The molecular basis of lynch-like syndrome

Abstract

Lynch-like syndrome (LLS) refers to individuals with MMR-deficient Lynch syndrome (LS) spectrum tumors (in the absence of MLH1 methylation), in which no pathogenic germline mutation has been identified. Patients and their first-degree relatives are considered to have an intermediate risk of developing cancer between LS and the general population. In this chapter, we aimed to review the most promising work in the area. Double somatic variants in MMR genes have been frequently reported (27-82% of LLS cases), while somatic promoter hypermethylation does not play a role. Carriers of germline MMR variants of unknown significance and missed mutations are part of LLS. Germline mutations in POLE and biallelic MUTYH mutations have been reported rarely. With the advent of NGS technologies, other genes like FAN1, BUB1, MCM9, and SETD2 are emerging as candidate responsible genes for LLS.