Zhang Shuai, Fu Guanyu, Sun Gongping, Tang Yuanxin, Meng Jin, Wang Zhigang, Su Rongjun, Liu Wei, Li Xiaoxia
Department of General Surgery, Yan'an people's Hospital, Shaanxi, China.
Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China.
Mol Genet Genomic Med. 2025 Jan;13(1):e2506. doi: 10.1002/mgg3.2506.
Lynch syndrome (LS) is an autosomal-dominant disorder that increases the risk of many cancers. To identify novel or rare pathogenic variants of MMR genes associated with LS, especially in Chinese pedigrees.
One four-generation Chinese Han family from northeast China with 29 members was enrolled. Clinical diagnosis of LS was established in this family, according to Amsterdam II. The proband and some relatives of the family were subjected to immunohistochemical analysis of MMR protein, microsatellite instability (MSI) testing, whole-exome sequencing, and Sanger sequencing.
Nine patients with 19 primary cancers were found in this family, with a wide spectrum of synchronous and metachronous cancers, including digestive, reproductive, respiratory, urinary, and other systems. In addition, one member of this family is found to have both thyroid and lung cancers, which have been reported only once in LS patients before but have not been considered extracolonic in the LS spectrum. The immunohistochemical analysis of the mother of the proband showed loss of MSH2 and MSH6 protein, and consistently, high microsatellite instability (MSI-H) was confirmed in LS patients. Furthermore, whole-exome sequencing identified a nonsense variant in MSH2, MSH2:NM_000251:c.351G > A(p.W117*), in all three tested LS patients (II-1, III-1, and III-4), but not in healthy relatives IV-1 in this family. This result is further verified by Sanger sequencing.
Uncover a rare nonsense variant in MSH2 gene, which contributes to LS of this family. The clinicopathological characteristics of LS in this family include common simultaneous or heterogeneous multiple primary cancers, a broad tumor spectrum, and a younger age with the continuation of genetic algebra.
林奇综合征（LS）是一种常染色体显性疾病，会增加多种癌症的发病风险。旨在鉴定与LS相关的错配修复（MMR）基因的新的或罕见的致病变异，尤其是在中国家系中。
招募了一个来自中国东北的四代汉族家庭，该家庭有29名成员。根据阿姆斯特丹标准Ⅱ，对这个家庭进行了LS的临床诊断。对该家系的先证者和一些亲属进行了MMR蛋白的免疫组化分析、微卫星不稳定性（MSI）检测、全外显子测序和桑格测序。
在这个家庭中发现了9名患有19种原发性癌症的患者，患有多种同时性和异时性癌症，包括消化系统、生殖系统、呼吸系统、泌尿系统和其他系统。此外，该家庭的一名成员同时患有甲状腺癌和肺癌，此前在LS患者中仅报道过一次，但在LS范围内未被视为结肠外癌症。先证者母亲的免疫组化分析显示MSH2和MSH6蛋白缺失，并且在LS患者中一致证实存在高微卫星不稳定性（MSI-H）。此外，全外显子测序在所有三名接受检测的LS患者（II-1、III-1和III-4）中鉴定出MSH2基因中的一个无义变异，即MSH2:NM_000251:c.351G＞A（p.W117*），但在该家庭的健康亲属IV-1中未发现。这一结果通过桑格测序得到进一步验证。
发现MSH2基因中的一种罕见无义变异，该变异导致了这个家庭的LS。这个家庭中LS的临床病理特征包括常见的同时性或异质性多原发性癌症、广泛的肿瘤谱以及遗传代数延续下的较年轻发病年龄。
