Whole-genome sequencing identified novel mutations in a Chinese family with lynch syndrome

Wan He; Shaowei Dong; Jing Shen; Jiutong Wu; Pan Zhao; Dongbing Li; Dongliang Wang; Na Tang; Chang Zou

doi:10.3389/fonc.2023.1036356

Whole-genome sequencing identified novel mutations in a Chinese family with lynch syndrome

Front Oncol. 2023 Feb 16:13:1036356. doi: 10.3389/fonc.2023.1036356. eCollection 2023.

Authors

Wan He^{1

2}, Shaowei Dong³, Jing Shen^{1

2}, Jiutong Wu⁴, Pan Zhao⁵, Dongbing Li⁶, Dongliang Wang⁶, Na Tang^{7

8}, Chang Zou⁹

Affiliations

¹ Department of Oncology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, Guangdong, China.
² Department of Oncology, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, China.
³ Department of Hematology and Oncology, Shenzhen Children's Hospital of China Medical University, Shenzhen, Guangdong, China.
⁴ Pathology Department, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, Guangdong, China.
⁵ School of Medicine, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, China.
⁶ Department of Medicine, ChosenMed Technology Beijing Co., Ltd, Beijing, China.
⁷ Department of Pathology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, Guangdong, China.
⁸ Department of Pathology, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, China.
⁹ School of Medicine, Life and Health Sciences, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, China.

Abstract

Background: 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.

Patients and methods: 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.

Results: 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.

Conclusion: 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.

Keywords: FSHR; Lynch syndrome; MMR pathway; MSH2; whole genome sequencing.

Grants and funding

This study was supported by the Shenzhen Science and Technology Innovation Commission (JCYJ20190807150403655, JCYJ20210324115800001, JCYJ20210324114402006, and JCYJ20180301170035531), the Health, Population and Family Planning Commission of Shenzhen Municipality (SZXJ2018023), the Guangdong Basic and Applied Basic Research Foundation (2020B1515120032, 2019B1515120033), the Shenzhen Key Medical Discipline Construction Fund (SZXK053 and SZXK018), and the Guangdong Provincial Natural Science Foundation (2021A1515010919).