DNA Mismatch Repair Gene Mosaicism Is Rare in People With Mismatch Repair-Deficient Cancers

Abstract

Lynch syndrome, the most common hereditary cancer syndrome (∼1 in 280 people), is caused by germline pathogenic variants in one of the DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2.1,2 People with Lynch syndrome have an increased risk of colorectal cancer (CRC), endometrial cancer (EC), and other cancers,3 including sebaceous skin tumors (SST).4 Identifying Lynch syndrome is important for clinical management and cancer prevention, but despite advances in next-generation sequencing, the detection of all pathogenic MMR gene variants remains challenging. Postzygotic mosaicism in the MMR genes is uncommon,5,6 but whether MMR mosaicism is truly rare or underdiagnosed due to the absence of systematic investigations is unclear.

Our aim in this study was to identify mosaic MMR pathogenic variants in people with MMR-deficient CRCs, ECs, or SSTs.