He Wan, Dong Shaowei, Shen Jing, Wu Jiutong, Zhao Pan, Li Dongbing, Wang Dongliang, Tang Na, Zou Chang
Department of Oncology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, Guangdong, China.
Department of Oncology, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, China.
Front Oncol. 2023 Feb 16;13:1036356. doi: 10.3389/fonc.2023.1036356. eCollection 2023.
Lynch syndrome (LS) is caused by a germline mutation in one of the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. The definition of Lynch syndrome is based on clinical, pathological, and genetic findings. Therefore, the identification of susceptibility genes is essential for accurate risk assessment and tailored screening programs in LS monitoring.
In this study, LS was diagnosed clinically in a Chinese family using Amsterdam II criteria. To further explore the molecular characteristics of this LS family, we performed whole genome sequencing (WGS) to 16 members in this family and summarized the unique mutational profiles within this family. We also used Sanger sequencing technology and immunohistochemistry (IHC) to verify some of the mutations identified in the WGS analysis.
We showed that mutations in mismatch repair (MMR) related genes, as well as pathways including DNA replication, base excision repair, nucleotide excision repair, and homologous recombination were enhanced in this family. Two specific variants, MSH2 (p.S860X) and FSHR (p.I265V) were identified in all five members with LS phenotypes in this family. The MSH2 (p.S860X) variant is the first reported variant in a Chinese LS family. This mutation would result in a truncated protein. Theoretically, these patients might benefit from PD-1 (Programmed death 1) immune checkpoint blockade therapy. The patients who received nivolumab in combination with docetaxel treatments are currently in good health.
Our findings extend the mutation spectrum of genes associated with LS in MLH2 and FSHR, which is essential for future screening and genetic diagnosis of LS.
林奇综合征（LS）由错配修复基因（MLH1、MSH2、MSH6和PMS2）之一或EPCAM基因的种系突变引起。林奇综合征的定义基于临床、病理和基因发现。因此，鉴定易感基因对于LS监测中的准确风险评估和定制筛查计划至关重要。
在本研究中，使用阿姆斯特丹II标准对一个中国家庭进行了林奇综合征的临床诊断。为了进一步探索这个LS家庭的分子特征，我们对该家庭的16名成员进行了全基因组测序（WGS），并总结了该家庭内独特的突变谱。我们还使用桑格测序技术和免疫组织化学（IHC）来验证WGS分析中鉴定的一些突变。
我们发现该家庭中错配修复（MMR）相关基因以及包括DNA复制、碱基切除修复、核苷酸切除修复和同源重组在内的途径中的突变有所增加。在该家庭中所有具有LS表型的五名成员中鉴定出两个特定变体，即MSH2（p.S860X）和FSHR（p.I265V）。MSH2（p.S860X）变体是中国LS家庭中首次报道的变体。这种突变将导致截短蛋白。理论上，这些患者可能从程序性死亡受体1（PD-1）免疫检查点阻断治疗中获益。接受纳武单抗联合多西他赛治疗的患者目前健康状况良好。
我们的研究结果扩展了与MLH2和FSHR中LS相关基因的突变谱，这对于未来LS的筛查和基因诊断至关重要。
