Wang Xiufang, Ni Haichun, Zhu Lin, Huang Hui, Deng Aiping, Hu Jifa, Cai Wei, Li Juyi
Department of Pain, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Med (Lausanne). 2025 Mar 14;12:1527249. doi: 10.3389/fmed.2025.1527249. eCollection 2025.
This study aimed to analyze the pathogenic variants in one family with colorectal cancer and another with endometrial cancer and provide appropriate personalized prevention strategies for carriers of these genetic mutations.
One proband with colorectal cancer and another with endometrial cancer and their family members were enrolled in this study. Whole-exome sequencing was used to identify pathogenic gene mutations in both families. We compared the structural difference between the wild-type and mutant MSH2 proteins using SWISS-MODEL and PyMOL visualization software.
We identified one novel mutation (NM_000251.2:c.1486delT:p.L496*) in the gene in Family I and a known mutation (NM_001258271.1:c.884 + 4A > G) in the gene in Family II. The novel mutation (NM_000251.2:c.1486delT:p.L496*) caused a stop gain mutation, resulting in the absence of amino acids 496-934 in the mutant MSH2 protein. This led to the loss of Domain 5 and alterations in the sequences of Domain 3 and Domain 4 regions, resulting in premature termination of MSH2 protein coding. The known mutation (NM_001258271.1:c.884 + 4A > G) in causes the skipping of exon 10, producing a truncated protein and undergoing nonsense-mediated decay based on literature reports. Thus, 5-fluorouracil-based adjuvant chemotherapy is not recommended for patients with lynch syndrome.
The novel stop gain mutant (NM_000251.2:c.1486delT:p.L496*) in is deemed pathogenic for LS, and the mutant (NM_001258271.1:c.884 + 4A > G) in has been further confirmed to be pathogenic. These findings expand the spectrum of mismatch repair gene variations in the ethnic group Han of China and reaffirm the importance of genetic testing for LS.
本研究旨在分析一个结直肠癌家族和另一个子宫内膜癌家族中的致病变异，并为这些基因突变携带者提供适当的个性化预防策略。
本研究纳入了一名患有结直肠癌的先证者、一名患有子宫内膜癌的先证者及其家庭成员。采用全外显子测序来鉴定两个家族中的致病基因突变。我们使用SWISS-MODEL和PyMOL可视化软件比较了野生型和突变型MSH2蛋白之间的结构差异。
我们在家族I的基因中鉴定出一个新突变（NM_000251.2:c.1486delT:p.L496*），在家族II的基因中鉴定出一个已知突变（NM_001258271.1:c.884 + 4A>G）。新突变（NM_000251.2:c.1486delT:p.L496*）导致了一个终止密码子获得突变，使得突变型MSH2蛋白中缺少496-934位氨基酸。这导致了结构域5的缺失以及结构域3和结构域4区域序列的改变，从而导致MSH2蛋白编码提前终止。根据文献报道，基因中的已知突变（NM_001258271.1:c.884 + 4A>G）导致外显子10跳跃，产生截短蛋白并经历无义介导的衰变。因此，不建议对林奇综合征患者使用基于5-氟尿嘧啶的辅助化疗。
基因中的新终止密码子获得突变体（NM_000251.2:c.1486delT:p.L496*）被认为对林奇综合征具有致病性，基因中的突变体（NM_001258271.1:c.884 + 4A>G）已被进一步确认为具有致病性。这些发现扩展了中国汉族人群错配修复基因变异的谱，并再次证实了林奇综合征基因检测的重要性。
