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1
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Thomas CE, Peters U. Genomic landscape of cancer in racially and ethnically diverse populations. Nat Rev Genet 2025; 26:336-349. [PMID: 39609636 DOI: 10.1038/s41576-024-00796-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2024] [Indexed: 11/30/2024]
Abstract
Cancer incidence and mortality rates can vary widely among different racial and ethnic groups, attributed to a complex interplay of genetic, environmental and social factors. Recently, substantial progress has been made in investigating hereditary genetic risk factors and in characterizing tumour genomes. However, most research has been conducted in individuals of European ancestries and, increasingly, in individuals of Asian ancestries. The study of germline and somatic genetics in cancer across racial and ethnic groups using omics technologies offers opportunities to identify similarities and differences in both heritable traits and the molecular features of cancer genomes. An improved understanding of population-specific cancer genomics, as well as translation of those findings across populations, will help reduce cancer disparities and ensure that personalized medicine and public health approaches are equitable across racial and ethnic groups.
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Affiliation(s)
- Claire E Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
- Department of Epidemiology, University of Washington, Seattle, WA, USA.
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Marabelli M, Calvello M, Marino E, Morocutti C, Gandini S, Dal Molin M, Zanzottera C, Mannucci S, Fava F, Feroce I, Lazzeroni M, Guerrieri-Gonzaga A, Bertolini F, Bonanni B. Germline Testing in Breast Cancer: A Single-Center Analysis Comparing Strengths and Challenges of Different Approaches. Cancers (Basel) 2025; 17:1419. [PMID: 40361347 PMCID: PMC12071043 DOI: 10.3390/cancers17091419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/04/2025] [Accepted: 04/22/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND/OBJECTIVES Compared to single gene testing (SGT), multigene panel testing (MGPT) improves pathogenic variants (PVs) detection. However, MGPT yields complex results, including secondary findings, heterozygous PVs in recessive genes, low-penetrance PVs, and variants of uncertain significance. We reported our mono-institutional experience of germline testing in breast cancer (BC), comparing SGT and MGPT. METHODS We retrospectively analyzed clinical and molecular data from 1084 BC patients: 308 underwent SGT (BRCA1/BRCA2) and 776 MGPT (for 28 cancer-related genes). We compared these approaches regarding the genetic classification of the findings (positive, uncertain, uninformative) and their impact on clinical management (primary findings (PFs); complex and inconclusive results). Additionally, we described clinical features supporting one approach over the other and focused on copy number variation (CNV) frequency in non-BRCA genes. RESULTS We found ≥1 PV in 165 patients (165/1084 = 15.2%), including 91 in BRCA1/BRCA2 (91/1084 = 8.4%), with 42 identified by SGT (42/308 = 13.6%) and 49 by MGPT (49/776 = 6.3%). MGPT detected PVs in non-BRCA genes in 74 patients (74/776 = 9.5%), including 40 PFs. Overall, MGPT identified 89 PFs (89/776 = 11.5%). We observed complex results in 21 patients (21/308 = 6.8%) with SGT and in 300 (300/776 = 38.7%) with MGPT. Compared to MGPT, SGT detected a similar percentage of PFs (13.6% vs. 11.5%) but a significantly reduced percentage of complex results (6.8% vs. 38.7%) (p < 0.001). Triple-negative BCs prevailed in BRCA1 carriers, while ER-positive BCs were more prevalent in ATM/CHEK2 carriers. Concerning non-BRCA genes, MGPT detected CNVs in PALB2, representing 20% of PVs in this gene. CONCLUSIONS Although MGPT increases hereditary BC detection, its complexity requires clear guidelines for optimal clinical management and strategies for merging the benefits of SGT and MGPT.
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Affiliation(s)
- Monica Marabelli
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Mariarosaria Calvello
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Elena Marino
- Laboratory of Medical Genetics, Cytogenetics and Molecular Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Chiara Morocutti
- Department of Experimental Oncology, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Sara Gandini
- Department of Experimental Oncology, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Matteo Dal Molin
- Laboratory of Medical Genetics, Cytogenetics and Molecular Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Cristina Zanzottera
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Sara Mannucci
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Francesca Fava
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Irene Feroce
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Matteo Lazzeroni
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Aliana Guerrieri-Gonzaga
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Francesco Bertolini
- Laboratory of Medical Genetics, Cytogenetics and Molecular Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
- Laboratory of Hematology-Oncology, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Bernardo Bonanni
- Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
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Foote MB, Walch H, Kemel Y, Vakiani E, Johannet P, Sheehan M, Chatila W, Chung S, Nash GM, Maio A, Shia J, Mandelker D, Berger M, Schultz N, Diaz LA, Cercek A, Stadler ZK. The Impact of Germline Alterations in Appendiceal Adenocarcinoma. Clin Cancer Res 2023; 29:2631-2637. [PMID: 37289003 PMCID: PMC10642170 DOI: 10.1158/1078-0432.ccr-22-3956] [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: 12/27/2022] [Revised: 03/08/2023] [Accepted: 05/15/2023] [Indexed: 05/19/2023]
Abstract
PURPOSE More than 10% of assessed patients with appendiceal adenocarcinoma have a pathogenic (P) or likely pathogenic (LP) germline variant, including genes implicated in heritable gastrointestinal cancer syndromes, such as Lynch syndrome. We defined the clinical and molecular impact of heritable alterations in appendiceal adenocarcinoma to evaluate the need for dedicated appendiceal screening and prevention strategies in patients with LP/P germline variants. EXPERIMENTAL DESIGN We performed an integrated germline and somatic molecular analysis for patients with confirmed appendiceal adenocarcinoma. Patients underwent paired tumor-normal sequencing for up to 90 hereditary cancer risk genes and 505 genes for somatic mutation profiling. We defined the cooccurrence of LP/P germline variants and second-hit pathogenic somatic alterations. The associations between germline variants and patient clinicopathologic features were also evaluated. RESULTS Twenty-five of 237 patients (10.5%) carried pathogenic or likely pathogenic germline variants in cancer susceptibility genes. Clinicopathologic characteristics and appendiceal adenocarcinoma-specific survival were similar in patients with or without germline variants. Most (92%, N = 23/25) patients with germline variants demonstrated no second-hit somatic alterations, including loss of heterozygosity. Two patients with a germline APC I1307K low-penetrance founder variant exhibited secondary somatic pathogenic alterations in APC. However, only one patient tumor exhibited APC-mediated WNT signaling dysregulation: a plausible consequence of multiple somatic APC mutations with no germline variant contribution. Four patients had germline variants in PMS2 or MSH2 associated with Lynch syndrome, yet their cancers were microsatellite-stable. CONCLUSIONS Germline variants are likely incidental without a contributory driver role in appendiceal adenocarcinoma. Appendiceal adenocarcinoma screening in patients with germline variants is not clearly merited.
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Affiliation(s)
- Michael B. Foote
- Division of Solid Tumor Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Henry Walch
- Human Oncology and Pathogenesis Program; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Yelena Kemel
- Niehaus Center for Inherited Cancer Genomics; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Efsevia Vakiani
- Department of Pathology and Laboratory Medicine; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Paul Johannet
- Division of Solid Tumor Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Margaret Sheehan
- Niehaus Center for Inherited Cancer Genomics; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Walid Chatila
- Human Oncology and Pathogenesis Program; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Sebastian Chung
- Department of Surgery; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Garrett M. Nash
- Department of Surgery; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Anna Maio
- Niehaus Center for Inherited Cancer Genomics; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Jinru Shia
- Department of Pathology and Laboratory Medicine; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Diana Mandelker
- Department of Pathology and Laboratory Medicine; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Michael Berger
- Human Oncology and Pathogenesis Program; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
- Department of Pathology and Laboratory Medicine; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Nikolaus Schultz
- Human Oncology and Pathogenesis Program; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Luis A. Diaz
- Division of Solid Tumor Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Andrea Cercek
- Division of Solid Tumor Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
| | - Zsofia K. Stadler
- Division of Solid Tumor Oncology; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
- Niehaus Center for Inherited Cancer Genomics; Memorial Sloan Kettering Cancer Center; NY, NY, 10065, USA
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Avnat E, Shapira G, Shoval S, Israel-Elgali I, Alkelai A, Shuldiner AR, Gonzaga-Jauregui C, Zidan J, Maray T, Shomron N, Friedman E. Comprehensive Genetic Analysis of Druze Provides Insights into Carrier Screening. Genes (Basel) 2023; 14:genes14040937. [PMID: 37107695 PMCID: PMC10137689 DOI: 10.3390/genes14040937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/24/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND Druze individuals, like many genetically homogeneous and isolated populations, harbor recurring pathogenic variants (PV) in autosomal recessive (AR) disorders. METHODS Variant calling of whole-genome sequencing (WGS) of 40 Druze from the Human Genome Diversity Project (HGDP) was performed (HGDP-cohort). Additionally, we performed whole exome sequencing (WES) of 118 Druze individuals: 38 trios and 2 couples, representing geographically distinct clans (WES-cohort). Rates of validated PV were compared with rates in worldwide and Middle Eastern populations, from the gnomAD and dbSNP datasets. RESULTS Overall, 34 PVs were identified: 30 PVs in genes underlying AR disorders, 3 additional PVs were associated with autosomal dominant (AD) disorders, and 1 PV with X-linked-dominant inherited disorder in the WES cohort. CONCLUSIONS The newly identified PVs associated with AR conditions should be considered for incorporation into prenatal-screening options offered to Druze individuals after an extension and validation of the results in a larger study.
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Affiliation(s)
- Eden Avnat
- Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Guy Shapira
- Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
- Edmond J. Safra Center for Bioinformatics, Tel Aviv University, Tel Aviv 69978, Israel
| | - Shelly Shoval
- The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Sheba Medical Center, Ramat Gan 52621, Israel
| | - Ifat Israel-Elgali
- Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
- Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv 69978, Israel
| | - Anna Alkelai
- Regeneron Genetics Center, Tarrytown, NY 10591, USA
| | | | - Claudia Gonzaga-Jauregui
- Regeneron Genetics Center, Tarrytown, NY 10591, USA
- International Laboratory for Human Genome Research, Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Juriquilla 04510, Querétaro, Mexico
| | - Jamal Zidan
- The Oncology Department, Ziv Medical Center, and the Azrieli Faculty of Medicine, Bar-Ilan University, Zefat 13206, Israel
| | - Taiseer Maray
- Golan for Development, Majdal Shams 1243800, Golan Heights
| | - Noam Shomron
- Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
- Edmond J. Safra Center for Bioinformatics, Tel Aviv University, Tel Aviv 69978, Israel
- Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv 69978, Israel
| | - Eitan Friedman
- Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
- The Meirav High Risk Clinic, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan 52621, Israel
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Ashkenazi Jewish and Other White APC I1307K Carriers Are at Higher Risk for Multiple Cancers. Cancers (Basel) 2022; 14:cancers14235875. [PMID: 36497357 PMCID: PMC9740723 DOI: 10.3390/cancers14235875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/25/2022] [Accepted: 11/25/2022] [Indexed: 12/02/2022] Open
Abstract
Purpose: APC I1307K has a higher prevalence among Ashkenazi Jews (AJ), and a two-fold increased risk for colorectal cancer (CRC) compared to non-Jewish populations. We assessed CRC and extracolonic malignancies among I1307K carriers from AJ and non-AJ whites (NAW). Methods: We compared the rate of I1307K in cancer patients who underwent germline genetic testing via a multi-gene panel with healthy subjects retrieved from the gnomAD database. Cases undergoing testing were not selected and testing was undertaken through a commercial laboratory. Results: Overall, 586/7624 (7.6%) AJ with cancer carried I1307K compared to 342/4918 (6.9%) in the AJ control group (p = NS). In the NAW, 318/141,673 (0.2%) cancer patients and 73/58,918 (0.1%) controls carried the variant [OR = 1.8, (95% CI 1.41−2.35), p < 0.001]. I1307K in NAW was associated with an increased risk of CRC [OR = 1.95, (95% CI 1.39−2.73), p < 0.01], melanoma [OR = 2.54, (95% CI 1.57−3.98)], breast [females, OR = 1.73, (95% CI 1.18−2.65), p < 0.01], and prostate cancer [males, OR = 2.42, (95% CI 1.45−3.94), p < 0.01]. Among AJ, the variant increased the risk for CRC [OR = 1.67, (95% CI 1.36−2.05), p < 0.001] and renal cancer [OR = 1.64, (95% CI 1.04−2.47)]. AJ men had a higher risk for any cancer [OR = 1.32, (95% CI 1.05−1.66), p < 0.05] and melanoma [OR = 2.04, (95% CI 1.24−3.22); p < 0.05]. Conclusions: This is the most extensive study to date conducted on I1307K carriers, although it is amenable to selection bias. NAW carrying I1307K had a higher risk of any cancer and several specific cancer types, whereas AJ carrying the variant had a risk for only a few select cancers. Our data add to the research base on I1307 carriers concerning future risk management.
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[Association of CDH1, FANCB and APC Gene Polymorphisms
with Lung Cancer Susceptibility in Chinese Population]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2022; 25:658-664. [PMID: 36172730 PMCID: PMC9549421 DOI: 10.3779/j.issn.1009-3419.2022.102.21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Lung cancer is the main cause of cancer-related death globally. Single nucleotide polymorphism (SNP) is one of the important factors leading to the occurrence of lung cancer, but its mechanism has not been elucidated. This study intends to investigate the relationship between SNPs of CDH1, FANCB, APC genes and lung cancer genetic susceptibility. METHODS The case-control study design was used. We collected blood samples from 270 lung cancer cases in the Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, as well as blood samples from 445 healthy volunteers as controls, and extracted genomic DNA for genotyping using the Taqman® SNP genotyping kit. The distribution of three SNP loci of CDH1 gene rs201141645, FANCB gene rs754552650 and APC gene rs149353082 in Chinese population was analyzed. Chi-square test and Logistic regression were used to analyze the relationship between different genotypes and the risk of lung cancer. RESULTS The distribution frequencies of AA, A/G and GG genotypes at rs754552650 of FANCB gene in the control group were 27.2%, 52.6% and 20.2%, respectively. The distribution frequencies of AA and A/G genotypes were 93.7% and 6.3% in the case group, respectively, and no GG genotype was detected. The A/G genotype of the rs754552650 locus of the FANCB gene was significantly different between the case group and the control group. Compared with the carriers of AA genotype, the individuals with FANCB rs754552650 A/G genotype had a lower risk of lung cancer (OR=0.035, 95%CI: 0.020-0.062, P<0.001). CDH1 gene rs201141645 A/C and CC genotypes only existed in the control group. In addition, only 1 sample was found to have APC rs149353082 genotype in the case group. CONCLUSIONS In the Chinese population, the lung cancer risk of the individuals with FANCB rs754552650 A/G genotype was significantly decreased.
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Ceyhan-Birsoy O, Jayakumaran G, Kemel Y, Misyura M, Aypar U, Jairam S, Yang C, Li Y, Mehta N, Maio A, Arnold A, Salo-Mullen E, Sheehan M, Syed A, Walsh M, Carlo M, Robson M, Offit K, Ladanyi M, Reis-Filho JS, Stadler ZK, Zhang L, Latham A, Zehir A, Mandelker D. Diagnostic yield and clinical relevance of expanded genetic testing for cancer patients. Genome Med 2022; 14:92. [PMID: 35971132 PMCID: PMC9377129 DOI: 10.1186/s13073-022-01101-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 08/03/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Genetic testing (GT) for hereditary cancer predisposition is traditionally performed on selected genes based on established guidelines for each cancer type. Recently, expanded GT (eGT) using large hereditary cancer gene panels uncovered hereditary predisposition in a greater proportion of patients than previously anticipated. We sought to define the diagnostic yield of eGT and its clinical relevance in a broad cancer patient population over a 5-year period. METHODS A total of 17,523 cancer patients with a broad range of solid tumors, who received eGT at Memorial Sloan Kettering Cancer Center between July 2015 to April 2020, were included in the study. The patients were unselected for current GT criteria such as cancer type, age of onset, and/or family history of disease. The diagnostic yield of eGT was determined for each cancer type. For 9187 patients with five common cancer types frequently interrogated for hereditary predisposition (breast, colorectal, ovarian, pancreatic, and prostate cancer), the rate of pathogenic/likely pathogenic (P/LP) variants in genes that have been associated with each cancer type was analyzed. The clinical implications of additional findings in genes not known to be associated with a patients' cancer type were investigated. RESULTS 16.7% of patients in a broad cancer cohort had P/LP variants in hereditary cancer predisposition genes identified by eGT. The diagnostic yield of eGT in patients with breast, colorectal, ovarian, pancreatic, and prostate cancer was 17.5%, 15.3%, 24.2%, 19.4%, and 15.9%, respectively. Additionally, 8% of the patients with five common cancers had P/LP variants in genes not known to be associated with the patient's current cancer type, with 0.8% of them having such a variant that confers a high risk for another cancer type. Analysis of clinical and family histories revealed that 74% of patients with variants in genes not associated with their current cancer type but which conferred a high risk for another cancer did not meet the current GT criteria for the genes harboring these variants. One or more variants of uncertain significance were identified in 57% of the patients. CONCLUSIONS Compared to targeted testing approaches, eGT can increase the yield of detection of hereditary cancer predisposition in patients with a range of tumors, allowing opportunities for enhanced surveillance and intervention. The benefits of performing eGT should be weighed against the added number of VUSs identified with this approach.
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Affiliation(s)
- Ozge Ceyhan-Birsoy
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Gowtham Jayakumaran
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yelena Kemel
- Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maksym Misyura
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Umut Aypar
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sowmya Jairam
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ciyu Yang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yirong Li
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nikita Mehta
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anna Maio
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Angela Arnold
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Erin Salo-Mullen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Margaret Sheehan
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Aijazuddin Syed
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael Walsh
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria Carlo
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mark Robson
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kenneth Offit
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Marc Ladanyi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jorge S Reis-Filho
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zsofia K Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Liying Zhang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Present Address: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Alicia Latham
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ahmet Zehir
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Present Address: Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, New York, NY, USA.
| | - Diana Mandelker
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Andrikopoulou A, Chatzinikolaou S, Kyriopoulos I, Bletsa G, Kaparelou M, Liontos M, Dimopoulos MA, Zagouri F. The Mutational Landscape of Early-Onset Breast Cancer: A Next-Generation Sequencing Analysis. Front Oncol 2022; 11:797505. [PMID: 35127508 PMCID: PMC8813959 DOI: 10.3389/fonc.2021.797505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 11/23/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Around 5%-7% of breast cancer cases are diagnosed in women younger than 40, making it the leading cause of female cancer in the 25- to 39-year-old age group. Unfortunately, young age at diagnosis is linked to a more aggressive tumor biology and a worse clinical outcome. The identification of the mutational landscape of breast cancer in this age group could optimize the management. METHODS We performed NGS analysis in paraffin blocks and blood samples of 32 young patients with breast cancer [<40 years] and 90 older patients during the period 2019 through 2021. All patients were treated in a single institution at the Oncology Department of "Alexandra" Hospital, Medical School, University of Athens, Greece. RESULTS Breast tumors were characterized more frequently by HER2 overexpression [25% vs 18.9%], higher ki67 levels [75% vs 61%] and lower differentiation [71.9% vs 60%] in the younger group. PIK3CA [6/20; 30%] and TP53 [6/20; 30%] were the most frequent pathogenic somatic mutations identified in young patients, while one case of BRCA2 somatic mutation [1/20; 5%] and one case of PTEN somatic mutation [1/20; 5%] were also identified. PIK3CA mutations [16/50; 32%] and TP53 mutations [20/50; 40%] were the most common somatic mutations identified in older patients, however other somatic mutations were also reported (ATM, AKT, CHEK2, NRAS, CDKN2A, PTEN, NF1, RB1, FGFR1, ERBB2). As for germline mutations, CHEK2 [3/25; 12%] was the most common pathogenic germline mutation in younger patients followed by BRCA1 [2/25; 8%]. Of note, CHEK2 germline mutations were identified less frequently in older patients [2/61; 3%] among others [BRCA1 (2/61; 3%), ATM (2/61; 3%), APC (1/61; 1,6%) and BRCA2 (1/61; 1,6%)]. CONCLUSION We here report the mutational profile identified via NGS in patients with early-onset breast cancer compared to their older counterparts. Although the sample size is small and no statistically significant differences were detected, we highlight the need of genetic testing to most patients in this subgroup.
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Affiliation(s)
| | | | - Ilias Kyriopoulos
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, Athens, Greece
| | | | - Maria Kaparelou
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, Athens, Greece
| | - Michalis Liontos
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, Athens, Greece
| | | | - Flora Zagouri
- Department of Clinical Therapeutics, Alexandra Hospital, Medical School, Athens, Greece
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Long JM, Powers JM, Katona BW. Evaluation of Classic, Attenuated, and Oligopolyposis of the Colon. Gastrointest Endosc Clin N Am 2022; 32:95-112. [PMID: 34798989 PMCID: PMC8607742 DOI: 10.1016/j.giec.2021.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The goal of this review is to provide an overview of evaluating patients with adenomatous polyposis of the colon, including elements such as generating a differential diagnosis, referral considerations for genetic testing, genetic testing options, and expected outcomes from genetic testing in these individuals. In more recent years, adenomatous colonic polyposis has evolved beyond the more robustly characterized familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) now encompassing more newly described genes and associated syndromes. Technological innovation, from whole-exome sequencing to multigene panel testing, has dramatically increased the amount of genotypic and phenotypic data amassed in adenomatous polyposis cohorts, which has contributed greatly to informing diagnosis and clinical management of affected individuals and their families.
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Affiliation(s)
- Jessica M. Long
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Jacquelyn M. Powers
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Bryson W. Katona
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
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10
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Srinivasan P, Bandlamudi C, Jonsson P, Kemel Y, Chavan SS, Richards AL, Penson AV, Bielski CM, Fong C, Syed A, Jayakumaran G, Prasad M, Hwee J, Sumer SO, de Bruijn I, Li X, Gao J, Schultz N, Cambria R, Galle J, Mukherjee S, Vijai J, Cadoo KA, Carlo MI, Walsh MF, Mandelker D, Ceyhan-Birsoy O, Shia J, Zehir A, Ladanyi M, Hyman DM, Zhang L, Offit K, Robson ME, Solit DB, Stadler ZK, Berger MF, Taylor BS. The context-specific role of germline pathogenicity in tumorigenesis. Nat Genet 2021; 53:1577-1585. [PMID: 34741162 PMCID: PMC8957388 DOI: 10.1038/s41588-021-00949-1] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 09/09/2021] [Indexed: 11/08/2022]
Abstract
Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management.
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Affiliation(s)
- Preethi Srinivasan
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Stanford University School of Medicine, Palo Alto, CA, USA
| | - Chaitanya Bandlamudi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Philip Jonsson
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yelena Kemel
- Robert and Kate Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Shweta S Chavan
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Allison L Richards
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alexander V Penson
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Craig M Bielski
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Christopher Fong
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Aijazuddin Syed
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Gowtham Jayakumaran
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Meera Prasad
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jason Hwee
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Selcuk Onur Sumer
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ino de Bruijn
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Xiang Li
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - JianJiong Gao
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nikolaus Schultz
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Roy Cambria
- Research and Technology Management, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jesse Galle
- Research and Technology Management, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Semanti Mukherjee
- Robert and Kate Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Joseph Vijai
- Robert and Kate Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Karen A Cadoo
- Robert and Kate Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria I Carlo
- Robert and Kate Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael F Walsh
- Robert and Kate Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Diana Mandelker
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ozge Ceyhan-Birsoy
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ahmet Zehir
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Marc Ladanyi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David M Hyman
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Loxo Oncology, Stamford, CT, USA
| | - Liying Zhang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Kenneth Offit
- Robert and Kate Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mark E Robson
- Robert and Kate Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David B Solit
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zsofia K Stadler
- Robert and Kate Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael F Berger
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Barry S Taylor
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Loxo Oncology, Stamford, CT, USA
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11
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Rosenblum A, Springer M, Eppolito A, Axell L, Mohler L. Homozygous Germline APC p.I1307K Variants: A Case Series. Case Rep Oncol 2021; 14:1295-1303. [PMID: 34720931 PMCID: PMC8460922 DOI: 10.1159/000518683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 07/18/2021] [Indexed: 11/25/2022] Open
Abstract
Approximately 10% of all colorectal cancer is estimated to be due to an inherited predisposition. Identification of a germline pathogenic variant can aid in treatment, screening, and surveillance and help stratify familial cancer risks based on gene-specific cancer associations. The APC gene contributes to a small percentage of hereditary colon cancer, with most pathogenic APC variants causing familial adenomatous polyposis syndrome. However, one specific variant in APC called p.I1307K, found in approximately 10% of Ashkenazi Jewish individuals, is associated with a moderate risk for colon cancer, but not polyposis. Heterozygous carriers of one p.I1307K variant are well documented in the literature, and guidelines recommend earlier and more frequent colonoscopies. Conversely, reports of homozygous carriers of 2 p.I1307K variants are limited, and guidelines for medical management are lacking. This case series describes 4 homozygous p.I1307K patients of Ashkenazi Jewish ancestry identified in cancer genetics clinics. Case 1 is a 73-year-old pancreatic cancer patient with a family history of melanoma and colon cancer. Case 2 is a 62-year-old patient with a personal history of 4 adenomatous colorectal polyps and a family history of breast, pancreatic, colon, and prostate cancers. Case 3 is a 52-year-old patient with a personal history of early-onset breast cancer and uveal melanoma and a family history of breast, prostate, and stomach cancers. Case 4 is a 70-year-old patient with a personal history of gallbladder adenocarcinoma and a family history of breast cancer. These cases exhibit wide phenotypic variability and contribute to the limited reports of homozygous p.I1307K variant carriers.
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Affiliation(s)
- Alexa Rosenblum
- Banner Health University of Arizona Cancer Center, Tucson, Arizona, USA
| | - Michelle Springer
- University of Colorado Hereditary Cancer Clinic, Denver, Colorado, USA
| | - Amanda Eppolito
- Piedmont Healthcare Cancer Genetics Program, Atlanta, Georgia, USA
| | - Lisen Axell
- University of Colorado Hereditary Cancer Clinic, Denver, Colorado, USA
| | - Lisa Mohler
- University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, USA
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12
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Elfatih A, Mifsud B, Syed N, Badii R, Mbarek H, Abbaszadeh F, Estivill X. Actionable genomic variants in 6045 participants from the Qatar Genome Program. Hum Mutat 2021; 42:1584-1601. [PMID: 34428338 DOI: 10.1002/humu.24278] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 08/18/2021] [Accepted: 08/20/2021] [Indexed: 01/26/2023]
Abstract
In a clinical setting, DNA sequencing can uncover findings unrelated to the purpose of genetic evaluation. The American College of Medical Genetics and Genomics (ACMG) recommends the evaluation and reporting of 59 genes from clinic genomic sequencing. While the prevalence of secondary findings is available from large population studies, these data lack Arab and other Middle Eastern populations. The Qatar Genome Program (QGP) generates whole-genome sequencing (WGS) data and combines it with phenotypic information to create a comprehensive database for studying the Qatari and wider Arab and Middle Eastern populations at the molecular level. This study identified and analyzed medically actionable variants in the 59 ACMG genes using WGS data from 6045 QGP participants. Our results identified a total of 60 pathogenic and likely pathogenic variants in 25 ACMG genes in 141 unique individuals. Overall, 2.3% of the QGP sequenced participants carried a pathogenic or likely pathogenic variant in one of the 59 ACMG genes. We evaluated the QGP phenotype-genotype association of additional nonpathogenic ACMG variants. These variants were found in patients from the Hamad Medical Corporation or reported incidental findings data in Qatar. We found a significant phenotype association for two variants, c.313+3A>C in LDLR, and c.58C>T (p.Gln20*) in the TPM1.
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Affiliation(s)
- Amal Elfatih
- Genomics and Precision Medicine, College of Health and Life Science, Hamad Bin Khalifa University, Doha, Qatar
| | - Borbala Mifsud
- Genomics and Precision Medicine, College of Health and Life Science, Hamad Bin Khalifa University, Doha, Qatar
- William Harvey Research Institute, Queen Mary University London, London, UK
| | - Najeeb Syed
- Applied Bioinformatics Core, Integrated Genomics Services, Research Branch, Sidra Medicine, Doha, Qatar
| | - Ramin Badii
- Molecular Genetics Laboratory, Hamad Medical Corporation, Doha, Qatar
| | - Hamdi Mbarek
- Qatar Genome Program, Qatar Foundation Research, Development and Innovation, Qatar Foundation, Doha, Qatar
| | | | - Xavier Estivill
- Research Department, T'havia Quantitative Genomics Laboratories (qGenomics), Barcelona, Spain
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13
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Haverfield EV, Esplin ED, Aguilar SJ, Hatchell KE, Ormond KE, Hanson-Kahn A, Atwal PS, Macklin-Mantia S, Hines S, Sak CWM, Tucker S, Bleyl SB, Hulick PJ, Gordon OK, Velsher L, Gu JYJ, Weissman SM, Kruisselbrink T, Abel C, Kettles M, Slavotinek A, Mendelsohn BA, Green RC, Aradhya S, Nussbaum RL. Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study. BMC Med 2021; 19:199. [PMID: 34404389 PMCID: PMC8371767 DOI: 10.1186/s12916-021-01999-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/29/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. METHODS Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates' correction. RESULTS Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. CONCLUSIONS This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.
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Affiliation(s)
| | | | | | | | - Kelly E Ormond
- Stanford University School of Medicine, Stanford, CA, USA
| | | | - Paldeep S Atwal
- Mayo Clinic, Jacksonville, FL, USA.,Atwal Clinic, Palm Beach, FL, USA.,PWNHealth, New York, NY, USA
| | | | | | | | | | | | | | - Ora K Gordon
- Providence Research Network, St John Cancer Institute, Los Angeles, CA, USA.,University of California, Los Angeles, CA, USA
| | | | | | - Scott M Weissman
- Genome Medical, San Francisco, CA, USA.,Chicago Genetic Consultants, Northbrook, IL, USA
| | | | | | | | - Anne Slavotinek
- University of California San Francisco, San Francisco, CA, USA
| | | | - Robert C Green
- Brigham and Women's Hospital, Boston, MA, USA.,The Broad Institute, Boston, MA, USA.,Ariadne Labs, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | | | - Robert L Nussbaum
- Invitae, 1400 16th Street, San Francisco, CA, 94103, USA.,Volunteer Faculty, University of California San Francisco, San Francisco, CA, USA
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14
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Bernstein-Molho R, Galmor L, Laitman Y, Segev S, Friedman E. Yield of targeted genotyping for the recurring pathogenic variants in cancer susceptibility genes in a healthy, multiethnic Israeli population. Cancer 2021; 127:3599-3604. [PMID: 34157778 DOI: 10.1002/cncr.33560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/08/2021] [Accepted: 03/12/2021] [Indexed: 11/07/2022]
Abstract
BACKGROUND Several recurring pathogenic variants in BRCA1/BRCA2 and other cancer susceptibility genes are encountered in ethnically diverse Jewish populations. The yield of genotyping for these recurring pathogenic variants in healthy Israeli individuals unselected for ethnicity, sex, or a family history of cancer has not been previously reported. METHODS Individuals voluntarily participating in annual medical surveillance at the Institute of Medical Screening of Sheba Medical Center were offered genotyping for predominant pathogenic variants in BRCA1/BRCA2 and recurring variants in CHEK2, MUTYH, APC, and the Lynch syndrome genes via a chip-based assay at the oncogenetic service of Sheba Medical Center from May 15, 2018, to December 15, 2020. All study participants were unrelated to one another. The study was approved by the Sheba ethics committee. RESULTS Overall, 1764 individuals, including 1008 females (57%), with a mean age of 54.2 years (range, 25-86 years) were genotyped. The yield of the testing was 4% (71 of 1764), and it was higher in Ashkenazi Jews (AJs) and mixed AJ-non-AJ participants (4.75% [58 of 1222]; 1.8% for BRCA1/BRCA2 pathogenic variants) than non-AJ patients (2.2% [9 of 401]; 1% for BRCA1 pathogenic variants). When BRCA1/BRCA2 pathogenic variants were excluded, 2.44% carried low-penetrance variants, including CHEK2 c.1283C>T (n = 3), APC c.3920T>A (n = 36), and heterozygous MUTYH c.1187G>A (n = 4). A family history of cancer was not associated with a higher yield of pathogenic variant detection. CONCLUSIONS The observed rates of positive genotyping in a healthy, unselected, multiethnic Israeli population warrant consideration of the inclusion of targeted genotyping of selected pathogenic variants in high-penetrance and perhaps lower penetrance cancer susceptibility genes for all Jewish individuals in Israel, regardless of their ethnicity or family history of cancer.
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Affiliation(s)
- Rinat Bernstein-Molho
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,Breast Cancer Unit, Oncology Institute, Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Lee Galmor
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Yael Laitman
- Oncogenetics Unit, Institute of Genetics, Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Shlomo Segev
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,Institute of Medical Screening, Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Eitan Friedman
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,Oncogenetics Unit, Institute of Genetics, Chaim Sheba Medical Center, Tel-Hashomer, Israel
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15
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Heald B, Hampel H, Church J, Dudley B, Hall MJ, Mork ME, Singh A, Stoffel E, Stoll J, You YN, Yurgelun MB, Kupfer SS. Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position statement on multigene panel testing for patients with colorectal cancer and/or polyposis. Fam Cancer 2021; 19:223-239. [PMID: 32172433 DOI: 10.1007/s10689-020-00170-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Multigene panel tests for hereditary cancer syndromes are increasingly utilized in the care of colorectal cancer (CRC) and polyposis patients. However, widespread availability of panels raises a number of questions including which patients should undergo testing, which genes should be included on panels, and the settings in which panels should be ordered and interpreted. To address this knowledge gap, key questions regarding the major issues encountered in clinical evaluation of hereditary CRC and polyposis were designed by the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position Statement Committee and leadership. A literature search was conducted to address these questions. Recommendations were based on the best available evidence and expert opinion. This position statement addresses which genes should be included on a multigene panel for a patient with a suspected hereditary CRC or polyposis syndrome, proposes updated genetic testing criteria, discusses testing approaches for patients with mismatch repair proficient or deficient CRC, and outlines the essential elements for ordering and disclosing multigene panel test results. We acknowledge that critical gaps in access, insurance coverage, resources, and education remain barriers to high-quality, equitable care for individuals and their families at increased risk of hereditary CRC.
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Affiliation(s)
- Brandie Heald
- Sanford R Weiss, MD, Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, USA.
| | - Heather Hampel
- Division of Human Genetics, Department of Internal Medicine and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - James Church
- Sanford R Weiss, MD, Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, USA
| | - Beth Dudley
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Michael J Hall
- Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Maureen E Mork
- Department of Clinical Cancer Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Aparajita Singh
- Department of Medicine, Division of Gastroenterology, University of California San Francisco, San Francisco, CA, USA
| | - Elena Stoffel
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jessica Stoll
- Gastrointestinal Cancer Risk and Prevention Clinic, University of Chicago, Chicago, IL, USA
| | - Y Nancy You
- Department of Clinical Cancer Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Matthew B Yurgelun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sonia S Kupfer
- Gastrointestinal Cancer Risk and Prevention Clinic, University of Chicago, Chicago, IL, USA
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16
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Belbin GM, Cullina S, Wenric S, Soper ER, Glicksberg BS, Torre D, Moscati A, Wojcik GL, Shemirani R, Beckmann ND, Cohain A, Sorokin EP, Park DS, Ambite JL, Ellis S, Auton A, Bottinger EP, Cho JH, Loos RJF, Abul-Husn NS, Zaitlen NA, Gignoux CR, Kenny EE. Toward a fine-scale population health monitoring system. Cell 2021; 184:2068-2083.e11. [PMID: 33861964 DOI: 10.1016/j.cell.2021.03.034] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/18/2020] [Accepted: 03/12/2021] [Indexed: 12/22/2022]
Abstract
Understanding population health disparities is an essential component of equitable precision health efforts. Epidemiology research often relies on definitions of race and ethnicity, but these population labels may not adequately capture disease burdens and environmental factors impacting specific sub-populations. Here, we propose a framework for repurposing data from electronic health records (EHRs) in concert with genomic data to explore the demographic ties that can impact disease burdens. Using data from a diverse biobank in New York City, we identified 17 communities sharing recent genetic ancestry. We observed 1,177 health outcomes that were statistically associated with a specific group and demonstrated significant differences in the segregation of genetic variants contributing to Mendelian diseases. We also demonstrated that fine-scale population structure can impact the prediction of complex disease risk within groups. This work reinforces the utility of linking genomic data to EHRs and provides a framework toward fine-scale monitoring of population health.
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Affiliation(s)
- Gillian M Belbin
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Sinead Cullina
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Stephane Wenric
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Emily R Soper
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Benjamin S Glicksberg
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Denis Torre
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Arden Moscati
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Genevieve L Wojcik
- Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA
| | - Ruhollah Shemirani
- Information Science Institute, University of Southern California, Marina del Rey, CA 90089, USA
| | - Noam D Beckmann
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ariella Cohain
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Elena P Sorokin
- Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA
| | - Danny S Park
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Jose-Luis Ambite
- Information Science Institute, University of Southern California, Marina del Rey, CA 90089, USA
| | - Steve Ellis
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Adam Auton
- Department of Genetics, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Erwin P Bottinger
- Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Judy H Cho
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ruth J F Loos
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Noura S Abul-Husn
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Noah A Zaitlen
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90033, USA
| | - Christopher R Gignoux
- Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Eimear E Kenny
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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A clinical study of newly-diagnosed colorectal cancer over 2 years in a gastroenterology center in Iraq. JOURNAL OF COLOPROCTOLOGY 2021. [DOI: 10.1016/j.jcol.2019.05.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Abstract
Background and study aims Colorectal cancer (CRC) is the most common gastrointestinal cancer and the third most commonly diagnosed malignancy affecting about one million individuals each year. The etiology for most cases of CRC appears to be related to environmental factors. This study to describe the main characteristics of this malignancy regarding age, gender, and anatomical sub site distribution, as well as the main presenting symptoms in Iraqi patients.
Patients and methods Patients with newly-diagnosed CRC by colonoscopy findings and confirmed by histopathological examination of endoscopic colonic biopsies were studied.
Results Sixty three cases with a newly-diagnosed CRC were included in this study. There were 31 (49.2%) males and 32 (50.8%) females. CRC peaked in the 60–69 years old age group (p < 0.05), more than 60% were between 40 and 69 years old. Fresh bleeding per rectum was the most common symptom occurred in 48 (76.2%) patients; while the least common was weight loss (19%). The mean duration of symptoms before referral was 7.3 ± 12.6 months. The tumor sites of the CRC were the rectum and sigmoid region seen in 77.8% (p < 0.05), the rectum alone reported in 37 patients (58.7%); followed by sigmoid colon in 12 (19%) patients, cecum in 7 (11.1%) patients and the ascending colon seen in 2 (3.2%) patients.
Conclusions In this study CRC occurs in relatively younger age groups in comparison to studies in the developed countries with rectal cancer predominates of all colorectal cancers.
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The impact of APC polymorphisms on the transition from polyps to colorectal cancer (CRC). Gene 2020; 740:144486. [PMID: 32087273 DOI: 10.1016/j.gene.2020.144486] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 02/17/2020] [Accepted: 02/18/2020] [Indexed: 11/24/2022]
Abstract
OBJECTIVE The purpose of this study was to investigate the function of APC polymorphisms (D1822V and E1317Q) on the transition from polyps to colorectal cancer (CRC). METHODS 259 patients with polyps were included in the study. APC polymorphisms were genotyped via polymerase chain reaction (PCR) and subsequent sequencing. χ2 test was performed to analyze the relationship of APC polymorphisms or CRC occurrence with clinical features. COX regression was used to find out risk factors for CRC. Hazard ratio (HR) and 95% confidence interval (CI) represented the risk of CRC. RESULTS Clinical information on sex, regular physical activity, smoking history, alcohol use and polyps types was recorded. Neither D1822V nor E1317Q polymorphism was associated with these factors. In following analysis, we found significant difference in the frequency of males between CRC and non-CRC patients (87.4% vs. 58.7%, P < 0.001). Distinct difference in the distribution of D1822V polymorphism was also observed between CRC and non-CRC patients (P = 0.001). In COX analysis, sex was identified as a risk factor for transition from polyps to CRC (HR = 2.442, 95%CI = 1.281-4.654). D1822V polymorphism tended to inhibit the transition process (HR = 0.286, 95%CI = 0.170-0.480). However, E1317Q seemed to have no significant effect on this process (HR = 1.042, 95%CI = 0.676-1.606). CONCLUSION In a word, APC D1822V polymorphism has strong effect on the transition from polyps to CRC.
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19
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Riggs ER, Andersen EF, Kantarci S, Kearney H, Patel A, Raca G, Ritter DI, South ST, Thorland EC, Pineda-Alvarez D, Aradhya S, Martin CL. Response to Maya et al. Genet Med 2020; 22:1278-1279. [PMID: 32341575 DOI: 10.1038/s41436-020-0796-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 03/27/2020] [Indexed: 11/09/2022] Open
Affiliation(s)
- Erin Rooney Riggs
- Autism & Developmental Medicine Institute, Geisinger, Danville, PA, USA
| | - Erica F Andersen
- ARUP Laboratories, Salt Lake City, UT, USA.,University of Utah, Salt Lake City, UT, USA
| | - Sibel Kantarci
- Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA
| | - Hutton Kearney
- Genomics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | | | - Gordana Raca
- Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Deborah I Ritter
- Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | | | - Erik C Thorland
- Genomics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | | | - Swaroop Aradhya
- Invitae, San Francisco, CA, USA.,Stanford University School of Medicine, Stanford, CA, USA
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20
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Diagnostic yield of multigene panel testing in an Israeli cohort: enrichment of low-penetrance variants. Breast Cancer Res Treat 2020; 181:445-453. [DOI: 10.1007/s10549-020-05633-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 04/07/2020] [Indexed: 01/09/2023]
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21
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Hong JT, Kim ER. Current state and future direction of screening tool for colorectal cancer. World J Meta-Anal 2019; 7:184-208. [DOI: 10.13105/wjma.v7.i5.184] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 05/25/2019] [Accepted: 05/28/2019] [Indexed: 02/06/2023] Open
Abstract
As the second-most-common cause of cancer death, colorectal cancer (CRC) has been recognized as one of the biggest health concerns in advanced countries. The 5-year survival rate for patients with early-stage CRC is significantly better than that for patients with CRC detected at a late stage. The primary target for CRC screening and prevention is advanced neoplasia, which includes both CRC itself, as well as benign but histologically advanced adenomas that are at increased risk for progression to malignancy. Prevention of CRC through detection of advanced adenomas is important. It is, therefore, necessary to develop more efficient detection methods to enable earlier detection and therefore better prognosis. Although a number of CRC diagnostic methods are currently used for early detection, including stool-based tests, traditional colonoscopy, etc., they have not shown optimal results due to several limitations. Hence, development of more reliable screening methods is required in order to detect the disease at an early stage. New screening tools also need to be able to accurately diagnose CRC and advanced adenoma, help guide treatment, and predict the prognosis along with being relatively simple and non-invasive. As part of such efforts, many proposals for the early detection of colorectal neoplasms have been introduced. For example, metabolomics, referring to the scientific study of the metabolism of living organisms, has been shown to be a possible approach for discovering CRC-related biomarkers. In addition, a growing number of high-performance screening methodologies could facilitate biomarker identification. In the present, evidence-based review, the authors summarize the current state as recognized by the recent guideline recommendation from the American Cancer Society, US Preventive Services Task Force and the United States Multi-Society Task Force and discuss future direction of screening tools for colorectal cancer. Further, we highlight the most interesting publications on new screening tools, like molecular biomarkers and metabolomics, and discuss these in detail.
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Affiliation(s)
- Ji Taek Hong
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon 24253, South Korea
| | - Eun Ran Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
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22
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El Shamieh S, Saleh F, Assaad S, Farhat F. Next-generation sequencing reveals mutations in RB1, CDK4 and TP53 that may promote chemo-resistance to palbociclib in ovarian cancer. Drug Metab Pers Ther 2019; 34:/j/dmdi.ahead-of-print/dmpt-2018-0027/dmpt-2018-0027.xml. [PMID: 31145688 DOI: 10.1515/dmpt-2018-0027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 03/13/2019] [Indexed: 12/18/2022]
Abstract
Because of the profound heterogeneity of ovarian cancer at the clinical, cellular and molecular levels, herein we discuss the molecular findings at the protein and genetic levels seen in our patient. Immunohistochemistry showed a complete loss of phosphatase and tensin homolog, this observation was the reason behind prescribing the CDK4/6 inhibitor palbociclib. However, there was no response to treatment. Next-generation sequencing analysis was performed showing a nonsense mutation, p.R552X in retinoblastoma 1 (RB1). This nonsense variation will possibly lead to a truncated protein lacking the domain responsible for interaction with E2F, an event that will induce cell cycle progression and, thus, be responsible for the chemo-resistance to palbociclib.
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Affiliation(s)
- Said El Shamieh
- Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon
| | - Fatima Saleh
- Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon
| | - Shafka Assaad
- Rammal Hassan Rammal Research Laboratory, Physiotoxicity (PhyTox), Faculty of Sciences, Lebanese University, Nabatieh, Lebanon
| | - Fadi Farhat
- Department of Hematology-Oncology, Saint Joseph Faculty of Medicine, Beirut, Lebanon.,Department of Hematology and Oncology, Hammoud Hospital UMC, Saida, Lebanon, Phone: +9613753155
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23
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Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. Int J Cancer 2019; 145:390-400. [DOI: 10.1002/ijc.32106] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 11/29/2018] [Accepted: 12/21/2018] [Indexed: 12/26/2022]
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Vacante M, Borzì AM, Basile F, Biondi A. Biomarkers in colorectal cancer: Current clinical utility and future perspectives. World J Clin Cases 2018; 6:869-881. [PMID: 30568941 PMCID: PMC6288499 DOI: 10.12998/wjcc.v6.i15.869] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 10/30/2018] [Accepted: 11/07/2018] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is a major cause of cancer death worldwide. CRC has poor prognosis and there is a crucial need for new diagnostic and prognostic biomarkers to avoid CRC-related deaths. CRC can be considered a sporadic disease in most cases (75%-80%), but it has been suggested that crosstalk between gene mutations (i.e., mutations of BRAF, KRAS, and p53 as well as microsatellite instability) and epigenetic alterations (i.e., DNA methylation of CpG island promoter regions) could play a pivotal role in cancer development. A number of studies have focused on molecular testing to guide targeted and conventional treatments for patients with CRC, sometimes with contrasting results. Some of the most useful innovations in the management of CRC include the possibility to detect the absence of KRAS, BRAF, NRAS and PIK3CA gene mutations with the subsequent choice to administer targeted adjuvant therapy with anti-epidermal growth factor receptor antibodies. Moreover, CRC patients can benefit from tests for microsatellite instability and for the detection of loss of heterozygosity of chromosome 18q that can be helpful in guiding therapeutic decisions as regards the administration of 5-FU. The aim of this review was to summarize the most recent evidence on the possible use of genetic or epigenetic biomarkers for diagnosis, prognosis and response to therapy in CRC patients.
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Affiliation(s)
- Marco Vacante
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Antonio Maria Borzì
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Francesco Basile
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Antonio Biondi
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
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25
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Rego S, Dagan-Rosenfeld O, Zhou W, Sailani MR, Limcaoco P, Colbert E, Avina M, Wheeler J, Craig C, Salins D, Röst HL, Dunn J, McLaughlin T, Steinmetz LM, Bernstein JA, Snyder MP. High-frequency actionable pathogenic exome variants in an average-risk cohort. Cold Spring Harb Mol Case Stud 2018; 4:a003178. [PMID: 30487145 PMCID: PMC6318774 DOI: 10.1101/mcs.a003178] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Accepted: 09/10/2018] [Indexed: 12/19/2022] Open
Abstract
Exome sequencing is increasingly utilized in both clinical and nonclinical settings, but little is known about its utility in healthy individuals. Most previous studies on this topic have examined a small subset of genes known to be implicated in human disease and/or have used automated pipelines to assess pathogenicity of known variants. To determine the frequency of both medically actionable and nonactionable but medically relevant exome findings in the general population we assessed the exomes of 70 participants who have been extensively characterized over the past several years as part of a longitudinal integrated multiomics profiling study. We analyzed exomes by identifying rare likely pathogenic and pathogenic variants in genes associated with Mendelian disease in the Online Mendelian Inheritance in Man (OMIM) database. We then used American College of Medical Genetics (ACMG) guidelines for the classification of rare sequence variants. Additionally, we assessed pharmacogenetic variants. Twelve out of 70 (17%) participants had medically actionable findings in Mendelian disease genes. Five had phenotypes or family histories associated with their genetic variants. The frequency of actionable variants is higher than that reported in most previous studies and suggests added benefit from utilizing expanded gene lists and manual curation to assess actionable findings. A total of 63 participants (90%) had additional nonactionable findings, including 60 who were found to be carriers for recessive diseases and 21 who have increased Alzheimer's disease risk because of heterozygous or homozygous APOE e4 alleles (18 participants had both). Our results suggest that exome sequencing may have considerably more utility for health management in the general population than previously thought.
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Affiliation(s)
- Shannon Rego
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Orit Dagan-Rosenfeld
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Wenyu Zhou
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
| | - M Reza Sailani
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Patricia Limcaoco
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Elizabeth Colbert
- Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Monika Avina
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Jessica Wheeler
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Colleen Craig
- Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Denis Salins
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Hannes L Röst
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Jessilyn Dunn
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
- Mobilize Center, Stanford University, Stanford, California 94305, USA
| | - Tracey McLaughlin
- Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Lars M Steinmetz
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
- Stanford Genome Technology Center, Stanford University, Palo Alto, California 94304, USA
- European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany
| | - Jonathan A Bernstein
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Michael P Snyder
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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26
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Bonache S, Esteban I, Moles-Fernández A, Tenés A, Duran-Lozano L, Montalban G, Bach V, Carrasco E, Gadea N, López-Fernández A, Torres-Esquius S, Mancuso F, Caratú G, Vivancos A, Tuset N, Balmaña J, Gutiérrez-Enríquez S, Diez O. Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings. J Cancer Res Clin Oncol 2018; 144:2495-2513. [PMID: 30306255 DOI: 10.1007/s00432-018-2763-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 10/01/2018] [Indexed: 12/15/2022]
Abstract
PURPOSE Few and small studies have been reported about multigene testing usage by massively parallel sequencing in European cancer families. There is an open debate about what genes should be tested, and the actionability of some included genes is under research. METHODS We investigated a panel of 34 known high/moderate-risk cancer genes, including 16 related to breast or ovarian cancer (BC/OC) genes, and 63 candidate genes to BC/OC in 192 clinically suspicious of hereditary breast/ovarian cancer (HBOC) Spanish families without pathogenic variants in BRCA1 or BRCA2 (BRCA1/2). RESULTS We identified 16 patients who carried a high- or moderate-risk pathogenic variant in eight genes: 4 PALB2, 3 ATM, 2 RAD51D, 2 TP53, 2 APC, 1 BRIP1, 1 PTEN and 1 PMS2. These findings led to increased surveillance or prevention options in 12 patients and predictive testing in their family members. We detected 383 unique variants of uncertain significance in known cancer genes, of which 35 were prioritized in silico. Eighteen loss-of-function variants were detected in candidate BC/OC genes in 17 patients (1 BARD1, 1 ERCC3, 1 ERCC5, 2 FANCE, 1 FANCI, 2 FANCL, 1 FANCM, 1 MCPH1, 1 PPM1D, 2 RBBP8, 3 RECQL4 and 1 with SLX4 and XRCC2), three of which also carry pathogenic variants in known cancer genes. CONCLUSIONS Eight percent of the BRCA1/2 negative patients carry pathogenic variants in other actionable genes. The multigene panel usage improves the diagnostic yield in HBOC testing and it is an effective tool to identify potentially new candidate genes.
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Affiliation(s)
- Sandra Bonache
- Oncogenetics Group, Vall d'Hebron Institute of Oncology-VHIO, Lab 2.02A, CELLEX CENTER, c/Natzaret, 115-117, 08035, Barcelona, Catalonia, Spain
| | - Irene Esteban
- High Risk and Cancer Prevention Group, VHIO, Barcelona, Spain
- Genetics and Microbiology Department, Universitat Autònoma de Barcelona, Campus UAB, Bellaterra, Spain
| | - Alejandro Moles-Fernández
- Oncogenetics Group, Vall d'Hebron Institute of Oncology-VHIO, Lab 2.02A, CELLEX CENTER, c/Natzaret, 115-117, 08035, Barcelona, Catalonia, Spain
| | - Anna Tenés
- Area of Clinical and Molecular Genetics, University Hospital of Vall d'Hebron, Barcelona, Spain
| | - Laura Duran-Lozano
- Oncogenetics Group, Vall d'Hebron Institute of Oncology-VHIO, Lab 2.02A, CELLEX CENTER, c/Natzaret, 115-117, 08035, Barcelona, Catalonia, Spain
| | - Gemma Montalban
- Oncogenetics Group, Vall d'Hebron Institute of Oncology-VHIO, Lab 2.02A, CELLEX CENTER, c/Natzaret, 115-117, 08035, Barcelona, Catalonia, Spain
| | - Vanessa Bach
- Oncogenetics Group, Vall d'Hebron Institute of Oncology-VHIO, Lab 2.02A, CELLEX CENTER, c/Natzaret, 115-117, 08035, Barcelona, Catalonia, Spain
| | - Estela Carrasco
- High Risk and Cancer Prevention Group, VHIO, Barcelona, Spain
| | - Neus Gadea
- High Risk and Cancer Prevention Group, VHIO, Barcelona, Spain
- Medical Oncology Department, University Hospital of Vall d'Hebron, Barcelona, Spain
| | | | | | - Francesco Mancuso
- Cancer Genomics Group, Vall d'Hebron Institute of Oncology, VHIO, Barcelona, Spain
| | - Ginevra Caratú
- Cancer Genomics Group, Vall d'Hebron Institute of Oncology, VHIO, Barcelona, Spain
| | - Ana Vivancos
- Cancer Genomics Group, Vall d'Hebron Institute of Oncology, VHIO, Barcelona, Spain
| | - Noemí Tuset
- Medical Oncology Department, Hospital Universitari Arnau de Vilanova, Lleida, Spain
| | - Judith Balmaña
- High Risk and Cancer Prevention Group, VHIO, Barcelona, Spain
- Medical Oncology Department, University Hospital of Vall d'Hebron, Barcelona, Spain
| | - Sara Gutiérrez-Enríquez
- Oncogenetics Group, Vall d'Hebron Institute of Oncology-VHIO, Lab 2.02A, CELLEX CENTER, c/Natzaret, 115-117, 08035, Barcelona, Catalonia, Spain.
| | - Orland Diez
- Oncogenetics Group, Vall d'Hebron Institute of Oncology-VHIO, Lab 2.02A, CELLEX CENTER, c/Natzaret, 115-117, 08035, Barcelona, Catalonia, Spain.
- Area of Clinical and Molecular Genetics, University Hospital of Vall d'Hebron, Barcelona, Spain.
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27
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Cox DM, Nelson KL, Clytone M, Collins DL. Hereditary cancer screening: Case reports and review of literature on ten Ashkenazi Jewish founder mutations. Mol Genet Genomic Med 2018; 6:1236-1242. [PMID: 30152102 PMCID: PMC6305650 DOI: 10.1002/mgg3.460] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 07/03/2018] [Accepted: 07/20/2018] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Historically, three founder mutations in the BRCA1/2 (OMIM 113705; OMIM 600185) genes have been the focus of cancer risks within the Ashkenazi Jewish (AJ) population. However, there are several additional mutations associated with increased susceptibility to cancer in individuals of AJ ancestry. METHODS We report three patients who exemplify the need to keep these additional founder mutations in mind when pursuing hereditary cancer genetic testing of individuals in this population. All gene sequences in this paper were aligned to reference sequences based on human genome build GRCh37/UCSC hg19. RESULTS review of the literature discusses that the combined risk is 12.36%-20.83% forhaving 1 of the 10 hereditary cancer AJ founder mutations in the BRCA1, BRCA2, CHEK2 (OMIM 604373), APC (OMIM 611731), MSH2 (OMIM 609309), MSH6 (OMIM 600678), and GREM1 (OMIM 603054) genes for individuals of AJ ancestry. CONCLUSION We recommend testing for all 10 of these AJ founder cancer susceptibility mutations for individuals within this population as standard screening in order to ensure appropriate cancer risk management and cascade testing.
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Affiliation(s)
- Devin M. Cox
- University of Kansas Cancer CenterWestwoodKansas
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28
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Heparan Sulfate Proteoglycans in Human Colorectal Cancer. Anal Cell Pathol (Amst) 2018; 2018:8389595. [PMID: 30027065 PMCID: PMC6031075 DOI: 10.1155/2018/8389595] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 05/14/2018] [Accepted: 05/20/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is the third most common cancer worldwide, accounting for more than 610,000 mortalities every year. Prognosis of patients is highly dependent on the disease stage at diagnosis. Therefore, it is crucial to investigate molecules involved in colorectal cancer tumorigenesis, with possible use as tumor markers. Heparan sulfate proteoglycans are complex molecules present in the cell membrane and extracellular matrix, which play vital roles in cell adhesion, migration, proliferation, and signaling pathways. In colorectal cancer, the cell surface proteoglycan syndecan-2 is upregulated and increases cell migration. Moreover, expression of syndecan-1 and syndecan-4, generally antitumor molecules, is reduced. Levels of glypicans and perlecan are also altered in colorectal cancer; however, their role in tumor progression is not fully understood. In addition, studies have reported increased heparan sulfate remodeling enzymes, as the endosulfatases. Therefore, heparan sulfate proteoglycans are candidate molecules to clarify colorectal cancer tumorigenesis, as well as important targets to therapy and diagnosis.
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Nerlich AG. Molecular paleopathology and paleo-oncology-State of the art, potentials, limitations and perspectives. INTERNATIONAL JOURNAL OF PALEOPATHOLOGY 2018; 21:77-82. [PMID: 29776884 DOI: 10.1016/j.ijpp.2017.02.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Revised: 02/05/2017] [Accepted: 02/06/2017] [Indexed: 06/08/2023]
Abstract
This paper reviews the current knowledge on molecular paleopathology with respect to oncological information. This covers both the information on the protein level (proteome) as well as the gene level (genome) and includes data on carcinogenic factors - such as molecular evidence for oncogenic viral infections. Currently, relatively little data is available for neoplastic disease in paleopathology. Likewise, few studies describe the biochemical or immunohistochemical analysis of tumors - a tool to potentially classify the tumor type and the underlying primary tumor in metastases. On the gene level, two studies described distinct molecular mutations in either a tumor-driving oncogene or a tumor suppressor gene, both being excellent examples for paleo-oncological studies. The paucity of historic tumor material - particularly when only osseous remains are available - represents the most hindering factor for molecular paleo-oncology. This can only be overcome in future by both the thorough investigation of mummified archaeological biomaterial and the improvement of analytical assays in order to trace even minute amounts of tumor material in osseous lesions.
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Affiliation(s)
- Andreas G Nerlich
- Institut für Pathologie, Klinikum München-Bogenhausen, Englschalkingerstr. 77, D-81925 München, Germany.
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Nikolouzakis TK, Vassilopoulou L, Fragkiadaki P, Sapsakos TM, Papadakis GZ, Spandidos DA, Tsatsakis AM, Tsiaoussis J. Improving diagnosis, prognosis and prediction by using biomarkers in CRC patients (Review). Oncol Rep 2018; 39:2455-2472. [PMID: 29565457 PMCID: PMC5983921 DOI: 10.3892/or.2018.6330] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 03/21/2018] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is among the most common cancers. In fact, it is placed in the third place among the most diagnosed cancer in men, after lung and prostate cancer, and in the second one for the most diagnosed cancer in women, following breast cancer. Moreover, its high mortality rates classifies it among the leading causes of cancer‑related death worldwide. Thus, in order to help clinicians to optimize their practice, it is crucial to introduce more effective tools that will improve not only early diagnosis, but also prediction of the most likely progression of the disease and response to chemotherapy. In that way, they will be able to decrease both morbidity and mortality of their patients. In accordance with that, colon cancer research has described numerous biomarkers for diagnostic, prognostic and predictive purposes that either alone or as part of a panel would help improve patient's clinical management. This review aims to describe the most accepted biomarkers among those proposed for use in CRC divided based on the clinical specimen that is examined (tissue, faeces or blood) along with their restrictions. Lastly, new insight in CRC monitoring will be discussed presenting promising emerging biomarkers (telomerase activity, telomere length and micronuclei frequency).
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Affiliation(s)
| | - Loukia Vassilopoulou
- Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, 71409 Heraklion, Crete, Greece
| | - Persefoni Fragkiadaki
- Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, 71409 Heraklion, Crete, Greece
| | - Theodoros Mariolis Sapsakos
- Laboratory of Anatomy and Histology, Nursing School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgios Z. Papadakis
- Foundation for Research and Technology Hellas (FORTH), Institute of Computer Sciences (ICS), Computational Biomedicine Laboratory (CBML), 71003 Heraklion, Crete, Greece
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Crete, Greece
| | - Aristides M. Tsatsakis
- Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, 71409 Heraklion, Crete, Greece
| | - John Tsiaoussis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion, Greece
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31
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Tan SC. Low penetrance genetic polymorphisms as potential biomarkers for colorectal cancer predisposition. J Gene Med 2018; 20:e3010. [PMID: 29424105 DOI: 10.1002/jgm.3010] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 01/12/2018] [Accepted: 01/19/2018] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer is a leading form of cancer in both males and females. Early detection of individuals at risk of colorectal cancer allows proper treatment and management of the disease to be implemented, which can potentially reduce the burden of colorectal cancer incidence, morbidity and mortality. In recent years, the role of genetic susceptibility factors in mediating predisposition to colorectal cancer has become more and more apparent. Identification of high-frequency, low-penetrance genetic polymorphisms associated with the cancer has therefore emerged as an important approach which can potentially aid prediction of colorectal cancer risk. However, the overwhelming amount of genetic epidemiology data generated over the past decades has made it difficult for one to assimilate the information and determine the exact genetic polymorphisms that can potentially be used as biomarkers for colorectal cancer. This review comprehensively consolidates, based primarily on results from meta-analyses, the recent progresses in the search of colorectal cancer-associated genetic polymorphisms, and discusses the possible mechanisms involved.
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Affiliation(s)
- Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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32
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Mandelker D, Zhang L. The emerging significance of secondary germline testing in cancer genomics. J Pathol 2018; 244:610-615. [PMID: 29293272 DOI: 10.1002/path.5031] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 12/20/2017] [Accepted: 12/22/2017] [Indexed: 12/13/2022]
Abstract
Many clinical laboratories now sequence the tumors from advanced cancer patients to identify oncogenic drivers and guide targeted therapies and clinical trials. One limitation of tumor sequencing is that it cannot distinguish between tumor-specific somatic (acquired) mutations and patients' germline (constitutional) variants. To definitively identify somatic variants, some clinical labs sequence both a normal sample from a patient and their tumor to subtract the germline variants from the somatic variants. Having a paired normal sample also allows for the identification of secondary germline mutations in cancer patients who may not meet the current clinical guidelines for genetic testing of cancer predisposition syndromes. Such simultaneous detection of somatic alterations and germline mutations during tumor-normal sequencing can guide therapeutic decision making for cancer patients and the identification and screening of at-risk family members. Here, we review the clinical workflow, advantages and disadvantages, and clinical utility of tumor-normal sequencing in the management of cancer patients. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Diana Mandelker
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Liying Zhang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Ospina Stella A, Turville S. All-Round Manipulation of the Actin Cytoskeleton by HIV. Viruses 2018; 10:v10020063. [PMID: 29401736 PMCID: PMC5850370 DOI: 10.3390/v10020063] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 01/24/2018] [Accepted: 01/29/2018] [Indexed: 12/21/2022] Open
Abstract
While significant progress has been made in terms of human immunodeficiency virus (HIV) therapy, treatment does not represent a cure and remains inaccessible to many people living with HIV. Continued mechanistic research into the viral life cycle and its intersection with many aspects of cellular biology are not only fundamental in the continued fight against HIV, but also provide many key observations of the workings of our immune system. Decades of HIV research have testified to the integral role of the actin cytoskeleton in both establishing and spreading the infection. Here, we review how the virus uses different strategies to manipulate cellular actin networks and increase the efficiency of various stages of its life cycle. While some HIV proteins seem able to bind to actin filaments directly, subversion of the cytoskeleton occurs indirectly by exploiting the power of actin regulatory proteins, which are corrupted at multiple levels. Furthermore, this manipulation is not restricted to a discrete class of proteins, but rather extends throughout all layers of the cytoskeleton. We discuss prominent examples of actin regulators that are exploited, neutralized or hijacked by the virus, and address how their coordinated deregulation can lead to changes in cellular behavior that promote viral spreading.
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Affiliation(s)
- Alberto Ospina Stella
- The Kirby Institute, University of New South Wales (UNSW), Sydney NSW 2052, Australia.
| | - Stuart Turville
- The Kirby Institute, University of New South Wales (UNSW), Sydney NSW 2052, Australia.
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34
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Nalbantoglu ILK, Blanc V, Davidson NO. Characterization of Colorectal Cancer Development in Apc (min/+) Mice. Methods Mol Biol 2017; 1422:309-27. [PMID: 27246043 DOI: 10.1007/978-1-4939-3603-8_27] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The Apc (min/+) mouse provides an excellent experimental model for studying genetic, environmental, and therapeutic aspects of intestinal neoplasia in humans. In this chapter, we will describe techniques for studying colon cancer development in Apc (min/+) mice on C57BL/6J (B6) background, focusing on the roles of environmental modifiers, including Dextran Sulfate Sodium (DSS), high fat diet, and bile acid supplementation in the context of experimental colorectal cancer. This chapter also includes protocols describing extraction and purification of DSS-contaminated RNA, as well as sampling, harvesting, and tissue processing. The common pathologic lesions encountered in these animals are described in detail.
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Affiliation(s)
- ILKe Nalbantoglu
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave, Box 8118, St. Louis, MO, 63110, USA.
| | - Valerie Blanc
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Nicholas O Davidson
- Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
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Mahasneh A, Al-Shaheri F, Jamal E. Molecular biomarkers for an early diagnosis, effective treatment and prognosis of colorectal cancer: Current updates. Exp Mol Pathol 2017; 102:475-483. [PMID: 28506769 DOI: 10.1016/j.yexmp.2017.05.005] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 05/11/2017] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is the third most prevalent cancer in the world. Globally, it has been estimated that about 1.4 million new cases of colorectal cancer are diagnosed every year. CRC is a multifactorial disease that arises due to genetics as well as epigenetic alterations in a number of oncogenes, tumor suppressor genes, mismatch repair genes, as well as cell cycle regulating genes in colon mucosal cells. These molecular alterations have been considered as potential CRC biomarkers because they can provide the physicians with diagnostic, prognostic and treatment response information. The goal is to identify relevant, cheap and applicable biomarkers that contribute to patient management decisions, resulting in direct benefits to patients. In this review, we will outline the most currently available and developing tumor tools, and blood molecular biomarkers. Also, we will illustrate their diagnostic, therapeutic and prognostic applications.
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Affiliation(s)
- Amjad Mahasneh
- Faculty of Arts and Science, Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid, Jordan.
| | - Fawaz Al-Shaheri
- Faculty of Applied Medical Sciences, Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan
| | - Eshraq Jamal
- Faculty of Applied Medical Sciences, Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan
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Pearlman R, Frankel WL, Swanson B, Zhao W, Yilmaz A, Miller K, Bacher J, Bigley C, Nelsen L, Goodfellow PJ, Goldberg RM, Paskett E, Shields PG, Freudenheim JL, Stanich PP, Lattimer I, Arnold M, Liyanarachchi S, Kalady M, Heald B, Greenwood C, Paquette I, Prues M, Draper DJ, Lindeman C, Kuebler JP, Reynolds K, Brell JM, Shaper AA, Mahesh S, Buie N, Weeman K, Shine K, Haut M, Edwards J, Bastola S, Wickham K, Khanduja KS, Zacks R, Pritchard CC, Shirts BH, Jacobson A, Allen B, de la Chapelle A, Hampel H. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol 2017; 3:464-471. [PMID: 27978560 DOI: 10.1001/jamaoncol.2016.5194] [Citation(s) in RCA: 508] [Impact Index Per Article: 63.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Importance Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined. Objective To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC. Design, Setting, and Participants Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing. Main Outcomes and Measures Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status. Results In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10 patients had mutations in low-penetrance CRC genes (3, APC c.3920T>A, p.I1307K; 7, monoallelic MUTYH). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation. Conclusions and Relevance Of 450 patients with early-onset CRC, 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset CRC.
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Affiliation(s)
- Rachel Pearlman
- The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus
| | - Wendy L Frankel
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
| | - Benjamin Swanson
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
| | - Weiqiang Zhao
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
| | - Ahmet Yilmaz
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
| | - Kristin Miller
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
| | - Jason Bacher
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
| | - Christopher Bigley
- The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus
| | - Lori Nelsen
- The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus
| | - Paul J Goodfellow
- The Ohio State University Comprehensive Cancer Center, Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus
| | - Richard M Goldberg
- The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus
| | - Electra Paskett
- The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus
| | - Peter G Shields
- The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus
| | - Jo L Freudenheim
- Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York
| | - Peter P Stanich
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus
| | - Ilene Lattimer
- The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus
| | - Mark Arnold
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus
| | - Sandya Liyanarachchi
- The Ohio State University Comprehensive Cancer Center, Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus
| | - Matthew Kalady
- Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio
| | - Brandie Heald
- Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio
| | - Carla Greenwood
- Department of Digestive Diseases and Surgery, Cleveland Clinic, Cleveland, Ohio
| | - Ian Paquette
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Marla Prues
- Cancer Center Research, The Christ Hospital Health Network, Cincinnati, Ohio
| | - David J Draper
- TriHealth Cancer Institute, Good Samaritan Hospital, Cincinnati, Ohio
| | - Carolyn Lindeman
- TriHealth Cancer Institute, Good Samaritan Hospital, Cincinnati, Ohio
| | | | - Kelly Reynolds
- Department of Cancer Services, Riverside Methodist Hospital, Columbus, Ohio
| | - Joanna M Brell
- Department of Medicine, MetroHealth Medical Center, Cleveland, Ohio
| | - Amy A Shaper
- Research Institute, MetroHealth Medical Center, Cleveland, Ohio
| | - Sameer Mahesh
- Department of Internal Medicine, Summa Cancer Institute, Summa Akron City Hospital, Akron, Ohio
| | - Nicole Buie
- Summa Center for Clinical Trials, Summa Akron City Hospital, Akron, Ohio
| | - Kisa Weeman
- Department of Hematology/Oncology, Aultman Hospital, Canton, Ohio
| | - Kristin Shine
- Department of Oncology Clinical Trials, Aultman Hospital, Canton, Ohio
| | | | | | - Shyamal Bastola
- Department of Oncology and Hematology, Genesis HealthCare System, Zanesville, Ohio
| | - Karen Wickham
- Department of Oncology and Hematology, Genesis HealthCare System, Zanesville, Ohio
| | - Karamjit S Khanduja
- Division of Colon and Rectal Surgery, Mount Carmel East Hospital, Columbus, Ohio
| | - Rosemary Zacks
- Department of Clinical Trials, Mount Carmel East Hospital, Columbus, Ohio
| | - Colin C Pritchard
- Department of Laboratory Medicine, University of Washington, Seattle
| | - Brian H Shirts
- Department of Laboratory Medicine, University of Washington, Seattle
| | - Angela Jacobson
- Department of Laboratory Medicine, University of Washington, Seattle
| | | | - Albert de la Chapelle
- The Ohio State University Comprehensive Cancer Center, Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus
| | - Heather Hampel
- The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus
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Zhang S, Wang XB, Han YD, Wang C, Zhou Y, Zheng F. Certain Polymorphisms in SP110 Gene Confer Susceptibility to Tuberculosis: A Comprehensive Review and Updated Meta-Analysis. Yonsei Med J 2017; 58:165-173. [PMID: 27873510 PMCID: PMC5122633 DOI: 10.3349/ymj.2017.58.1.165] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 01/14/2016] [Accepted: 06/02/2016] [Indexed: 12/22/2022] Open
Abstract
PURPOSE Numerous studies have assessed the association of SP110 gene variants with tuberculosis (TB), but the results were inconsistent. Through a comprehensive review and meta-analysis, our study aimed to clarify the nature of genetic risks contributed by 11 polymorphisms for the development of TB. MATERIALS AND METHODS Through searching PubMed, web of science, China National Knowledge Infrastructure (CNKI) databases, a total of 11 articles including 13 independent studies were selected. The pooled odd ratios (ORs) along with their corresponding 95% confidence interval (CI) were estimated for allelic comparisons, additive model (homozygote comparisons; heterozygote comparisons), dominant model and recessive model. We also assessed the heterogeneity across the studies and publication bias. RESULTS The results of combined analysis revealed a significantly increased risk of TB for single nucleotide polymorphism (SNP) rs9061 in all five comparisons (allelic comparisons: OR=1.28, 95% CI=1.14-1.44, p<0.0001; homozygote comparisons: OR=2.84, 95% CI=1.84-4.38, p<0.00001; heterozygote comparisons: OR=1.23, 95% CI=1.05-1.43, p=0.009; dominant model: OR=1.32, 95% CI=1.14-1.53, p=0.0003; recessive model: OR=2.26, 95% CI=1.18-4.34, p=0.01). In subgroup analysis, the risk of TB associated with SNP rs9061 appeared to be increased. Moreover, increased risk of TB was also found in Asian subgroup of SNP rs11556887, while decreased risk of TB appeared in large sample size subgroup of SNP rs1135791. No significant association was observed between other SNPs and the risk of TB. CONCLUSION Our meta-analysis suggested that the variant of SNP rs9061 might be a risk factor for TB.
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Affiliation(s)
- Shuai Zhang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xue Bin Wang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Ya Di Han
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Chen Wang
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Ye Zhou
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Fang Zheng
- Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, Hubei, China.
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Yang J, Liu QW, Li LW, Wang QZ, Hong M, Dong J. Familial adenomatous polyposis in China. Oncol Lett 2016; 12:4877-4882. [PMID: 28105195 DOI: 10.3892/ol.2016.5330] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 10/04/2016] [Indexed: 12/11/2022] Open
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant disease with a poor prognosis, and has been studied by clinicians and geneticists in China for the past three decades. It is estimated that FAP has an incidence of between 1 in 8,000 and 1 in 10,000 individuals, and accounts for 0.94% of colorectal cancer cases in China. Recent advances in the understanding of FAP suggest that the genotype of the patient may allow for early diagnosis and surveillance, and guide surgical and chemopreventive management. However, the genetic mechanisms of FAP vary between different countries. FAP in China has its own characteristics, and this may be due to ethnic and geographical genetic variation. In the present review the clinical manifestations and genetics of FAP in China are discussed, as well as the surgical strategies, chemotherapeutics and traditional Chinese medicines used in its treatment. Increased insight into the genetic and clinical features of FAP in the Chinese population may aid in the prevention and management of the disorder.
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Affiliation(s)
- Jun Yang
- Department of Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Qing Wei Liu
- Department of Internal Medicine-Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Liang Wen Li
- Department of Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Qiang Zhi Wang
- Department of Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Min Hong
- Department of Internal Medicine-Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Jian Dong
- Department of Internal Medicine-Oncology, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650106, P.R. China
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Graffeo R, Livraghi L, Pagani O, Goldhirsch A, Partridge AH, Garber JE. Time to incorporate germline multigene panel testing into breast and ovarian cancer patient care. Breast Cancer Res Treat 2016; 160:393-410. [DOI: 10.1007/s10549-016-4003-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 09/23/2016] [Indexed: 02/07/2023]
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40
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Family-Specific Variants and the Limits of Human Genetics. Trends Mol Med 2016; 22:925-934. [PMID: 27742414 DOI: 10.1016/j.molmed.2016.09.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 09/10/2016] [Accepted: 09/13/2016] [Indexed: 01/28/2023]
Abstract
Every single-nucleotide change compatible with life is present in the human population today. Understanding these rare human variants defines an extraordinary challenge for genetics and medicine. The new clinical practice of sequencing many genes for hereditary cancer risk has illustrated the utility of clinical next-generation sequencing in adults, identifying more medically actionable variants than single-gene testing. However, it has also revealed a linear relationship between the length of DNA evaluated and the number of rare 'variants of uncertain significance' reported. We propose that careful approaches to phenotype-genotype inference, distinguishing between diagnostic and screening intent, in conjunction with expanded use of family-scale genetics studies as a source of information on family-specific variants, will reduce variants of uncertain significance reported to patients.
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Association of APC I1307K and E1317Q polymorphisms with colorectal cancer among Egyptian subjects. Fam Cancer 2016; 15:49-56. [PMID: 26314409 DOI: 10.1007/s10689-015-9834-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Colorectal cancer is a multifactorial disease that involves both environmental and genetic factors. The gene encoding adenomatous polyposis coli (APC) has been reported to be associated with colorectal cancer (CRC) risk in several ethnic populations. The aim of this work is to assess the association of the APC I1307K and E1317Q polymorphisms with CRC risk among Egyptian subjects. This study included 120 unrelated CRC Egyptian patients who were compared to 100 healthy controls from the same locality. For all subjects, DNA was genotyped for APC I1307K and E1317Q polymorphisms using the PCR-ARMS technique. The frequency of APC I1307K carrier (TA+AA genotypes) was noted to be significantly higher among cases with CRC compared to controls (18.3 vs. 9.0 %, OR 2.58, 95 % CI 1.09-6.09, p = 0.03). Also the frequency of the APC I1307K A allele was significantly higher among cases compared to controls (10.4 vs. 4.5 %, OR 2.47; 95 % CI 1.12-5.42, p = 0.03). On the contrast, the frequencies of APC E1317Q GC genotype and C allele showed no significant difference among CRC patients compared to controls (3.3 vs. 2.0 %, OR 1.69; 95 % CI 0.30-9.42, p = 0.69 and 2.1 vs. 1.0 %, OR 2.11; 95 % CI 0.40-10.97, p = 0.46, respectively). Cases of the APC I1307K and E1317Q carriers (TA+AA and GC) showed no significant difference compared to those with I1307K and E1317Q non-carriers (TT and GG) regarding their clinical and laboratory markers. APC I1307K variant was associated with an increased risk of CRC among Egyptian subjects.
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Tung N, Domchek SM, Stadler Z, Nathanson KL, Couch F, Garber JE, Offit K, Robson ME. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol 2016; 13:581-8. [PMID: 27296296 PMCID: PMC5513673 DOI: 10.1038/nrclinonc.2016.90] [Citation(s) in RCA: 225] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The use of multigene panels for the assessment of cancer susceptibility is expanding rapidly in clinical practice, particularly in the USA, despite concerns regarding the uncertain clinical validity for some gene variants and the uncertain clinical utility of most multigene panels. So-called 'moderate-penetrance' gene mutations associated with cancer susceptibility are identified in approximately 2-5% of individuals referred for clinical testing; some of these mutations are potentially actionable. Nevertheless, the appropriate management of individuals harbouring such moderate-penetrance genetic variants is unclear. The cancer risks associated with mutations in moderate-penetrance genes are lower and different than those reported for high-penetrance gene mutations (such as mutations in BRCA1 and BRCA2, and those associated with Lynch syndrome). The extrapolation of guidelines for the management of individuals with high-penetrance variants of cancer-susceptibility genes to the clinical care of patients with moderate-penetrance gene mutations could result in substantial harm. Thus, we provide a framework for clinical decision-making pending the development of a sufficient evidence base to document the clinical utility of the interventions for individuals with inherited moderate-penetrance gene mutations associated with an increased risk of cancer.
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Affiliation(s)
- Nadine Tung
- Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA
| | - Susan M Domchek
- Abramson Cancer Center, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA, and the Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA
| | - Zsofia Stadler
- Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue; and the Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA
| | - Katherine L Nathanson
- Abramson Cancer Center, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA, and the Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA
| | - Fergus Couch
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street South West, Rochester, Minnesota 55905, USA
| | - Judy E Garber
- Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA
| | - Kenneth Offit
- Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue; and the Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA
| | - Mark E Robson
- Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue; and the Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA
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Van Allen EM, Robinson D, Morrissey C, Pritchard C, Imamovic A, Carter S, Rosenberg M, McKenna A, Wu YM, Cao X, Chinnaiyan A, Garraway L, Nelson PS. A comparative assessment of clinical whole exome and transcriptome profiling across sequencing centers: implications for precision cancer medicine. Oncotarget 2016; 7:52888-52899. [PMID: 27167109 PMCID: PMC5288156 DOI: 10.18632/oncotarget.9184] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Accepted: 03/29/2016] [Indexed: 11/25/2022] Open
Abstract
Advances in next generation sequencing technologies provide approaches to comprehensively determine genomic alterations within a tumor that occur as a cause or consequence of neoplastic growth. Though providers offering various cancer genomics assays have multiplied, the level of reproducibility in terms of the technical sensitivity and the conclusions resulting from the data analyses have not been assessed.We sought to determine the reproducibility of ascertaining tumor genome aberrations using whole exome sequencing (WES) and RNAseq. Samples of the same metastatic tumors were independently processed and subjected to WES of tumor and constitutional DNA, and RNAseq of RNA, at two sequencing centers. Overall, the sequencing results were highly comparable. Concordant mutation calls ranged from 88% to 93% of all variants including 100% agreement across 154 cancer-associated genes. Regions of copy losses and gains were uniformly identified and called by each sequencing center and chromosomal plots showed nearly identical patterns. Transcript abundance levels also exhibited a high degree of concordance (r2 ≥ 0.78;Pearson). Biologically-relevant gene fusion events were concordantly called. Exome sequencing of germline DNA samples provided a minimum of 30X coverage depth across 56 genes where incidental findings are recommended to be reported. One possible pathogenic variant in the APC gene was identified by both sequencing centers.The findings from this study demonstrate that results of somatic and germline sequencing are highly concordant across sequencing centers that have substantial experience in the technological requirements for preparing, sequencing and annotating DNA and RNA from human biospecimens.
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Affiliation(s)
- Eliezer M Van Allen
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, 02142, MA, USA
| | - Dan Robinson
- Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA
| | - Colm Morrissey
- Department of Urology, University of Washington, Seattle, 98195, WA, USA
| | - Colin Pritchard
- Department of Laboratory Medicine, University of Washington, Seattle, 98195, WA, USA
| | - Alma Imamovic
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, 02142, MA, USA
| | - Scott Carter
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, 02142, MA, USA
| | - Mara Rosenberg
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, 02142, MA, USA
| | - Aaron McKenna
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, 02142, MA, USA
| | - Yi-Mi Wu
- Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA
| | - Xuhong Cao
- Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA
| | - Arul Chinnaiyan
- Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, 48109, MI, USA
| | - Levi Garraway
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, 02142, MA, USA
| | - Peter S Nelson
- Department of Urology, University of Washington, Seattle, 98195, WA, USA
- Department of Medicine, University of Washington, Seattle, 98195, WA, USA
- Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, 98109, WA, USA
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Yang J, Liu WQ, Li WL, Chen C, Zhu Z, Hong M, Wang ZQ, Dong J. Investigating polymorphisms by bioinformatics is a potential cost-effective method to screen for germline mutations in Chinese familial adenomatous polyposis patients. Oncol Lett 2016; 12:421-428. [PMID: 27347161 PMCID: PMC4907044 DOI: 10.3892/ol.2016.4646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 04/12/2016] [Indexed: 12/22/2022] Open
Abstract
The aim of this study was to investigate germline mutations of the APC, MUTYH and AXIN2 genes in Chinese patients with familial adenomatous polyposis (FAP), and further assess the value of bioinformatics in screening the pathogenic changes predisposing to FAP. APC genes from 11 unrelated FAP patients in Yunnan province in China were firstly examined by exon-specific DNA sequencing. For samples without already known pathogenic changes predisposing to FAP in the APC gene, whole-gene sequencing of MUTYH and AXIN2 was performed. Mutational analysis of each gene was performed by bioinformatics. Eleven different types of APC polymorphisms were observed in the cohort of families analyzed. Of these polymorphisms, four were missense substitutions (V1822D, V1173G, P1760H and K2057), one was a nonsense substitution (S1196X), and six were silent substitutions (Y486Y, T449T, T1493T, G1678G, S1756S and P1960P). One missense mutation (Q335H) and two intronic substitutions (c.264+11G>A and c.420+35A>G) were detected in the MUTYH gene, and four synonymous mutations (I144I, P455P, P462P and L688L) and three intonic mutations (c.1060–77G>T, c.1060–287A>G and c.1060–282 A>G) of the AXIN2 gene were observed. In addition to the already reported pathogenic mutations, by using function assessment tools and databases, the synonymous substitutions observed in the APC gene of our samples were predicted to affect splicing regulation in the translation of mRNA, while the missense mutations observed in the APC gene and MUTYH gene were predicted to be disease-related polymorphisms; however, no functional effect of the mutations was observed in the AXIN2 gene. Comprehensive screening for germline mutations in APC, MUTYH and AXIN2 genes followed by prediction of pathogenicity using bioinformatic tools contributes to a cost-effective way of screening germline mutations in Chinese familial adenomatous polyposis patients.
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Affiliation(s)
- Jun Yang
- Department of Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Wei Qing Liu
- Department of Internal Medicine-Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Wen Liang Li
- Department of Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Cheng Chen
- Department of Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Zhu Zhu
- Department of Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Min Hong
- Department of Internal Medicine-Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Zhi Qiang Wang
- Department of Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Jian Dong
- Department of Internal Medicine-Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China; Department of Internal Medicine-Oncology, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650106, P.R. China
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Interaction between APC and Fen1 during breast carcinogenesis. DNA Repair (Amst) 2016; 41:54-62. [PMID: 27088617 DOI: 10.1016/j.dnarep.2016.04.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 04/06/2016] [Indexed: 02/07/2023]
Abstract
Aberrant DNA base excision repair (BER) contributes to malignant transformation. However, inter-individual variations in DNA repair capacity plays a key role in modifying breast cancer risk. We review here emerging evidence that two proteins involved in BER - adenomatous polyposis coli (APC) and flap endonuclease 1 (Fen1) - promote the development of breast cancer through novel mechanisms. APC and Fen1 expression and interaction is increased in breast tumors versus normal cells, APC interacts with and blocks Fen1 activity in Pol-β-directed LP-BER, and abrogation of LP-BER is linked with cigarette smoke condensate-induced transformation of normal breast epithelial cells. Carcinogens increase expression of APC and Fen1 in spontaneously immortalized human breast epithelial cells, human colon cancer cells, and mouse embryonic fibroblasts. Since APC and Fen1 are tumor suppressors, an increase in their levels could protect against carcinogenesis; however, this does not seem to be the case. Elevated Fen1 levels in breast and lung cancer cells may reflect the enhanced proliferation of cancer cells or increased DNA damage in cancer cells compared to normal cells. Inactivation of the tumor suppressor functions of APC and Fen1 is due to their interaction, which may act as a susceptibility factor for breast cancer. The increased interaction of APC and Fen1 may occur due to polypmorphic and/or mutational variation in these genes. Screening of APC and Fen1 polymorphic and/or mutational variations and APC/Fen1 interaction may permit assessment of individual DNA repair capability and the risk for breast cancer development. Such individuals might lower their breast cancer risk by reducing exposure to carcinogens. Stratifying individuals according to susceptibility would greatly assist epidemiologic studies of the impact of suspected environmental carcinogens. Additionally, a mechanistic understanding of the interaction of APC and Fen1 may provide the basis for developing new and effective targeted chemopreventive and chemotherapeutic agents.
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Montazeri Z, Theodoratou E, Nyiraneza C, Timofeeva M, Chen W, Svinti V, Sivakumaran S, Gresham G, Cubitt L, Carvajal-Carmona L, Bertagnolli MM, Zauber AG, Tomlinson I, Farrington SM, Dunlop MG, Campbell H, Little J. Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas. Int J Epidemiol 2016; 45:186-205. [PMID: 26451011 PMCID: PMC5860727 DOI: 10.1093/ije/dyv185] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Low penetrance genetic variants, primarily single nucleotide polymorphisms, have substantial influence on colorectal cancer (CRC) susceptibility. Most CRCs develop from colorectal adenomas (CRA). Here we report the first comprehensive field synopsis that catalogues all genetic association studies on CRA, with a parallel online database [http://www.chs.med.ed.ac.uk/CRAgene/]. METHODS We performed a systematic review, reviewing 9750 titles, and then extracted data from 130 publications reporting on 181 polymorphisms in 74 genes. We conducted meta-analyses to derive summary effect estimates for 37 polymorphisms in 26 genes. We applied the Venice criteria and Bayesian False Discovery Probability (BFDP) to assess the levels of the credibility of associations. RESULTS We considered the association with the rs6983267 variant at 8q24 as 'highly credible', reaching genome-wide statistical significance in at least one meta-analysis model. We identified 'less credible' associations (higher heterogeneity, lower statistical power, BFDP > 0.02) with a further four variants of four independent genes: MTHFR c.677C>T p.A222V (rs1801133), TP53 c.215C>G p.R72P (rs1042522), NQO1 c.559C>T p.P187S (rs1800566), and NAT1 alleles imputed as fast acetylator genotypes. For the remaining 32 variants of 22 genes for which positive associations with CRA risk have been previously reported, the meta-analyses revealed no credible evidence to support these as true associations. CONCLUSIONS The limited number of credible associations between low penetrance genetic variants and CRA reflects the lower volume of evidence and associated lack of statistical power to detect associations of the magnitude typically observed for genetic variants and chronic diseases. The CRA gene database provides context for CRA genetic association data and will help inform future research directions.
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Affiliation(s)
- Zahra Montazeri
- School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada
| | - Evropi Theodoratou
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK
| | - Christine Nyiraneza
- School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada
| | - Maria Timofeeva
- Colon Cancer Genetics Group and Academic Coloproctology, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit Western General Hospital, Edinburgh, UK
| | - Wanjing Chen
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK
| | - Victoria Svinti
- Colon Cancer Genetics Group and Academic Coloproctology, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit Western General Hospital, Edinburgh, UK
| | - Shanya Sivakumaran
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK
| | - Gillian Gresham
- School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada
| | - Laura Cubitt
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK
| | - Luis Carvajal-Carmona
- Biochemistry and Molecular Medicine, Genome and Biomedical Sciences Facility, UC Davis School of Medicine, University of California Davis, Davis, CA, USA
| | | | - Ann G Zauber
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA and
| | - Ian Tomlinson
- Wellcome Trust Centre for Human Genetics, Oxford, UK
| | - Susan M Farrington
- Colon Cancer Genetics Group and Academic Coloproctology, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit Western General Hospital, Edinburgh, UK
| | - Malcolm G Dunlop
- Colon Cancer Genetics Group and Academic Coloproctology, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit Western General Hospital, Edinburgh, UK
| | - Harry Campbell
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK, Colon Cancer Genetics Group and Academic Coloproctology, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit Western General Hospital, Edinburgh, UK
| | - Julian Little
- School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada,
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Estrada SS, LeGrazie B, McKamie T, Montgomery S. Next-Generation Gene Sequencing: Looking Beyond Hereditary Breast and Ovarian Cancer. Oncol Nurs Forum 2015; 42:691-4. [PMID: 26488839 DOI: 10.1188/15.onf.691-694] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Oncology nurses have long been aware of the significance of recognizing patients' hereditary risk of cancer. Obtaining an accurate family history is an integral part of patient assessment and has helped to guide referrals for genetic counseling and testing for hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome.
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Affiliation(s)
- Sylvia S Estrada
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA
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Leshno A, Shapira S, Liberman E, Kraus S, Sror M, Harlap-Gat A, Avivi D, Galazan L, David M, Maharshak N, Moanis S, Arber N, Moshkowitz M. The APC I1307K allele conveys a significant increased risk for cancer. Int J Cancer 2015; 138:1361-7. [PMID: 26421687 DOI: 10.1002/ijc.29876] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 09/05/2015] [Accepted: 09/22/2015] [Indexed: 01/07/2023]
Abstract
This study is the first attempt to evaluate the association between the APC I1307K variant and overall cancer risk. It is unique in both its large sample size and in the reliability of data in the control group. The findings described in this article have major implications in terms of identifying asymptomatic individuals who are at increased risk to harbor cancer and therefore targeted to be enrolled in specific early detection and prevention programs. The prevalence of the APC I1307K missense mutation among Ashkenazi Jews is ∼ 6%. Carriers are at an increased risk for colorectal neoplasia. In this study, we examined the association of this variant with non-colorectal cancers. Consecutive 13,013 healthy subjects who underwent screening at the Integrated Cancer Prevention Center between 2006 and 2014 were enrolled. This population was supplemented with 1,611 cancer patients from the same institution. Demographics, medical history, and pathological data were recorded. Mortality data were obtained from the Ministry of Health's registry. The prevalence of APC I1307K in cancer patients and healthy subjects was compared. The APC I1307K variant was detected in 189 (11.8%) cancer patients compared to 614 (4.7%) healthy subjects, reflecting an adjusted age and sex odds ratio (OR) of 2.53 (p < 0.0001). History of two or more cancer types was associated with a positive carrier prevalence (OR = 4.38 p < 0.0001). Males had significantly increased carrier prevalence in lung, urologic, pancreatic, and skin cancers. The carrier prevalence among females was significantly higher only in breast and skin cancers. Female carriers developed cancer at a significantly older age compared to non-carriers (average 62.7 years vs. 57.8, respectively, p = 0.027), had better survival rates (HR = 0.58, p = 0.022) and overall increased longevity (average age of death 78.8 vs. 70.4 years, respectively, p = 0.003). In conclusion, the APC I1307K variant is a reliable marker for overall cancer risk (OR 2.53). Further studies are needed to evaluate its use for specific cancer types-particularly in males. Female carriers have better prognosis and increased lifespan.
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Affiliation(s)
- Ari Leshno
- Integrated Cancer Prevention Center, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Shiran Shapira
- Integrated Cancer Prevention Center, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Eliezer Liberman
- Integrated Cancer Prevention Center, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Sarah Kraus
- Integrated Cancer Prevention Center, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Miri Sror
- Integrated Cancer Prevention Center, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Amira Harlap-Gat
- Integrated Cancer Prevention Center, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Doran Avivi
- Integrated Cancer Prevention Center, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Lior Galazan
- Integrated Cancer Prevention Center, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Maayan David
- Integrated Cancer Prevention Center, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Nitsan Maharshak
- Integrated Cancer Prevention Center, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,Department of Gastroenterology, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Serhan Moanis
- Integrated Cancer Prevention Center, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Nadir Arber
- Integrated Cancer Prevention Center, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,Department of Gastroenterology, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Menachem Moshkowitz
- Integrated Cancer Prevention Center, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,Department of Gastroenterology, Tel- Aviv Sourasky Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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Abstract
Colorectal cancer (CRC) is a complex disease that develops as a consequence of both genetic and environmental risk factors. A small proportion (3-5%) of cases arise from hereditary syndromes predisposing to early onset CRC as a result of mutations in over a dozen well defined genes. In contrast, CRC is predominantly a late onset 'sporadic' disease, developing in individuals with no obvious hereditary syndrome. In recent years, genome wide association studies have discovered that over 40 genetic regions are associated with weak effects on sporadic CRC, and it has been estimated that increasingly large genome wide scans will identify many additional novel genetic regions. Subsequent experimental validations have identified the causally related variant(s) in a limited number of these genetic regions. Further biological insight could be obtained through ethnically diverse study populations, larger genetic sequencing studies and development of higher throughput functional experiments. Along with inherited variation, integration of the tumour genome may shed light on the carcinogenic processes in CRC. In addition to summarising the genetic architecture of CRC, this review discusses genetic factors that modify environmental predictors of CRC, as well as examples of how genetic insight has improved clinical surveillance, prevention and treatment strategies. In summary, substantial progress has been made in uncovering the genetic architecture of CRC, and continued research efforts are expected to identify additional genetic risk factors that further our biological understanding of this disease. Subsequently these new insights will lead to improved treatment and prevention of colorectal cancer.
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Affiliation(s)
- Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA
| | - Stephanie Bien
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Niha Zubair
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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Puerta-García E, Cañadas-Garre M, Calleja-Hernández MÁ. Molecular biomarkers in colorectal carcinoma. Pharmacogenomics 2015; 16:1189-222. [PMID: 26237292 DOI: 10.2217/pgs.15.63] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer is a tumor with increasing incidence which represents one of the first leading causes of death worldwide. Gene alterations described for colorectal cancer include genome instability (microsatellite and chromosomal instability), CpG islands methylator phenotype, microRNA, histone modification, protein biomarkers, gene mutations (RAS, BRAF, PI3K, TP53, PTEN) and polymorphisms (APC, CTNNB1, DCC). In this article, biomarkers with prognostic value commonly found in colorectal cancer will be reviewed.
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Affiliation(s)
- Elena Puerta-García
- Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain
| | - Marisa Cañadas-Garre
- Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain
| | - Miguel Ángel Calleja-Hernández
- Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain
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