PMS2 germline mutation c.943C>T (p.Arg315*)-induced Lynch syndrome-associated ovarian cancer

Abstract

Background: Lynch syndrome (LS) is an autosomal dominant cancer predisposition condition caused by germline heterozygous mutations in mismatch repair (MMR) genes. However, as one of the MMR genes, PMS2 mutation-induced LS-associated ovarian cancer (LSAOC) has rarely been reported. Methods: Next-generation sequencing (NGS) or Sanger sequencing was used to detect the genetic status of one family including four generations with 16 members. Then, quantitative real-time PCR (qPCR), western blotting, immunohistochemistry (IHC) staining, and Swiss-Model software were used to identify the function of the PMS2 mutation. Results: Five individuals [I-1, II-1, II-2, II-4, and III-2 (proband)] suffered from LS-associated cancers, for example, colon cancer, gastric cancer, and ovarian cancer, with the age of onset ranging from 39 to 70 years old. A PMS2 germline heterozygous mutation (c.943C>T) was confirmed in three members [II-9, III-2, and IV-1] by gene sequencing. In addition, this PMS2 mutation was verified by qPCR, western blotting, and IHC, and a dramatic change with partial loss of the C-terminal domain in an α-helix might be exhibited. Conclusion: Carrying PMS2 germline mutations (c.943C>T) confers an extremely high susceptibility of suffering from LS-associated cancers. Thus, close clinical monitoring and prophylactic surgery is highly recommended to help reduce the morbidity and mortality of LS-associated cancers.