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Polymorphisms of DNA repair genes are associated with colorectal cancer in patients with Lynch syndrome.

ABSTRACT: BACKGROUND:DNA repair genes are crucial for maintaining genomic stability by preventing mutagenesis and carcinogenesis. The present retrospective cohort study aimed at investigating whether MLH1, APEX1, MUTYH, OGG1, NUDT1, XRCC5, XPA, and ERCC2 single nucleotide polymorphisms (SNPs) are associated with colorectal cancer (CRC) in Chinese population with Lynch syndrome. METHODS:From Amsterdam criteria family registry, we identified 270 patients with Lynch syndrome. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between DNA repair SNPs and CRC were calculated using a weighted Cox proportional hazard regression model. RESULTS:Heterozygous variants of rs1799832 in NUDT1 (HR = 2.97, 95% CI = 1.51-5.83) and rs13181 in ERCC2 (HR = 2.69, 95% CI = 1.10-6.55) were significantly associated with an increased risk of CRC compared with wild-type homozygous CC and TT genotypes, respectively. However, the variant CG+GG genotype of MUTYH rs3219489 was associated with a decreased risk of CRC (HR = 0.49, 95% CI = 0.26-0.91) compared with the homozygous CC wild-type counterparts. CONCLUSION:Our findings revealed that polymorphisms of DNA repair genes that include NUDT1, ERCC2, and MUTYH are associated with CRC in patients with Lynch syndrome in Chinese population. Further studies with large sample size are needed to confirm our findings.

SUBMITTER: Kamiza AB

PROVIDER: S-EPMC6081223 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Polymorphisms of DNA repair genes are associated with colorectal cancer in patients with Lynch syndrome.

Kamiza Abram B AB Hsieh Ling-Ling LL Tang Reiping R Chien Huei-Tzu HT Lai Chih-Hsiung CH Chiu Li-Ling LL Lo Tsai-Ping TP Hung Kuan-Yi KY You Jeng-Fu JF Wang Wen-Chang WC Hsiung Chao A CA Yeh Chih-Ching CC

Molecular genetics & genomic medicine 20180417

<h4>Background</h4>DNA repair genes are crucial for maintaining genomic stability by preventing mutagenesis and carcinogenesis. The present retrospective cohort study aimed at investigating whether MLH1, APEX1, MUTYH, OGG1, NUDT1, XRCC5, XPA, and ERCC2 single nucleotide polymorphisms (SNPs) are associated with colorectal cancer (CRC) in Chinese population with Lynch syndrome.<h4>Methods</h4>From Amsterdam criteria family registry, we identified 270 patients with Lynch syndrome. Hazard ratios (HR ...[more]

PMID: 29664240

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Project description:Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear.To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands.Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10,206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data.Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening).Of 10,206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach.Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.

Dataset Information

Polymorphisms of DNA repair genes are associated with colorectal cancer in patients with Lynch syndrome.

Publications

Polymorphisms of DNA repair genes are associated with colorectal cancer in patients with Lynch syndrome.

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