Branching out: the clinical relevance of mismatch repair variants

Abstract

Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition syndrome caused by pathogenic variants (PVs) in mismatch repair (MMR) genes, leading to increased cancer risks, especially colorectal and endometrial cancers. Universal tumor screening through immunohistochemistry testing is now standard for CRC and EC patients diagnosed before age 70, helping identify LS even without family history. This dissertation aimed to improve LS detection strategies, refine cancer risk estimates, and explore the utility of mutational signature analysis for variant interpretation.

Key findings include a meta-analysis of 58,580 CRC cases showing that 38% of MMR-deficient tumors were linked to LS. For MSH6-associated LS, cancer risk estimates by age 80 were determined, with significant risks for colorectal and endometrial cancers, but no increased risk for breast or prostate cancer. Furthermore, the study explored the role of somatic sequencing in resolving diagnostic discrepancies and the impact of gene-specific and sex-specific surveillance. Finally, the utility of mutational signature analysis in classifying variants of uncertain significance was evaluated, revealing its potential but limited standalone value. The research advocates for refined, individualized surveillance strategies incorporating both germline and somatic data.