Tumor analysis of MMR genes in Lynch-like syndrome: Challenges associated with results interpretation

Abstract

Lynch syndrome; Mismatch repair genes; Tumor testing

Síndrome de Lynch; Genes reparadores de desajustes; Pruebas de tumores

Síndrome de Lynch; Gens reparadors de desajustaments; Proves de tumors

Background 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 a variable range of LLS-associated tumors. Moreover, translating tumor testing results into patient management remains controversial. Our aim is to assess the challenges associated with the implementation of tumoral MMR gene testing in routine workflows. Methods Here, we present the clinical characterization of 229 LLS patients. MMR gene testing was performed in 39 available tumors, and results were analyzed using two variant allele frequency (VAF) thresholds (≥5% and ≥10%). Results and Discussion More biallelic somatic events were identified at VAF ≥ 5% than ≥10% (35.9% vs. 25.6%), although the rate of nonconcordant results regarding immunohistochemical pattern increased (30.8% vs. 20.5%). Interpretation difficulties question the current utility of the identification of MMR somatic hits in the diagnostic algorithm of suspected LS cases.

This study was supported by Carlos III National Health Institute and Ministerio de Ciencia e Innovación and funded by FEDER funds—a way to build Europe [PI19/00553; PID2019-111254RB-I00]; CIBERONC [CB16/12/00234]; and the Government of Catalonia (Secretariat for Universities and Research of the Department of Business and Knowledge, grant 2021SGR01112).