Research Unit, Ålesund Hospital, Møre and Romsdal Hospital Trust, Ålesund, Norway.
Department of Medicine, Ålesund Hospital, Møre and Romsdal Hospital Trust, Ålesund, Norway.
Sci Rep. 2023 Nov 1;13(1):18783. doi: 10.1038/s41598-023-44120-8.
Lynch syndrome (LS) is characterised by an increased risk of developing colorectal cancer (CRC) and other extracolonic epithelial cancers. It is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes or the EPCAM gene, leading to a less functional DNA MMR system. Individuals diagnosed with LS (LS individuals) have a 10-80% lifetime risk of developing cancer. However, there is considerable variability in the age of cancer onset, which cannot be attributed to the specific MMR gene or variant alone. It is speculated that multiple genetic and environmental factors contribute to this variability, including two single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene: C677T (rs1801133) and A1298C (rs1801131). By decreasing MTHFR activity, these SNPs theoretically reduce the silencing of DNA repair genes and increase the availability of nucleotides for DNA synthesis and repair, thereby protecting against early-onset cancer in LS. We investigated the effect of these SNPs on LS disease expression in 2,723 LS individuals from Australia, Poland, Germany, Norway and Spain. The association between age at cancer onset and SNP genotype (risk of cancer) was estimated using Cox regression adjusted for gender, country and affected MMR gene. For A1298C (rs1801131), both the AC and CC genotypes were significantly associated with a reduced risk of developing CRC compared to the AA genotype, but no association was seen for C677T (rs1801133). However, an aggregated effect of protective alleles was seen when combining the alleles from the two SNPs, especially for LS individuals carrying 1 and 2 alleles. For individuals with germline pathogenic variants in MLH1, the CC genotype of A1298C was estimated to reduce the risk of CRC significantly by 39% (HR = 0.61, 95% CI 0.42, 0.89, p = 0.011), while for individuals with pathogenic germline MSH2 variants, the AC genotype (compared to AA) was estimated to reduce the risk of CRC by 26% (HR = 0.66, 95% CI 0.53, 0.83, p = 0.01). In comparison, no association was observed for C677T (rs1801133). In conclusion, our study suggests that combining the MMR gene information with the MTHFR genotype, including the aggregated effect of protective alleles, could be useful in developing an algorithm that estimates the risk of CRC in LS individuals.
林奇综合征（LS）的特征是结直肠癌（CRC）和其他结外上皮癌的发病风险增加。它是由 DNA 错配修复（MMR）基因或 EPCAM 基因中的致病性种系变异引起的，导致 DNA MMR 系统功能降低。诊断为 LS（LS 个体）的个体一生中患癌症的风险为 10-80%。然而，癌症发病的年龄存在相当大的差异，不能仅归因于特定的 MMR 基因或变异。据推测，多种遗传和环境因素导致了这种变异性，包括亚甲基四氢叶酸还原酶（MTHFR）基因中的两个单核苷酸多态性（SNP）：C677T（rs1801133）和 A1298C（rs1801131）。这些 SNP 理论上通过降低 MTHFR 活性，减少 DNA 修复基因的沉默，并增加核苷酸用于 DNA 合成和修复的可用性，从而预防 LS 中早发性癌症。我们在来自澳大利亚、波兰、德国、挪威和西班牙的 2723 名 LS 个体中研究了这些 SNP 对 LS 疾病表达的影响。使用 Cox 回归调整性别、国家和受影响的 MMR 基因，估计癌症发病年龄与 SNP 基因型（癌症风险）之间的关联。对于 A1298C（rs1801131），与 AA 基因型相比，AC 和 CC 基因型均与 CRC 发病风险降低显著相关，但 C677T（rs1801133）未见相关。然而，当结合两个 SNP 的保护性等位基因时，会看到聚合效应，尤其是对于携带 1 和 2 个等位基因的 LS 个体。对于 MLH1 种系致病性变异的个体，A1298C 的 CC 基因型估计可使 CRC 的风险显著降低 39%（HR=0.61，95%CI 0.42，0.89，p=0.011），而对于 MSH2 种系致病性变异的个体，AC 基因型（与 AA 相比）估计可使 CRC 的风险降低 26%（HR=0.66，95%CI 0.53，0.83，p=0.01）。相比之下，C677T（rs1801133）未见相关。总之，我们的研究表明，将 MMR 基因信息与 MTHFR 基因型（包括保护性等位基因的聚合效应）相结合，可能有助于开发一种估计 LS 个体 CRC 风险的算法。
