Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers

Abstract

Background: Along with early onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; however, the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often unknown. Methods: We screened 71 patients with MPC of the stomach, colorectal, and endometrium, sequencing 65 cancer predisposition genes. A subset of 19 patients with early onset MPC of stomach and colorectum were further evaluated for at DNA repair and cancer related genes using both normal (germline) and tumor (somatic) whole exome sequencing. Results: Among 71 patients with MPCs, variants predicted to be pathogenic were observed in 15 (21.1%) patients and affected Lynch Syndrome (LS) genes: MLH1 (n=10), MSH6 (n=2), PMS2 (n=2), and MSH2 (n=1). All carriers had tumors with high microsatellite instability and 13 of them (86.7%) were early-onset, consistent with LS. In 19 patients with early-onset MPCs, loss of function (LoF) variants in RECQL5, including a rare East-Asian specific variant, were more prevalent in non-LS MPC than in matched sporadic cancer patients (OR=31.6, p=0.001). Additional evaluation of bi-allelic alterations in the tumor correctly identified LS genes in LS patients and candidates genes in non-LS patients including high-confidence LoF variants in 2 patients, FANCG (c.307+1G>C) and CASP8 (p.R221Sfs*17) both accompanied by somatic loss of heterozygosity in a gastric and a colorectal tumor, respectively. Conclusions: The results suggest that genetic screening should be considered for synchronous cancers and metachronous MPCs of the LS tumor spectrum, particularly in early-onset patients. Susceptibility variants in non-LS genes for MPC patients may exist, but evidence for their role is more elusive than for LS patients.