PMS2 Pathogenic Variant in Lynch Syndrome-Associated Colorectal Cancer with Polyps

Abstract

Background Lynch syndrome (LS) is an autosomal dominant condition due to the germline mutation in the mismatch repair (MMR) genes including MLH1 , MSH2 , MSH6, and PMS2 (post-meiotic segregation increased 2). The MMR mutation carriers have high risk for cancers. Pathogenic PMS2 variants are rarely reported in LS-associated colorectal cancer (CRC) with colorectal polyps. The aim of the study was to investigate the genetic etiology of CRC in an individual with CRC with multiple colorectal polyps and a family history of cancers. Patients and Methods The index patient was an African male affected by CRC with multiple colorectal polyps. The clinical diagnostic for LS was based on the Amsterdam II criteria and pedigree. Next-generation sequencing with inherited cancer genes panel was used to detect the pathogenic variant. Results The patient fulfilled the Amsterdam II criteria and the pedigree revealed a family history of recurrent CRC. A deleterious PMS2 germline heterozygous mutation c.2192_2196delTAACT was detected. Conclusion Our study supports the notion that LS may be associated with polyps and shows the predisposition of PMS2 heterozygous mutation in LS-associated CRC at young age.

Keywords: PMS2 deficiency; colorectal cancer; lynch syndrome; mismatch repair gene.

Fig. 1

Family pedigree of the index patient with a deleterious PMS2 mutation. (c.2192_2196delTAACT). Note three successive affected generations (vertical transmission). The index patient had colorectal cancer (CRC) at the age of 51 years and three family members also had cancer. His daughter (first-degree) 22-years old had breast cancer (BC). His sister at the age of 40 years, and his father (first-degree) died from CCR. CCT, clinical complete response.

Fig. 2

Macroscopic tumor per colonoscopy . Note hemorrhagic appearance of the tumor and presence of colonic polyps.

Fig. 3

PMS2 mutation. Mutation in exon 13 of PMS2 by deletion of five dinucleotides: thymine (T), adenines (A), cytosine (C), at position 2192 to 2196, defined as « c.2192_2196delTAACT ». This mutation is at the origin of a predictive pathogenic variant « p. Leu731Cysfs*3 »: codon substitution leucine position 731 in cysteine and premature stop codon, 3 amino acids later the substitution. rg, reference genome; pg, patient genome.