the epidemiological associations found between KRAS mutations and dietary factors.
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Affiliation(s)
- Achraf El Asri
- Laboratory of Epidemiology and Research in Health Sciences, Faculty of Medicine and Pharmacy, Sidi Mohammed Ben Abdallah University, Fez, Morocco
- Medical Genetics and Oncogenetics Unit, Hassan II University Hospital, Fez, Morocco
| | - Btissame Zarrouq
- Laboratory of Epidemiology and Research in Health Sciences, Faculty of Medicine and Pharmacy, Sidi Mohammed Ben Abdallah University, Fez, Morocco
- Teacher’s Training College (Ecole Normale Superieure), Department of Biology and Geology, Sidi Mohammed Ben Abdallah University, Fez, Morocco
| | - Khaoula El Kinany
- Laboratory of Epidemiology and Research in Health Sciences, Faculty of Medicine and Pharmacy, Sidi Mohammed Ben Abdallah University, Fez, Morocco
| | - Laila Bouguenouch
- Medical Genetics and Oncogenetics Unit, Hassan II University Hospital, Fez, Morocco
| | - Karim Ouldim
- Medical Genetics and Oncogenetics Unit, Hassan II University Hospital, Fez, Morocco
- Cancer Research Institute, Fez, Morocco
| | - Karima El Rhazi
- Laboratory of Epidemiology and Research in Health Sciences, Faculty of Medicine and Pharmacy, Sidi Mohammed Ben Abdallah University, Fez, Morocco
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Al-Shaheri FN, Al-Shami KM, Gamal EH, Mahasneh AA, Ayoub NM. Association of DNA repair gene polymorphisms with colorectal cancer risk and treatment outcomes. Exp Mol Pathol 2019; 113:104364. [PMID: 31881200 DOI: 10.1016/j.yexmp.2019.104364] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/16/2019] [Accepted: 12/24/2019] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the third most common carcinoma worldwide. Despite the progress in screening and treatment, CRC remains a leading cause of cancer-related mortality. Alterations to normal nucleic acid processing may drive neoplastic transformation of colorectal epithelium. DNA repair machinery performs an essential function in the protection of genome by reducing the number of genetic polymorphisms/variations that may drive carcinogenicity. Four essential DNA repair systems are known which include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and double-strand break repair (DSBR). Polymorphisms of DNA repair genes have been shown to influence the risk of cancer development as well as outcomes of treatment. Several studies demonstrated the association between genetic polymorphism of DNA repair genes and increased risk of CRC in different populations. In this review, we have summarized the impact of DNA repair gene polymorphisms on risk of CRC development and treatment outcomes. Advancements of the current understanding for the impact of DNA repair gene polymorphisms on the risk and treatment of CRC may support diagnostic and predictive roles in patients with CRC.
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Affiliation(s)
- Fawaz N Al-Shaheri
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 580, 69120 Heidelberg, Germany; Medical Faculty Heidelberg, University of Heidelberg, ImNeuenheimer Feld 672, 69120 Heidelberg, Germany; Faculty of Applied Medical Sciences, Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan.
| | - Kamal M Al-Shami
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, 720 South Donahue Drive, Auburn, Alabama 36849, United States of America; Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan.
| | - Eshrak H Gamal
- Department of Oncology, Collage of Medicine, Bonn University, Germany; Faculty of Applied Medical Sciences, Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan.
| | - Amjad A Mahasneh
- Department of Applied Biological Sciences, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid 22110, Jordan.
| | - Nehad M Ayoub
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan.
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8
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Liu L, Nevo D, Nishihara R, Cao Y, Song M, Twombly TS, Chan AT, Giovannucci EL, VanderWeele TJ, Wang M, Ogino S. Utility of inverse probability weighting in molecular pathological epidemiology. Eur J Epidemiol 2017; 33:381-392. [PMID: 29264788 DOI: 10.1007/s10654-017-0346-8] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 12/12/2017] [Indexed: 12/17/2022]
Abstract
As one of causal inference methodologies, the inverse probability weighting (IPW) method has been utilized to address confounding and account for missing data when subjects with missing data cannot be included in a primary analysis. The transdisciplinary field of molecular pathological epidemiology (MPE) integrates molecular pathological and epidemiological methods, and takes advantages of improved understanding of pathogenesis to generate stronger biological evidence of causality and optimize strategies for precision medicine and prevention. Disease subtyping based on biomarker analysis of biospecimens is essential in MPE research. However, there are nearly always cases that lack subtype information due to the unavailability or insufficiency of biospecimens. To address this missing subtype data issue, we incorporated inverse probability weights into Cox proportional cause-specific hazards regression. The weight was inverse of the probability of biomarker data availability estimated based on a model for biomarker data availability status. The strategy was illustrated in two example studies; each assessed alcohol intake or family history of colorectal cancer in relation to the risk of developing colorectal carcinoma subtypes classified by tumor microsatellite instability (MSI) status, using a prospective cohort study, the Nurses' Health Study. Logistic regression was used to estimate the probability of MSI data availability for each cancer case with covariates of clinical features and family history of colorectal cancer. This application of IPW can reduce selection bias caused by nonrandom variation in biospecimen data availability. The integration of causal inference methods into the MPE approach will likely have substantial potentials to advance the field of epidemiology.
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Affiliation(s)
- Li Liu
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 450 Brookline Ave., Room SM1036, Boston, MA, 02215, USA.,Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Daniel Nevo
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, 677 Huntington Ave., Boston, MA, 02215, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Reiko Nishihara
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 450 Brookline Ave., Room SM1036, Boston, MA, 02215, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Yin Cao
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Mingyang Song
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Tyler S Twombly
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Andrew T Chan
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Edward L Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Tyler J VanderWeele
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, 677 Huntington Ave., Boston, MA, 02215, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Molin Wang
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, 677 Huntington Ave., Boston, MA, 02215, USA. .,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. .,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
| | - Shuji Ogino
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. .,Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 450 Brookline Ave., Room SM1036, Boston, MA, 02215, USA. .,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. .,Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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9
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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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10
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Chau R, Dashti SG, Ait Ouakrim D, Buchanan DD, Clendenning M, Rosty C, Winship IM, Young JP, Giles GG, Macrae FA, Boussioutas A, Parry S, Figueiredo JC, Levine AJ, Ahnen DJ, Casey G, Haile RW, Gallinger S, Le Marchand L, Thibodeau SN, Lindor NM, Newcomb PA, Potter JD, Baron JA, Hopper JL, Jenkins MA, Win AK. Multivitamin, calcium and folic acid supplements and the risk of colorectal cancer in Lynch syndrome. Int J Epidemiol 2016; 45:940-53. [PMID: 27063605 DOI: 10.1093/ije/dyw036] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND People with a DNA mismatch repair (MMR) gene mutation have a substantially elevated risk of colorectal cancer (CRC) but the modifiers of this risk are not well established. We investigated the association between dietary supplement intake and CRC risk for carriers. METHODS This study included 1966 (56% female) carriers of an MMR gene mutation (719 MLH1, 931 MSH2, 211 MSH6 and 105 PMS2) who were recruited from the USA, Canada, Australia and New Zealand into the Colon Cancer Family Registry between 1997 and 2012. Information on lifestyle factors including supplement intake was collected at the time of recruitment. Using Cox proportional hazards regression weighted to correct for ascertainment bias, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between self-reported multivitamin, calcium and folic acid supplement intake and CRC risk. RESULTS Of 744 carriers with CRC, 18%, 6% and 5% reported intake of multivitamin, calcium and folic acid supplements for at least 1 month, respectively, compared with 27%, 11% and 10% of 1222 carriers without CRC. After adjusting for identified confounding variables, a decreased CRC risk was associated with multivitam inintake for at least 3 years (HR 0.47, 95% CI 0.32-0.69) and calcium intake for at least 3 years(HR 0.42, 95% CI 0.23-0.74), compared with never users. There was no evidence of an association between folic acid supplement intake and CRC risk (P = 0.82). CONCLUSION Intake of multivitamin and calcium supplements might be associated with a decreased risk of CRC for MMR gene mutation carriers.
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Affiliation(s)
- Rowena Chau
- Centre for Molecular, Environmental, Genetic and Analytic Epidemiology
| | | | - Driss Ait Ouakrim
- Centre for Molecular, Environmental, Genetic and Analytic Epidemiology
| | - Daniel D Buchanan
- Centre for Molecular, Environmental, Genetic and Analytic Epidemiology Colorectal Oncogenomics Group, Department of Pathology, University of Melbourne, Parkville, VIC, Australia
| | - Mark Clendenning
- Colorectal Oncogenomics Group, Department of Pathology, University of Melbourne, Parkville, VIC, Australia
| | - Christophe Rosty
- Colorectal Oncogenomics Group, Department of Pathology, University of Melbourne, Parkville, VIC, Australia School of Medicine, University of Queensland, Herston, QLD, Australia
| | - Ingrid M Winship
- Department of Medicine Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Joanne P Young
- Departments of Haematology and Oncology, Queen Elizabeth Hospital SAHMRI Colorectal Node, Basil Hetzel Institute for Translational Research, Woodville, SA, Australia School of Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Graham G Giles
- Centre for Molecular, Environmental, Genetic and Analytic Epidemiology Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia
| | - Finlay A Macrae
- Department of Medicine Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Alex Boussioutas
- Department of Medicine Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
| | - Susan Parry
- New Zealand Familial Gastrointestinal Cancer Service, Auckland, New Zealand
| | - Jane C Figueiredo
- Norris Comprehensive Cancer Centre, University of Southern California, Los Angeles, CA, USA
| | - A Joan Levine
- Department of Medicine, Stanford Cancer Institute, Stanford University, CA, USA
| | - Dennis J Ahnen
- Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA
| | - Graham Casey
- Norris Comprehensive Cancer Centre, University of Southern California, Los Angeles, CA, USA
| | - Robert W Haile
- Department of Medicine, Stanford Cancer Institute, Stanford University, CA, USA
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | | | - Stephen N Thibodeau
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Noralane M Lindor
- Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, WA, USA School of Public Health, University of Washington, Seattle, WA, USA
| | - John D Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, WA, USA School of Public Health, University of Washington, Seattle, WA, USA Centre for Public Health Research, Massey University, Wellington, New Zealand
| | - John A Baron
- Department of Medicine, University of North Carolina, Chapel Hill, Nc, USA
| | - John L Hopper
- Centre for Molecular, Environmental, Genetic and Analytic Epidemiology Department of Epidemiology and Institute of Health and Environment, School of Public Health, Seoul National University, Seoul, Korea
| | - Mark A Jenkins
- Centre for Molecular, Environmental, Genetic and Analytic Epidemiology
| | - Aung Ko Win
- Centre for Molecular, Environmental, Genetic and Analytic Epidemiology
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11
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Folate, vitamin B6, vitamin B12 and methionine intakes and risk for nasopharyngeal carcinoma in Chinese adults: a matched case-control study. Br J Nutr 2015; 115:121-8. [PMID: 26515433 DOI: 10.1017/s0007114515004146] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Many studies have suggested that folate-related one-carbon metabolism-related nutrients may play a role in certain cancer risks, but few studies have assessed their associations with the risk for nasopharyngeal carcinoma (NPC). In this study, we investigated the association between four folate-related one-carbon metabolism-related nutrients (folate, vitamin B6, vitamin B12 and methionine) and NPC risk in Chinese adults. A total of 600 patients newly diagnosed (within 3 months) with NPC were individually matched with 600 hospital-based controls by age, sex and household type (urban v. rural). Folate, vitamin B6, vitamin B12 and methionine intakes were measured using a validated seventy-eight-item FFQ. A higher dietary folate or vitamin B6 intake was associated with a lower NPC risk after adjusting for potential confounders. The adjusted OR of NPC for quartiles 2-4 (v. 1) were 0·66 (95% CI 0·48, 0·91), 0·52 (95% CI 0·37, 0·74) and 0·34 (95% CI 0·23, 0·50) (P(trend)<0·001) for folate and 0·72 (95% CI 0·52, 1·00), 0·55 (95% CI 0·39, 0·78) and 0·44 (95% CI 0·30, 0·63) (P(trend)<0·001) for vitamin B6. No significant association with NPC risk was observed for dietary vitamin B12 or methionine intake. The risk for NPC with dietary folate intake was more evident in the participants who were not exposed to toxic substances than in those who were exposed (P(interaction)=0·014). This study suggests that dietary folate and vitamin B6 may be protective for NPC in a high-risk population.
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12
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A dose-response meta-analysis reveals an association between vitamin B12 and colorectal cancer risk. Public Health Nutr 2015; 19:1446-56. [PMID: 26373257 DOI: 10.1017/s136898001500261x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE The current meta-analysis evaluated the association between vitamin B12 intake and blood vitamin B12 level and colorectal cancer (CRC) risk. DESIGN The PubMed and EMBASE databases were searched. A dose-response analysis was performed with generalized least squares regression, with the relative risk (RR) and 95 % CI as effect values. SETTING The meta-analysis included seventeen studies. SUBJECTS A total of 10 601 patients. RESULTS The non-linear dose-response relationship between total vitamin B12 intake and CRC risk was insignificant (P=0·690), but the relationship between dietary vitamin B12 intake and CRC risk was significant (P<0·001). Every 4·5 μg/d increment in total and dietary vitamin B12 intake was inversely associated with CRC risk (total intake: RR=0·963; 95 % CI 0·928, 0·999; dietary intake: RR=0·914; 95 % CI 0·856, 0·977). The inverse association between vitamin B12 intake and CRC risk was also significant when vitamin B12 intake was over a dosage threshold, enhancing the non-linear relationship. The non-linear dose-response relationship between blood vitamin B12 level and CRC risk was insignificant (P=0·219). There was an insignificant association between every 150 pmol/l increment in blood vitamin B12 level and CRC risk (RR=1·023; 95 % CI 0·881, 1·187). CONCLUSIONS Our meta-analysis indicates that evidence supports the use of vitamin B12 for cancer prevention, especially among populations with high-dose vitamin B12 intake, and that the association between CRC risk and total vitamin B12 intake is stronger than between CRC risk and dietary vitamin B12 intake only.
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13
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Liu Y, Yu Q, Zhu Z, Zhang J, Chen M, Tang P, Li K. Vitamin and multiple-vitamin supplement intake and incidence of colorectal cancer: a meta-analysis of cohort studies. Med Oncol 2015; 32:434. [PMID: 25491145 DOI: 10.1007/s12032-014-0434-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 12/03/2014] [Indexed: 02/06/2023]
Abstract
This paper systematically evaluated the association of intake of different vitamins and multiple-vitamin supplements and the incidence of colorectal cancer. Relevant studies were identified in MEDLINE via PubMed (published up to April 2014). We extracted data from articles on vitamins A, C, D, E, B9 (folate), B2, B3, B6, and B12 and multiple-vitamin supplements. We used multivariable-adjusted relative risks (RRs) and a random-effects model for analysis and random effects. With heterogeneity, we looked for the source of heterogeneity or performed sensitivity and stratified analyses. We found 47 articles meeting the inclusion criteria. The multivariable-adjusted RR for pooled studies for the association between the highest versus lowest vitamin B9 (folate) intake and colorectal cancer was 0.88 [95 % confidence interval (95 % CI) 0.81-0.95]. Vitamin D was 0.87 (95 % CI 0.77-0.99); vitamin B6, 0.88 (95 % CI 0.79-0.99); vitamin B2, 0.86 (95 % CI, 0.76-0.97); vitamin A, 0.87 (95 % CI, 0.75-1.03); vitamin C, 0.92 (95 % CI, 0.80-1.06); vitamin E, 0.94 (95 % CI, 0.82-1.07); vitamin B12, 1.10 (95 % CI, 0.92-1.32); vitamin B3, 1.18 (95 % CI, 0.76-1.84). Vitamin B9 (folate), D, B6, and B2 intake was inversely associated with risk of colorectal cancer, but further study is needed. Our study featured unacceptable heterogeneity for studies of multiple-vitamin supplements, so findings were inconclusive.
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Affiliation(s)
- Yan Liu
- Department of Public Health, Shantou University Medical College, No. 22 Xinling Road, Shantou, 515041, Guangdong, China,
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14
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Heinen MM, van den Brandt PA, Schouten LJ, Goldbohm RA, Schouten HC, Verhage BAJ. Dietary one-carbon nutrient intake and risk of lymphoid and myeloid neoplasms: results of the Netherlands cohort study. Cancer Epidemiol Biomarkers Prev 2014; 23:2153-64. [PMID: 25047896 DOI: 10.1158/1055-9965.epi-14-0136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Previous epidemiologic research suggests a protective role of one-carbon nutrients in carcinogenesis. Folate, however, may play a dual role in neoplasms development: protect early in carcinogenesis and promote carcinogenesis at a later stage. We prospectively examined associations between intake of total folate, methionine, riboflavin, vitamin B6, and risk of lymphoid and myeloid neoplasms (including subtypes) and investigated whether alcohol modified the effects of folate. METHODS The Netherlands Cohort Study consists of 120,852 individuals who completed a baseline questionnaire in 1986, including a 150-item food-frequency questionnaire. After 17.3 years of follow-up, 1,280 cases of lymphoid and 222 cases of myeloid neoplasms were available for analysis. RESULTS Intakes of folate, methionine, and riboflavin were not associated with lymphoid or myeloid neoplasms. For vitamin B6, a statistically significantly increased myeloid neoplasms risk was observed (highest vs. lowest quintile: HR = 1.87; 95% confidence intervals, 1.08-3.25). When analyzing by lymphoid and myeloid neoplasms subtypes, no clear associations were observed for most subtypes, with just a few increased risks for some subtypes and nutrients. Some risks became nonsignificant after excluding early cases. No interaction between alcohol and folate was observed. CONCLUSIONS We observed a few significant positive associations; however, some of these would be expected to arise due to chance alone. Furthermore, some risks became nonsignificant after excluding early cases. Therefore, we conclude that there is no association between one-carbon nutrient intake and risk of lymphoid and myeloid neoplasms. IMPACT This study contributes substantially to the limited and inconclusive evidence on the association with one-carbon nutrients.
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Affiliation(s)
- Mirjam M Heinen
- Department of Epidemiology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Piet A van den Brandt
- Department of Epidemiology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Leo J Schouten
- Department of Epidemiology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - R Alexandra Goldbohm
- Department of Prevention and Health, TNO Quality of Life, Leiden, the Netherlands
| | - Harry C Schouten
- Division of Hematology, Department of Internal Medicine, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Bas A J Verhage
- Department of Epidemiology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre+, Maastricht, the Netherlands.
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Moran DM, Trusk PB, Pry K, Paz K, Sidransky D, Bacus SS. KRAS mutation status is associated with enhanced dependency on folate metabolism pathways in non-small cell lung cancer cells. Mol Cancer Ther 2014; 13:1611-24. [PMID: 24688052 DOI: 10.1158/1535-7163.mct-13-0649] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
KRAS gene mutation is linked to poor prognosis and resistance to therapeutics in non-small cell lung cancer (NSCLC). In this study, we have explored the possibility of exploiting inherent differences in KRAS-mutant cell metabolism for treatment. This study identified a greater dependency on folate metabolism pathways in KRAS mutant compared with KRAS wild-type NSCLC cell lines. Microarray gene expression and biologic pathway analysis identified higher expression of folate metabolism- and purine synthesis-related pathways in KRAS-mutant NSCLC cells compared with wild-type counterparts. Moreover, pathway analysis and knockdown studies suggest a role for MYC transcriptional activity in the expression of these pathways in KRAS-mutant NSCLC cells. Furthermore, KRAS knockdown and overexpression studies demonstrated the ability of KRAS to regulate expression of genes that comprise folate metabolism pathways. Proliferation studies demonstrated higher responsiveness to methotrexate, pemetrexed, and other antifolates in KRAS-mutant NSCLC cells. Surprisingly, KRAS gene expression is downregulated in KRAS wild-type and KRAS-mutant cells by antifolates, which may also contribute to higher efficacy of antifolates in KRAS-mutant NSCLC cells. In vivo analysis of multiple tumorgraft models in nude mice identified a KRAS-mutant tumor among the pemetrexed-responsive tumors and also demonstrated an association between expression of the folate pathway gene, methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), and antifolate activity. Collectively, we identify altered regulation of folate metabolism in KRAS-mutant NSCLC cells that may account for higher antifolate activity in this subtype of NSCLC.
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Affiliation(s)
- Diarmuid M Moran
- Authors' Affiliations: Translational R&D Oncology Group, Quintiles, Westmont; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland; and Champions Oncology, Inc., Hackensack, New Jersey and Baltimore, Maryland
| | - Patricia B Trusk
- Authors' Affiliations: Translational R&D Oncology Group, Quintiles, Westmont; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland; and Champions Oncology, Inc., Hackensack, New Jersey and Baltimore, Maryland
| | - Karen Pry
- Authors' Affiliations: Translational R&D Oncology Group, Quintiles, Westmont; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland; and Champions Oncology, Inc., Hackensack, New Jersey and Baltimore, Maryland
| | - Keren Paz
- Authors' Affiliations: Translational R&D Oncology Group, Quintiles, Westmont; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland; and Champions Oncology, Inc., Hackensack, New Jersey and Baltimore, Maryland
| | - David Sidransky
- Authors' Affiliations: Translational R&D Oncology Group, Quintiles, Westmont; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland; and Champions Oncology, Inc., Hackensack, New Jersey and Baltimore, MarylandAuthors' Affiliations: Translational R&D Oncology Group, Quintiles, Westmont; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland; and Champions Oncology, Inc., Hackensack, New Jersey and Baltimore, Maryland
| | - Sarah S Bacus
- Authors' Affiliations: Translational R&D Oncology Group, Quintiles, Westmont; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland; and Champions Oncology, Inc., Hackensack, New Jersey and Baltimore, MarylandAuthors' Affiliations: Translational R&D Oncology Group, Quintiles, Westmont; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland; and Champions Oncology, Inc., Hackensack, New Jersey and Baltimore, Maryland
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16
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Lin JH, Giovannucci E. Environmental Exposure and Tumor Heterogeneity in Colorectal Cancer Risk and Outcomes. CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0208-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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17
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Zhou ZY, Wan XY, Cao JW. Dietary methionine intake and risk of incident colorectal cancer: a meta-analysis of 8 prospective studies involving 431,029 participants. PLoS One 2013; 8:e83588. [PMID: 24340103 PMCID: PMC3858442 DOI: 10.1371/journal.pone.0083588] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2013] [Accepted: 11/14/2013] [Indexed: 12/21/2022] Open
Abstract
Background Methionine is one of the key components of one carbon metabolism. Experimental studies indicate that methionine may reduce inflammation-induced colon cancer. However, epidemiologic findings as to whether dietary methionine intake influences colorectal cancer incidence in humans are inconsistent. Objective To investigate the relationship between dietary methionine intake and risk of colorectal cancer by performing a meta-analysis of prospective studies. Methods Eligible studies were identified by searching PubMed and Embase and by reviewing the bibliographies of the retrieved publications. The summary risk estimates were computed using both a random- effects and a fixed-effects model. Results Eight eligible prospective cohort studies involving 431,029 participants and 6,331 colorectal cancer cases were identified. According to the random-effects model, the summary relative risks (RRs) for the highest compared with the lowest intake of methionine were 0.89 (95% confidence interval [CI] = 0.77-1.03) for colorectal cancer, 0.77 (95% CI = 0.64 - 0.92) for colon cancer, and 0.88 (95% CI = 0.55-1.42) for rectal cancer. In the stratified analysis, a significant inverse association between dietary methionine intake and risk of colorectal cancer was observed in studies with longer follow-up time (RR=0.81, 95% CI= 0.70- 0.95), in Western studies (RR= 0.83, 95% CI = 0.73 - 0.95) and in men (RR = 0.75, 95% CI= 0.57-0.99). We found no indication of publication bias. Conclusion This meta-analysis indicates that dietary methionine intake may be associated with decreased risk of colorectal cancer, especially colon cancer. More prospective studies with long follow-up time are needed to confirm these findings.
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Affiliation(s)
- Zhong-Yin Zhou
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
- * E-mail:
| | - Xin-Yue Wan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Ji-Wang Cao
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
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18
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Bassett JK, Severi G, Hodge AM, Baglietto L, Hopper JL, English DR, Giles GG. Dietary Intake of B Vitamins and Methionine and Colorectal Cancer Risk. Nutr Cancer 2013; 65:659-67. [DOI: 10.1080/01635581.2013.789114] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Razzak AA, Oxentenko AS, Vierkant RA, Tillmans LS, Wang AH, Weisenberger DJ, Laird PW, Lynch CF, Anderson KE, French AJ, Haile RW, Harnack LJ, Potter JD, Slager SL, Smyrk TC, Thibodeau SN, Cerhan JR, Limburg PJ. Associations between intake of folate and related micronutrients with molecularly defined colorectal cancer risks in the Iowa Women's Health Study. Nutr Cancer 2013; 64:899-910. [PMID: 23061900 DOI: 10.1080/01635581.2012.714833] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Folate and related micronturients may affect colorectal cancer (CRC) risk, but the molecular mechanism(s) remain incompletely defined. We analyzed associations between dietary folate, vitamin B6, vitamin B12, and methionine with incident CRC, overall and by microsatellite instability (MSS/MSI-L or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive), BRAF mutation (negative or positive), and KRAS mutation (negative or positive) status in the prospective, population-based Iowa Women's Health Study (IWHS; 55-69 years at baseline; n = 41,836). Intake estimates were obtained from baseline, self-reported food frequency questionnaires. Molecular marker data were obtained for 514 incident CRC cases. Folate intake was inversely associated with overall CRC risk in age-adjusted Cox regression models, whereas methionine intake was inversely associated with overall CRC risk in multivariable-adjusted models [relative risk (RR) = 0.81; 95% CI = 0.69-0.95; P trend = 0.001 and RR = 0.72; 95% CI = 0.54-0.96; P trend = 0.03 for highest vs. lowest quartiles, respectively]. None of the dietary exposures were associated with MSI, CIMP, BRAF, or KRAS defined CRC subtypes. These data provide minimal support for major effects from the examined micronutrients on overall or molecularly defined CRC risks in the IWHS cohort.
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Affiliation(s)
- Anthony A Razzak
- Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA
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Zhang XH, Ma J, Smith-Warner SA, Lee JE, Giovannucci E. Vitamin B6 and colorectal cancer: current evidence and future directions. World J Gastroenterol 2013; 19:1005-10. [PMID: 23467420 PMCID: PMC3581987 DOI: 10.3748/wjg.v19.i7.1005] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 12/25/2012] [Accepted: 01/11/2013] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer remains the third most common cancer in both women and men worldwide. Identifying modifiable dietary factors is crucial in developing primary prevention strategies. Vitamin B6 is involved in more than 100 coenzyme reactions, and may influence colorectal cancer risk in multiple ways including through its role in one-carbon metabolism related DNA synthesis and methylation and by reducing inflammation, cell proliferation, and oxidative stress. Observational studies of dietary or dietary plus supplementary intake of vitamin B6 and colorectal cancer risk have been inconsistent with most studies reporting nonsignificant positive or inverse associations. However, published studies of plasma pyridoxal 5'-phosphate (the active form of vitamin B6) levels consistently support an approximately 30%-50% reduction in risk of colorectal cancer comparing high with low concentrations. The reasons for the discrepancy in the results between dietary-based and plasma-based studies remain unresolved. Other unresolved questions include the effects of vitamin B6 intake in early life (i.e., childhood or adolescence) and of suboptimal vitamin B6 status on colorectal cancer risk, whether the associations with vitamin B6 differ across molecular subtypes of colorectal cancer, and whether the vitamin B6-colorectal cancer association is modified by genetic variants of one-carbon metabolism.
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Galluzzi L, Vacchelli E, Michels J, Garcia P, Kepp O, Senovilla L, Vitale I, Kroemer G. Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses. Oncogene 2013; 32:4995-5004. [PMID: 23334322 DOI: 10.1038/onc.2012.623] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2012] [Revised: 11/21/2012] [Accepted: 11/26/2012] [Indexed: 12/17/2022]
Abstract
Pyridoxal-5'-phosphate (PLP), the bioactive form of vitamin B6, reportedly functions as a prosthetic group for >4% of classified enzymatic activities of the cell. It is therefore not surprising that alterations of vitamin B6 metabolism have been associated with multiple human diseases. As a striking example, mutations in the gene coding for antiquitin, an evolutionary old aldehyde dehydrogenase, result in pyridoxine-dependent seizures, owing to the accumulation of a metabolic intermediate that inactivates PLP. In addition, PLP is required for the catabolism of homocysteine by transsulfuration. Hence, reduced circulating levels of B6 vitamers (including PLP as well as its major precursor pyridoxine) are frequently paralleled by hyperhomocysteinemia, a condition that has been associated with an increased risk for multiple cardiovascular diseases. During the past 30 years, an intense wave of clinical investigation has attempted to dissect the putative links between vitamin B6 and cancer. Thus, high circulating levels of vitamin B6, as such or as they reflected reduced amounts of circulating homocysteine, have been associated with improved disease outcome in patients bearing a wide range of hematological and solid neoplasms. More recently, the proficiency of vitamin B6 metabolism has been shown to modulate the adaptive response of tumor cells to a plethora of physical and chemical stress conditions. Moreover, elevated levels of pyridoxal kinase (PDXK), the enzyme that converts pyridoxine and other vitamin B6 precursors into PLP, have been shown to constitute a good, therapy-independent prognostic marker in patients affected by non-small cell lung carcinoma (NSCLC). Here, we will discuss the clinical relevance of vitamin B6 metabolism as a prognostic factor in cancer patients.
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Affiliation(s)
- L Galluzzi
- 1] Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France [2] Institut Gustave Roussy, Villejuif, France
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Zhang X, Lee JE, Ma J, Je Y, Wu K, Willett WC, Fuchs CS, Giovannucci EL. Prospective cohort studies of vitamin B-6 intake and colorectal cancer incidence: modification by time? Am J Clin Nutr 2012; 96:874-81. [PMID: 22875713 PMCID: PMC3441113 DOI: 10.3945/ajcn.112.037267] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The relation between vitamin B-6 intake and colorectal cancer risk remains uncertain. OBJECTIVE We prospectively evaluated whether a higher vitamin B-6 intake in the remote past is more strongly associated with a lower risk of colorectal cancer than is an intake in the recent past in the Nurses' Health Study and the Health Professionals Follow-Up Study. DESIGN We assessed vitamin B-6 intake every 4 y by using validated food-frequency questionnaires and followed 86,440 women and 44,410 men for ≤28 y. Cox proportional hazards regression was used to estimate multivariable RRs and 95% CIs. RESULTS The total vitamin B-6 intake was significantly associated with an ∼20-30% lower risk of colorectal cancer in age-adjusted results, but this association became attenuated and nonsignificant after additional adjustment for nondietary and dietary factors. When the highest to lowest quintiles of cumulative total vitamin B-6 intake were compared, RRs (95% CIs) for colorectal cancer were 0.99 (0.80, 1.24; P-trend = 0.55) for women and 0.95 (0.73, 1.23; P-trend = 0.75) for men. For the same comparison, RRs were 0.92 (0.73, 1.16) for total vitamin B-6 intake 0-4 y before diagnosis, 0.99 (0.78, 1.26) for intake 4-8 y before diagnosis, 0.92 (0.71, 1.21) for intake 8-12 y before diagnosis, and 0.93 (0.69, 1.26) for intake 12-16 y before diagnosis in women. Corresponding RRs for men were 0.86 (0.63, 1.17), 0.96 (0.70, 1.32), 0.90 (0.63, 1.29), and 1.16 (0.75, 1.79). Results did not differ by cancer subsite, source of vitamin B-6 (food or supplement), alcohol consumption, or folate intake. CONCLUSION Our data do not support a strong role of adulthood vitamin B-6 intake in colorectal carcinogenesis in these US health professionals.
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Affiliation(s)
- Xuehong Zhang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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Epigenomic diversity of colorectal cancer. Epigenomics 2012. [DOI: 10.1017/cbo9780511777271.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Association of folate intake, dietary habits, smoking and COX-2 promotor -765G>C polymorphism with K-ras mutation in patients with colorectal cancer. J Egypt Natl Canc Inst 2012; 24:115-22. [PMID: 22929917 DOI: 10.1016/j.jnci.2012.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Accepted: 05/15/2012] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Understanding the role of environmental and molecular influences on the nature and rate of K-ras mutations in colorectal neoplasms is crucial. COX-2 polymorphisms -765G>C may play a role in carcinogenic processes in combination with specific life-style conditions or dependent on the racial composition of a particular population. If mutational events play an important role in colorectal carcinogenesis sequence, one can hypothesize that modification of these events by life-style or other factors would be a useful prevention strategy. AIM OF WORK To explore the association between K-ras mutation and potential variables known or suspected to be related to the risk of colorectal cancer (CRC) as well as determining the possible modulating effect of the COX-2 polymorphism, -765G>C. SUBJECTS AND METHODS The study was conducted on 80 patients with colorectal cancer from Tropical Medicine and Gastrointestinal Tract endoscopy Departments and those attending clinic of the National Cancer Institute, Cairo University during the period extending from April 2009 to March 2010. Full history taking with emphasis on the risk factors of interest, namely age, sex, family history, smoking and dietary history. Serum CEA and CA19-9, RBCs folic acid and occult blood in stool were done to all samples. K-ras protooncogene mutation at codon 12 (exon 1) and cyclooxygenase 2 (COX-2) -765G>C polymorphism were determined by PCR-RFLP. RESULTS The K-ras mutation was positive in 23 (28.7%) patients. COX-2 polymorphism revealed GG in 62.5%, GC in 26.2 % and CC genotype was found in 11.3 % of cases. The mean red blood cell folic acid level was lower in the K-ras positive group (100.96±51.3 ng/ml) than the negative group (216.6±166.4 ng/ml), (P<0.01). Higher folate levels were found in males than females (median=173 ng/ml and 85 ng/ml; respectively, P=0.002) with adjusted odds ratio (OR) of 0.984. Only, the RBCs folate (P=0.0018) followed by gender (P=0.036) contributed significantly in the discrimination between patients prone to develop K-ras mutation and those who are not. CONCLUSION RBC folic acid was significantly deficient in CRC (colorectal cancer) patients with K-ras mutations in comparison with CRC patients free of the mutations, suggesting that folic acid may be a risk factor for K-ras mutation development.
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Cortessis VK, Thomas DC, Levine AJ, Breton CV, Mack TM, Siegmund KD, Haile RW, Laird PW. Environmental epigenetics: prospects for studying epigenetic mediation of exposure-response relationships. Hum Genet 2012; 131:1565-89. [PMID: 22740325 PMCID: PMC3432200 DOI: 10.1007/s00439-012-1189-8] [Citation(s) in RCA: 194] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Accepted: 06/07/2012] [Indexed: 12/15/2022]
Abstract
Changes in epigenetic marks such as DNA methylation and histone acetylation are associated with a broad range of disease traits, including cancer, asthma, metabolic disorders, and various reproductive conditions. It seems plausible that changes in epigenetic state may be induced by environmental exposures such as malnutrition, tobacco smoke, air pollutants, metals, organic chemicals, other sources of oxidative stress, and the microbiome, particularly if the exposure occurs during key periods of development. Thus, epigenetic changes could represent an important pathway by which environmental factors influence disease risks, both within individuals and across generations. We discuss some of the challenges in studying epigenetic mediation of pathogenesis and describe some unique opportunities for exploring these phenomena.
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Affiliation(s)
- Victoria K. Cortessis
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089 USA
| | - Duncan C. Thomas
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N. Soto St., SSB-202F, Los Angeles, CA 90089-9234 USA
| | - A. Joan Levine
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089 USA
| | - Carrie V. Breton
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N. Soto St., Los Angeles, CA 90089-9234 USA
| | - Thomas M. Mack
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089 USA
| | - Kimberly D. Siegmund
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N. Soto St., Los Angeles, CA 90089-9234 USA
| | - Robert W. Haile
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089 USA
| | - Peter W. Laird
- Departments of Surgery, Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, USC Norris Comprehensive Cancer Center, Epigenome Center, 1441 Eastlake Avenue, Los Angeles, CA 90089-9601 USA
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Razzak AA, Oxentenko AS, Vierkant RA, Tillmans LS, Wang AH, Weisenberger DJ, Laird PW, Lynch CF, Anderson KE, French AJ, Haile RW, Harnack LJ, Slager SL, Smyrk TC, Thibodeau SN, Cerhan JR, Limburg PJ. Alcohol intake and colorectal cancer risk by molecularly defined subtypes in a prospective study of older women. Cancer Prev Res (Phila) 2011; 4:2035-43. [PMID: 21900595 PMCID: PMC3584678 DOI: 10.1158/1940-6207.capr-11-0276] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Increased alcohol consumption is a putative colorectal cancer (CRC) risk factor. However, existing data are less conclusive for women than men. Also, to date, relatively few studies have reported alcohol-related CRC risks based on molecularly defined tumor subtypes. We evaluated associations between alcohol intake and incident CRC, overall and by microsatellite instability [MSI high (MSI-H) or MSI low/microsatellite stable (MSI-L/MSS)], CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation (mutated or wild-type) status in the prospective, population-based Iowa Women's Health Study (IWHS; n = 41,836). Subjects were 55 to 69 years at baseline (1986), and exposure data were obtained by self-report. Incident CRCs were prospectively identified and archived, paraffin-embedded tissue specimens were collected from 732 representative cases, diagnosed through December 31, 2002. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI). Among alcohol consumers, the median intake (range) was 3.4 (0.9-292.8) g/d. Compared with nonconsumers, alcohol intake levels of 3.4 g/d or less (RR = 1.00; 95% CI, 0.86-1.15) and more than 3.4 g/d (RR = 1.06; 95% CI, 0.91-1.24) were not significantly associated with overall CRC risk. Analyses based on alcohol intake levels of 30 g/d or less and more than 30 g/d or quartile distributions yielded similar risk estimates. Null associations were also observed between each alcohol intake level and the MSI-, CIMP- or, BRAF-defined CRC subtypes (P > 0.05 for each comparison). These data do not support an adverse effect from alcohol intake on CRC risk, overall or by specific molecularly defined subtypes, among older women.
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Affiliation(s)
| | | | - Robert A. Vierkant
- Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, MN
| | - Lori S. Tillmans
- Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN
| | - Alice H. Wang
- Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, MN
| | | | | | | | | | - Amy J. French
- Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN
| | - Robert W. Haile
- Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, CA
| | - Lisa J. Harnack
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Susan L. Slager
- Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, MN
| | - Thomas C. Smyrk
- Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN
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Gay LJ, Arends MJ, Mitrou PN, Bowman R, Ibrahim AE, Happerfield L, Luben R, McTaggart A, Ball RY, Rodwell SA. MLH1 promoter methylation, diet, and lifestyle factors in mismatch repair deficient colorectal cancer patients from EPIC-Norfolk. Nutr Cancer 2011; 63:1000-1010. [PMID: 21875327 DOI: 10.1080/01635581.2011.596987] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
There is conflicting evidence for the role diet and lifestyle play in the development of mismatch repair (MMR)-deficient colorectal cancers (CRC). In this study, associations between MMR deficiency, clinicopathological characteristics, and dietary and lifestyle factors in sporadic CRC were investigated. Tumor samples from 185 individuals in the EPIC-Norfolk study were analyzed for MLH1 gene promoter methylation and microsatellite instability (MSI). Dietary and lifestyle data were collected prospectively using 7-day food diaries (7dd) and questionnaires. MMR-deficient tumor cases (MLH1 promoter methylation positive, MSI-H) were more likely to be female, older at diagnosis, early Dukes' stage (A/B), and proximal in location (MSI-H P = 0.03, 0.03, 0.02, and 0.001, respectively). Tumors with positive MLH1 promoter methylation (>20%) were associated with poor differentiation (P = 0.03). Low physical activity was associated with cases without MSI (P = 0.05). MMR deficiency was not significantly associated with cigarette smoking or alcohol, folate, fruit, vegetable, or meat consumption. We conclude that MMR-deficient tumors represent a distinct subset of sporadic CRC that are proximal in location, early Dukes' stage, and poorly differentiated, in cases that are female and older at diagnosis. There is no overall role for diet and lifestyle in MMR status in CRC, consistent with age-related susceptibility to MLH1 promoter methylation.
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Affiliation(s)
- Laura J Gay
- Medical Research Council Dunn Human Nutrition Unit, Cambridge, United Kingdom
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28
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Schernhammer ES, Giovannucci E, Baba Y, Fuchs CS, Ogino S. B vitamins, methionine and alcohol intake and risk of colon cancer in relation to BRAF mutation and CpG island methylator phenotype (CIMP). PLoS One 2011; 6:e21102. [PMID: 21738611 PMCID: PMC3124479 DOI: 10.1371/journal.pone.0021102] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Accepted: 05/20/2011] [Indexed: 12/13/2022] Open
Abstract
Background One-carbon metabolism appears to play an important role in DNA methylation reaction. Evidence suggests that a low intake of B vitamins or high alcohol consumption increases colorectal cancer risk. How one-carbon nutrients affect the CpG island methylator phenotype (CIMP) or BRAF mutation status in colon cancer remains uncertain. Methods Utilizing incident colon cancers in a large prospective cohort of women (the Nurses' Health Study), we determined BRAF status (N = 386) and CIMP status (N = 375) by 8 CIMP-specific markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and 8 other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT-1, MINT-31, p14, and WRN). We examined the relationship between intake of one-carbon nutrients and alcohol and colon cancer risk, by BRAF mutation or CIMP status. Results Higher folate intake was associated with a trend towards low risk of CIMP-low/0 tumors [total folate intake ≥400 µg/day vs. <200 µg/day; the multivariate relative risk = 0.73; 95% CI = 0.53–1.02], whereas total folate intake had no influence on CIMP-high tumor risks (Pheterogeneity = 0.73). Neither vitamin B6, methionine or alcohol intake appeared to differentially influence risks for CIMP-high and CIMP-low/0 tumors. Using the 16-marker CIMP panel did not substantially alter our results. B vitamins, methionine or alcohol intake did not affect colon cancer risk differentially by BRAF status. Conclusions This molecular pathological epidemiology study suggests that low level intake of folate may be associated with an increased risk of CIMP-low/0 colon tumors, but not that of CIMP-high tumors. However, the difference between CIMP-high and CIMP-low/0 cancer risks was not statistically significant, and additional studies are necessary to confirm these observations.
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Affiliation(s)
- Eva S Schernhammer
- Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
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Lee JE, Willett WC, Fuchs CS, Smith-Warner SA, Wu K, Ma J, Giovannucci E. Folate intake and risk of colorectal cancer and adenoma: modification by time. Am J Clin Nutr 2011; 93:817-25. [PMID: 21270374 PMCID: PMC3057549 DOI: 10.3945/ajcn.110.007781] [Citation(s) in RCA: 104] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Accepted: 12/22/2010] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Experimental and observational studies have suggested that folate may play dual roles in colorectal cancer risk depending on the timing and dose. OBJECTIVE We examined the latency between folate intake and the incidence of colorectal cancer. DESIGN We prospectively examined associations between folate intake assessed every 2 to 4 y by using validated food-frequency questionnaires and risk of colorectal cancer and adenoma in the Nurses' Health Study and Health Professionals Follow-Up Study, which included 2299 incident colorectal cancers and 5655 colorectal adenomas from 1980 to 2004. RESULTS There was an association between total folate intake 12-16 y before diagnosis and lower risk of colorectal cancer (relative risk: 0.69; 95% CI: 0.51, 0.94; ≥800 compared with <250 μg folate/d), but there was no association between intake in the recent past and colorectal cancer risk. Long- and short-term intakes of total folate were associated with a lower risk of colorectal adenoma, with a strong association with intake 4-8 y before diagnosis (odds ratio: 0.68; 95% CI: 0.60, 0.78; ≥800 compared with <250 μg folate/d). The current use of multivitamins for >15 y, but not a shorter duration of use, was associated with lower risk of colorectal cancer; and a shorter duration of use was related to lower risk of adenoma. We did not observe an adverse effect of total folate or synthetic folic acid on risk of colorectal cancer or adenoma even during the folic acid fortification era. CONCLUSION Folate intake is inversely associated with risk of colorectal cancer only during early preadenoma stages.
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Affiliation(s)
- Jung Eun Lee
- Department of Food and Nutrition, Sookmyung Women's University, Seoul, Republic of Korea
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30
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Ogino S, Chan AT, Fuchs CS, Giovannucci E. Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field. Gut 2011; 60:397-411. [PMID: 21036793 PMCID: PMC3040598 DOI: 10.1136/gut.2010.217182] [Citation(s) in RCA: 450] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is a complex disease resulting from somatic genetic and epigenetic alterations, including locus-specific CpG island methylation and global DNA or LINE-1 hypomethylation. Global molecular characteristics such as microsatellite instability (MSI), CpG island methylator phenotype (CIMP), global DNA hypomethylation, and chromosomal instability cause alterations of gene function on a genome-wide scale. Activation of oncogenes including KRAS, BRAF and PIK3CA affects intracellular signalling pathways and has been associated with CIMP and MSI. Traditional epidemiology research has investigated various factors in relation to an overall risk of colon and/or rectal cancer. However, colorectal cancers comprise a heterogeneous group of diseases with different sets of genetic and epigenetic alterations. To better understand how a particular exposure influences the carcinogenic and pathologic process, somatic molecular changes and tumour biomarkers have been studied in relation to the exposure of interest. Moreover, an investigation of interactive effects of tumour molecular changes and the exposures of interest on tumour behaviour (prognosis or clinical outcome) can lead to a better understanding of tumour molecular changes, which may be prognostic or predictive tissue biomarkers. These new research efforts represent 'molecular pathologic epidemiology', which is a multidisciplinary field of investigations of the inter-relationship between exogenous and endogenous (eg, genetic) factors, tumoural molecular signatures and tumour progression. Furthermore, integrating genome-wide association studies (GWAS) with molecular pathological investigation is a promising area (GWAS-MPE approach). Examining the relationship between susceptibility alleles identified by GWAS and specific molecular alterations can help elucidate the function of these alleles and provide insights into whether susceptibility alleles are truly causal. Although there are challenges, molecular pathological epidemiology has unique strengths, and can provide insights into the pathogenic process and help optimise personalised prevention and therapy. In this review, we overview this relatively new field of research and discuss measures to overcome challenges and move this field forward.
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Affiliation(s)
- Shuji Ogino
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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31
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Curtin K, Samowitz WS, Ulrich CM, Wolff RK, Herrick JS, Caan BJ, Slattery ML. Nutrients in folate-mediated, one-carbon metabolism and the risk of rectal tumors in men and women. Nutr Cancer 2011; 63:357-66. [PMID: 21462086 PMCID: PMC3127576 DOI: 10.1080/01635581.2011.535965] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
In an investigation of rectal tumors characterized by CpG island methylator phenotype (CIMP), KRAS2 mutation, and TP53 mutation, we examined associations with dietary and supplemental folate, riboflavin, vitamins B(6) and B(12), and methionine, nutrients involved in folate-mediated 1-carbon metabolism. We also examined folate intake and common MTHFR polymorphisms in relation to CIMP. Data from a population-based study of 951 cases (750 with tumor markers) and 1,205 controls were evaluated using multiple logistic regression models and generalized estimating equations. Reduced risk of methylated tumors was suggested in women with the upper tertile of folate intake (≥0.42 mg/day) vs. the lower tertile: OR = 0.6, 95%CI = 0.3-1.2. In men, a significant 3-fold increased risk of CIMP+ tumor was observed for the upper tertile of folate (≥0.75 mg/day) vs. the lower tertile (<0.44 mg/day): OR = 3.2, 95%CI = 1.5-6.7. These men consumed a greater proportion of folic acid fortified foods relative to natural, primarily plant-based sources (52% vs. 48%) than women with CIMP+ tumors (22% vs. 78%). MTHFR 1298A>C influenced folate in male CIMP+ risk (P interaction < 0.01). Our findings suggest folate supplementation effects may differ between genders, perhaps due to variation in MTHFR and/or endogenous/exogenous hormones, and may be important in the initiation and progression of methylated rectal tumors in men.
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Affiliation(s)
- Karen Curtin
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA.
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32
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Kennedy DA, Stern SJ, Moretti M, Matok I, Sarkar M, Nickel C, Koren G. Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis. Cancer Epidemiol 2010; 35:2-10. [PMID: 21177150 DOI: 10.1016/j.canep.2010.11.004] [Citation(s) in RCA: 113] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2010] [Revised: 11/04/2010] [Accepted: 11/17/2010] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Folic acid fortification and supplementation to prevent neural tube defects has led to concerns regarding increased risk of colorectal cancer. The results of existing studies have been inconclusive. The purpose was to examine the relationship between level of folate intake and the incidence of colorectal cancer. METHODS A systematic review and meta analysis were conducted. MEDLINE, Embase, and SCOPUS were searched from inception to October 2009 with the following search terms "folic acid," "folate", "colorectal cancer," "colon neoplasms," rectal neoplasms." Observational studies in adult populations were included that defined levels of folate intake and incidence of colorectal cancer. RESULT Out of 6427 references, 27 studies met our inclusion criteria. The summary risk estimate for case control studies comparing high versus low total folate intake was 0.85 (CI 95% 0.74-0.99) with no significant heterogeneity among studies. Similarly, for cohort studies, the resulting summary risk estimate for high versus low dietary folate intake was 0.92 (CI 95% 0.81-1.05) with no significant heterogeneity. However, defining what represents a higher intake of folic acid is difficult as there is variability in the upper limit of folic acid intake used in the studies. DISCUSSION These results suggest that higher folate intake levels offer a reduction in one of the perceived risks associated with developing colorectal cancer. These data can serve to help reassure women planning a pregnancy to increase folic intake during the preconception period to levels sufficient to prevent neural tube defects.
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Affiliation(s)
- Deborah A Kennedy
- The Motherisk Program, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8 Canada.
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Schernhammer ES, Giovannuccci E, Kawasaki T, Rosner B, Fuchs CS, Ogino S. Dietary folate, alcohol and B vitamins in relation to LINE-1 hypomethylation in colon cancer. Gut 2010; 59:794-9. [PMID: 19828464 PMCID: PMC2895465 DOI: 10.1136/gut.2009.183707] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Although critical for methylation reactions, how dietary folate and B vitamins affect global DNA methylation level in colorectal cancers is currently unknown. Long interspersed nucleotide element-1 (LINE-1) is an emerging indicator of genome-wide DNA methylation level that has previously been linked to colon cancer survival. METHODS We examined the association between dietary intake of folate, alcohol and B vitamins and LINE-1 hypomethylation in 609 incident colon cancers, utilising the database of two independent prospective cohort studies. RESULTS Participants with > or = 400 microg folate intake per day were significantly less likely to develop LINE-1 hypomethylated colon cancers than those reporting <200 microg of folate intake per day (RR=0.57, 95% CI=0.36 to 0.91 for <55% LINE-1 methylated colon tumours; RR=0.74, 95% CI=0.51 to 1.06 for 55-64% LINE-1 methylated colon tumours; and RR=1.08, 95% CI=0.66 to 1.75 for > or = 65% LINE-1 methylated tumours; P(interaction)=0.01). By contrast, high alcohol consumption conferred a higher risk of LINE-1 hypomethylated cancers (> or = 15 g alcohol per day versus none, RR=1.67, 95% CI=1.04 to 2.67 for <55% LINE1 methylated tumours; and RR=1.55, 95% CI=1.10 to 2.18 for 55-64% LINE-1 methylated tumours) but had no association with > or = 65% LINE-1 methylated tumours (RR=1.06, 95% CI=0.69 to 1.62). High intakes of vitamin B(6), B(12) or methionine were not significantly associated with colon cancers, regardless of LINE-1 methylation level. CONCLUSION The influence of dietary folate intake and alcohol consumption on colon cancer risk differs significantly according to tumoral LINE-1 methylation level.
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Affiliation(s)
- E S Schernhammer
- Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA,Department of Epidemiology, Harvard School of Public Health, Boston, MA,Ludwig Boltzmann-Institute for Applied Cancer Research, KFJ-Spital, Vienna, Austria and Applied Cancer Research - Institution for Translational Research Vienna (ACR–ITR VIEnna), Austria
| | - E Giovannuccci
- Department of Epidemiology, Harvard School of Public Health, Boston, MA
| | - T Kawasaki
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - B Rosner
- Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - C S Fuchs
- Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - S Ogino
- Department of Epidemiology, Harvard School of Public Health, Boston, MA,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA,Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
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Ogino S, Stampfer M. Lifestyle factors and microsatellite instability in colorectal cancer: the evolving field of molecular pathological epidemiology. J Natl Cancer Inst 2010; 102:365-7. [PMID: 20208016 DOI: 10.1093/jnci/djq031] [Citation(s) in RCA: 154] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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Mechanisms of resistance to HER family targeting antibodies. Exp Cell Res 2010; 316:1083-100. [PMID: 20064507 DOI: 10.1016/j.yexcr.2010.01.009] [Citation(s) in RCA: 120] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2009] [Revised: 12/08/2009] [Accepted: 01/05/2010] [Indexed: 12/22/2022]
Abstract
The epidermal growth factor (EGF) family of receptor tyrosine kinases consists of four members: EGFR (HER1/ErbB1), HER2/neu (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Receptor activation via ligand binding leads to downstream signaling that influence cell proliferation, angiogenesis, invasion and metastasis. Aberrant expression or activity of EGFR and HER2 have been strongly linked to the etiology of several human epithelial cancers including but not limited to head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and breast cancer. With this, intense efforts have been made to inhibit the activity of the EGFR and HER2 by designing antibodies against the ligand binding domains (cetuximab, panitumumab and trastuzumab) or small molecules against the tyrosine kinase domains (erlotinib, gefitinib, and lapatinib). Both approaches have shown considerable clinical promise. However, increasing evidence suggests that the majority of patients do not respond to these therapies, and those who show initial response ultimately become refractory to treatment. While mechanisms of resistance to tyrosine kinase inhibitors have been extensively studied, resistance to monoclonal antibodies is less well understood, both in the laboratory and in the clinical setting. In this review, we discuss resistance to antibody-based therapies against the EGFR and HER2, similarities between these resistance profiles, and strategies to overcome resistance to HER family targeting monoclonal antibody therapy.
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Durner J. Die klinische Chemie - Herausforderung der Medizin für die analytische Chemie und die Nanowissenschaften. Angew Chem Int Ed Engl 2009. [DOI: 10.1002/ange.200903363] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Durner J. Clinical Chemistry: Challenges for Analytical Chemistry and the Nanosciences from Medicine. Angew Chem Int Ed Engl 2009; 49:1026-51. [DOI: 10.1002/anie.200903363] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Egloff AM, Grandis JR. Improving Response Rates to EGFR-Targeted Therapies for Head and Neck Squamous Cell Carcinoma: Candidate Predictive Biomarkers and Combination Treatment with Src Inhibitors. JOURNAL OF ONCOLOGY 2009; 2009:896407. [PMID: 19636423 PMCID: PMC2712676 DOI: 10.1155/2009/896407] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/14/2009] [Accepted: 05/17/2009] [Indexed: 11/17/2022]
Abstract
The epidermal growth factor receptor- (EGFR-) directed antibody, cetuximab, was FDA-approved for the treatment of squamous cell carcinoma of the head and neck (SCCHN) in 2006. Additional EGFR-targeting agents in clinical development for SCCHN include other EGFR-directed antibodies, tyrosine kinase inhibitors and antisense DNA. Although the majority of SCCHN overexpress EGFR, SCCHN clinical responses to EGFR-targeting agents have been modest. Molecular predictors for SCCHN response to EGFR-targeted therapies have not been identified. However, molecular correlate studies in lung cancer and colon cancer, which have EGFR-targeted therapeutics FDA-approved for treatment, may provide insights. We describe candidate predictive markers for SCCHN response to EGFR-targeted therapies and their prevalence in SCCHN. Clinical response will likely be improved by targeted therapy combination treatments. Src family kinases mediate EGFR-dependent and -independent tumor progression pathways in many cancers including SCCHN. Several Src-targeting agents are in clinical development for solid malignancies. Molecular correlate studies for Src-targeting therapies are few and biomarkers correlated with patient response are limited. Identifying SCCHN patients who will respond to combined EGFR- and Src-targeting will require further characterization of molecular correlates. We discuss rationale for EGFR and Src co-targeting for SCCHN treatment and describe recent clinical trials implementing combined Src- and EGFR-targeted therapeutics.
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Affiliation(s)
- Ann Marie Egloff
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Jennifer Rubin Grandis
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Eye and Ear Institute, Suite 500 200 Lothrop Street, Pittsburgh, PA 15213, USA
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