Lin Xiaojuan, Bian Ce, Liang Dongni, Li Lin, Tang Qingqing, Li Qingli
Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610041, P.R. China.
Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Chengdu, 610041, P.R. China.
BMC Cancer. 2025 Jul 11;25(1):1165. doi: 10.1186/s12885-025-14554-6.
Lynch syndrome (LS) is the most common inherited disorder predisposing individuals to colorectal cancer (CRC). It results from germline defects in DNA mismatch repair (MMR) genes, which are critical for maintaining genomic integrity. Here, we demonstrate that the expression of the MMR genes MLH1 and PMS2 are significantly reduced in colon tumor tissues from a proband with CRC, potentially resulting from inherited mutations in the MLH1 gene in LS cases. We identified a previously unreported in-frame deletion mutation in the MLH1 gene, classified as a variant of uncertain significance (VUS) due to its undefined role in oncogenesis. The majority of functionally inactive mutants were located in the residues Phe614 to Lys617, which form crucial hydrogen bonds. Taken together, our data reveals a correlation between this mutation and increased susceptibility to LS-associated tumors. The study offers a valuable insight for evaluating cancer susceptibility in carriers of MLH1 mutants, potentially elucidating the functional roles of MLH1 in oncogenesis.
林奇综合征（LS）是最常见的遗传性疾病，使个体易患结直肠癌（CRC）。它由DNA错配修复（MMR）基因的种系缺陷引起，这些基因对于维持基因组完整性至关重要。在此，我们证明在一名患有CRC的先证者的结肠肿瘤组织中，MMR基因MLH1和PMS2的表达显著降低，这可能是由于LS病例中MLH1基因的遗传突变所致。我们在MLH1基因中鉴定出一种先前未报道的框内缺失突变，由于其在肿瘤发生中的作用不明确，被归类为意义未明的变异（VUS）。大多数功能失活的突变体位于形成关键氢键的Phe614至Lys617残基处。综上所述，我们的数据揭示了这种突变与LS相关肿瘤易感性增加之间的相关性。该研究为评估MLH1突变携带者的癌症易感性提供了有价值的见解，可能阐明MLH1在肿瘤发生中的功能作用。
