Wang Ting-Yao, Chen Chao-Yu, Chuang Huei-Chieh, Jiang Yuan-Yuan, Lung Jrhau
Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital Chiayi, Chiayi, 613, Taiwan.
Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Chiayi, Chiayi, 613, Taiwan.
Mol Cytogenet. 2025 Mar 11;18(1):5. doi: 10.1186/s13039-025-00708-5.
Lynch syndrome is an autosomal dominant disorder predisposing individuals to colorectal and other cancers, primarily caused by variants in mismatch repair genes. This study describes a novel MSH6 variant affecting transcript structure in a Taiwanese family meeting the Amsterdam II criteria for Lynch syndrome. A 67-year-old male presented with jejunal adenocarcinoma and a strong family history of colorectal cancer. Immunohistochemistry revealed loss of MSH6 expression, while next-generation sequencing performed on tumor tissue failed to detect any MSH6 variants. Comprehensive genetic analysis, including RT-PCR and Sanger sequencing of both cDNA and genomic DNA, identified a novel exon 5-6 skipping variant in the MSH6 gene transcript (NM_000179.3:r.3262_3645del), linked to a 2268 bp deletion from the 3' portion of intron 4 to the middle of intron 6 of the MSH6 gene (NC_000002.12:g.47803007_47805274del). This variant was also detected in two of the patient's asymptomatic sons, highlighting its heritability and potential cancer predisposition. The study emphasizes the limitations of capture-enrichment NGS panels in detecting certain types of variants and underscores the value of orthogonal confirmation using cDNA analysis for transcript aberrations. The identification of this novel variant expands our understanding of Lynch syndrome's mutational spectrum and has implications for genetic diagnosis and counseling. Based on these findings, the patient was treated with pembrolizumab, resulting in stable disease for 8 months. This case highlights the importance of comprehensive genetic approaches in suspected Lynch syndrome cases and the potential utility of mRNA-based screening as an additional method when NGS analysis is negative and the clinical presentation strongly suggests Lynch syndrome.
林奇综合征是一种常染色体显性疾病，使个体易患结直肠癌和其他癌症，主要由错配修复基因的变异引起。本研究描述了一个符合林奇综合征阿姆斯特丹II标准的台湾家庭中一种影响转录结构的新型MSH6变异。一名67岁男性患有空肠腺癌，且有结直肠癌的家族病史。免疫组化显示MSH6表达缺失，而对肿瘤组织进行的二代测序未能检测到任何MSH6变异。包括对cDNA和基因组DNA进行逆转录聚合酶链反应（RT-PCR）和桑格测序在内的综合基因分析，在MSH6基因转录本中鉴定出一种新型的外显子5-6跳跃变异（NM_000179.3:r.3262_3645del），该变异与MSH6基因（NC_000002.12:g.47803007_47805274del）内含子4的3'部分到内含子6中部的2268 bp缺失有关。在该患者的两名无症状儿子中也检测到了这种变异，突出了其遗传性和潜在的癌症易感性。该研究强调了捕获富集二代测序面板在检测某些类型变异方面的局限性，并强调了使用cDNA分析对转录异常进行正交确认的价值。这种新型变异的鉴定扩展了我们对林奇综合征突变谱的理解，并对基因诊断和咨询具有重要意义。基于这些发现，该患者接受了帕博利珠单抗治疗，病情稳定了8个月。该病例突出了在疑似林奇综合征病例中采用综合基因方法的重要性，以及当二代测序分析为阴性且临床表现强烈提示林奇综合征时，基于mRNA的筛查作为一种额外方法的潜在效用。
