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.MethodsFrom 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.ResultsHeterozygous 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.ConclusionOur 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.
Highlights
Lynch syndrome is a germline mutation in mismatch repair (MMR) genes (Boland, 2005)
The genotype frequencies of each DNA repair single nucleotide polymorphisms (SNPs) conformed to the Hardy–Weinberg equilibrium (HWE) (p value >.05)
The heterozygous CT genotype of NUDT1 rs1799832 was significantly associated with an increased risk of colorectal cancer (CRC) (HR = 2.97, 95% confidence intervals (CIs) = 1.51–5.83) compared with a wild-type homozygous CC genotype
Summary
Lynch syndrome is a germline mutation in mismatch repair (MMR) genes (Boland, 2005). MLH1 (OMIM: 120436), MSH2 (OMIM: 609309), MSH6 (OMIM: 600678), PMS2 (OMIM: 600259), and EPCAM (OMIM: 185535) germline mutations are responsible for Lynch syndrome (Lynch et al, 2009). In addition to the MMR, DNA repair genes such as APEX1 (OMIM: 107748), MUTYH (OMIM: 604933), OGG1 (OMIM: 601982), NUDT1 (OMIM: 600312), XRCC5 (OMIM: 194364), XPA (OMIM: 611153), and ERCC2 (OMIM: 126340) play a crucial role in repairing DNA mutations and preventing cancer development (Sancar, Lindsey-Boltz, Unsal-Kaßcmaz, & Linn, 2004). Polymorphisms of MLH1, APEX1, MUTYH, OGG1, NUDT1, and XRCC5 are associated with sporadic CRC (Kim et al, 2004; Lai et al, 2016; Yang et al, 2009) and other site-specific cancers (Li et al, 2011; Savina et al, 2016; Smith et al, 2011). The association between DNA repair genes and CRC in germline mutation carriers has rarely been investigated. Since germline mutation carriers have dysfunctional MMR genes and are at an increased risk of CRC, DNA repair genes are crucial for preventing mutations and cancer development. Rs1799832, XRCC5 rs828907, XPA rs1800975, and ERCC2 rs13181 were associated with CRC
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