Wang Sumeng, Zhang Ke, Cheng Yifei, Liu Lingxiang, Du Mulong
Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 China.
Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166 China.
Phenomics. 2025 Mar 26;5(2):183-191. doi: 10.1007/s43657-024-00202-9. eCollection 2025 Apr.
Lynch syndrome (LS) is an inherited condition caused by germline mutations in genes involved in DNA mismatch repair (MMR), which could increase the risk of developing colorectal cancer and other types of cancers. Current understanding of MMR gene mutations cannot fully account for the genetic predisposition to LS-associated colon cancer. This study uncovered a novel germline mutation, c.661 A > G, in members of a three-generation family using next-generation sequencing technique, which was related to a vertically transmitted risk for LS-associated colon cancer. Genetically, c.661 A > G was proposed to modulate the transcriptional activity of through the DNA methylation alteration, as well as influence the stability of EpCAM protein. Through spatial transcriptomic analysis, we discovered a "cold" tumor microenvironment feature and distinct cellular interactions among epithelial cell subpopulations. In conclusion, these findings highlight the importance of identifying and characterizing novel pathogenic mutations of MMR genes to better understand the genetic basis of LS and its association with colon cancer.
The online version contains supplementary material available at 10.1007/s43657-024-00202-9.
林奇综合征（LS）是一种由参与DNA错配修复（MMR）的基因种系突变引起的遗传性疾病，它会增加患结直肠癌和其他类型癌症的风险。目前对MMR基因突变的认识尚不能完全解释LS相关结肠癌的遗传易感性。本研究使用下一代测序技术在一个三代家族成员中发现了一种新的种系突变c.661 A＞G，它与LS相关结肠癌的垂直传播风险有关。从遗传学角度来看，c.661 A＞G被认为通过DNA甲基化改变来调节 的转录活性，并影响EpCAM蛋白的稳定性。通过空间转录组分析，我们发现了一种“冷”肿瘤微环境特征以及上皮细胞亚群之间独特的细胞相互作用。总之，这些发现凸显了识别和表征MMR基因新致病突变对于更好地理解LS的遗传基础及其与结肠癌关联的重要性。
在线版本包含可在10.1007/s43657-024-00202-9获取的补充材料。
