Prevalence and clinical correlations of Lynch syndrome (LS) in northeast Brazil.

Abstract

e22547 Background: LS is an autosomal dominant inherited condition with high risk for colorectal (CRC) and endometrial cancer, mostly. The LS is determined by a deficient Mismacht Repair (dMMR) system following germline mutations of MSH2, MLH1, MSH6, PMS2 and EPCAM genes. Identification of LS patients promotes adequate prevention and possible reduction of mortality for these population. The present study objetives to determine the frequencies of LS in a mixed race population from Northeast of Brazil, usually not represented in literature and characterize its genotype-fenotype feature. Methods: Our study prospectively screened 150 cancer patients (mostly CRC) with risk for LS according to NCCN guideline v2020 and performed germline mutational testing with a 33-multigene panel by NGS. Results: Median age was 48years and mainly female gender (63,3%). CRC was the most frequent tumor (n = 121, 80.7%), followed by breast cancer (11.3%), endometrium cancer (9.3%) and others (3,3% each). CCR patients presented MMR deficiency (dMMR) detected by IHC in a frequency of 29.3%. It was identified 32.7% of PV or PPV (according to ACMG criteria) with 20.7% for LS genes (mMMR). Two patients had 2 genes mutated. For CRC patients there was association of stage I-II tumors (p = 0,009) and right location (p < 0,001) with mutational status. There is no significant correlation of mutational status and other clinical caractheristics. MSH2 was the most frequently mutated (11) followed by MSH6 (10), heterozygous MUTYH (5), homozygous MUTHY (3), PMS2 (7), APC (4) and MLH1 (3) and others. MSH2 most frequent variants were c.388 389del (4) and c.2581C > T (2). Of the NCCN criteria for LS, personal history of CRC or endometrial cancer under 50 years of age was the most prevalent (67.3%) followed by tumoral dMMR (37.3%). dMMR tumor was the criteria with the best accuracy (sensibility 80.0 – 100.0% and specificity 76.6 – 93.5%) for LS detection. Patients with more than three criteria presented high sensibility and specificity values (80.6 and 90.3%, respectively). There were more than 60% of variants of uncertain significance variants (VUS). Conclusions: Our study detected a lower frequency of PV of LS genes (20,7%) than others even from Brazil, however it differs from these on criteria for LS (more inclusive), sequencing method (NGS multigene painel) and the population (derived from mixed caucasians, africans and native Indians). LS genotype correlates with CRC stages I-II and from right colon location. The most frequent mutated gene was MSH2 (c.388 389del and c.2581C > T). MLH1 was the less frequent mutated gene in our cohort.