ArticleGastroenterology2015
Genetic Variants That Predispose to DNA Double-Strand Breaks in Lymphocytes From a Subset of Patients With Familial Colorectal Carcinomas.
Article in Gastroenterology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it, 37 citations in OpenAlex.
- A Systematic Literature Review of Whole Exome and Genome Sequencing Population Studies of Genetic Susceptibility to Cancer.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2020Pooled it
- Familial colorectal cancer: search for novel predisposition genes.Human genomics · 2025Article
- Case Report: Expansion of theFrontiers in oncology · 2025Article
- Association of Mutations in Replicative DNA Polymerase Genes with Human Disease: Possible Application ofInternational journal of molecular sciences · 2023Review
- Candidate variants in DNA replication and repair genes in early-onset renal cell carcinoma patients referred for germline testing.BMC genomics · 2023Article
- NEDD9 Restrains dsDNA Damage Response during Non-Small Cell Lung Cancer (NSCLC) Progression.Cancers · 2022Article
- Therapeutic implications of germline vulnerabilities in DNA repair for precision oncology.Cancer treatment reviews · 2022Review
- Review
- From APC to the genetics of hereditary and familial colon cancer syndromes.Human molecular genetics · 2021Review
- Biomarkers of therapeutic response with immune checkpoint inhibitors.Annals of translational medicine · 2021Review
- Exome sequencing of early-onset patients supports genetic heterogeneity in colorectal cancer.Scientific reports · 2021Article
- Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal Cancers.Cancers · 2021Article
- Prevalence and Spectrum of Predisposition Genes With Germline Mutations Among Chinese Patients With Bowel Cancer.Frontiers in genetics · 2021Article
- Candidate Gene Discovery in Hereditary Colorectal Cancer and Polyposis Syndromes-Considerations for Future Studies.International journal of molecular sciences · 2020Review
- Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer.Scientific reports · 2020Article
- Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes.Journal of clinical medicine · 2020Review
- Synthetic Lethal Targeting of Mitotic Checkpoints in HPV-Negative Head and Neck Cancer.Cancers · 2020Article
- Existing and Emerging Biomarkers for Immune Checkpoint Immunotherapy in Solid Tumors.Advances in therapy · 2019Review
- Implication of DNA repair genes in Lynch-like syndrome.Familial cancer · 2019Article
- A novel 4-gene prognostic signature for hypermutated colorectal cancer.Cancer management and research · 2019Article
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsDNA structural lesions are prevalent in sporadic colorectal cancer. Therefore, we proposed that gene variants that predispose to DNA double-strand breaks (DSBs) would be found in patients with familial colorectal carcinomas of an undefined genetic basis (UFCRC).
methodsWe collected primary T cells from 25 patients with UFCRC and matched patients without colorectal cancer (controls) and assayed for DSBs. We performed exome sequence analyses of germline DNA from 20 patients with UFCRC and 5 undiagnosed patients with polyposis. The prevalence of identified variants in genes linked to DNA integrity was compared with that of individuals without a family history of cancer. The effects of representative variants found to be associated with UFCRC was confirmed in functional assays with HCT116 cells.
resultsPrimary T cells from most patients with UFCRC had increased levels of the DSB marker γ(phosphorylated)histone2AX (γH2AX) after treatment with DNA damaging agents, compared with T cells from controls (P < .001). Exome sequence analysis identified a mean 1.4 rare variants per patient that were predicted to disrupt functions of genes relevant to DSBs. Controls (from public databases) had a much lower frequency of variants in the same genes (P < .001). Knockdown of representative variant genes in HCT116 CRC cells increased γH2AX. A detailed analysis of immortalized patient-derived B cells that contained variants in the Werner syndrome, RecQ helicase-like gene (WRN, encoding T705I), and excision repair cross-complementation group 6 (ERCC6, encoding N180Y) showed reduced levels of these proteins and increased DSBs, compared with B cells from controls. This phenotype was rescued by exogenous expression of WRN or ERCC6. Direct analysis of the recombinant variant proteins confirmed defective enzymatic activities.
conclusionsThese results provide evidence that defects in suppression of DSBs underlie some cases of UFCRC; these can be identified by assays of circulating lymphocytes. We specifically associated UFCRC with variants in WRN and ERCC6 that reduce the capacity for repair of DNA DSBs. These observations could lead to a simple screening strategy for UFCRC, and provide insight into the pathogenic mechanisms of colorectal carcinogenesis.
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