Tumor analysis of MMR genes in Lynch-like syndrome: challenges associated to results interpretation

Abstract

Abstract Up to 70% of suspected Lynch syndrome patients harboring MMR deficient tumors lack identifiable germline pathogenic variants in MMR genes, being referred to as Lynch-like syndrome (LLS). Previous studies have reported biallelic somatic MMR inactivation in 15–95% LLS-associated tumors. However, translating tumor testing results into patient management remains controversial. Our aim is to assess the challenges associated to the implementation of tumoral analyses in routine genetic testing workflows. Here we present the clinical characterization of 229 LLS patients. MMR testing was performed in 39 available tumors, and results were analyzed using two variant allele frequency (VAF) thresholds (≥ 5% and ≥ 10%). More biallelic somatic MMR inactivating events were identified at VAF ≥ 5% than ≥ 10% (35.9% vs. 25.6%), although the rate of non-concordant results regarding immunohistochemical pattern increased (30.8% vs. 20.5%). Standardized protocols for the analysis and interpretation of tumoral MMR testing are needed to improve management of LLS individuals.