Cancer Spectrum and Gene-Specific Patterns in Lynch Syndrome: Insights From 47 Families in a Brazilian Institutional Cohort.

Abstract

To characterize tumor-site distribution, age at diagnosis, sex distribution, and tumor multiplicity in a Brazilian institutional Lynch syndrome (LS) cohort stratified by mismatch repair (MMR) gene and genetic testing status, and to assess the impact of including nontested (NT) relatives. We conducted a retrospective, registry-based family cohort study of families ascertained in 2013-2019 with pathogenic or likely pathogenic variants in <i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i>, <i>PMS2</i>, or <i>EPCAM</i>. For each proband, pedigree enumeration was limited to one cancer-enriched parental lineage. Adults (≥18 years) were included for tumor-site analyses. Relatives were classified as carriers (genotype-confirmed), noncarriers, or NT. Only primary malignant tumors were counted. Outcomes were any primary malignancy, multiplicity (≥2 primaries), age at first primary, and gene-specific tumor profiles summarized per person and per tumor. Forty-seven families comprised 729 relatives; 111 (15.2%) underwent testing, identifying 78 carriers. Cohort composition was 78 (10.7%) carriers, 33 (4.5%) noncarriers, and 618 (84.8%) NT. Carriers were more often affected (≥1 tumor: 64.1% <i>v</i> 37.9% NT <i>v</i> 18.2% noncarriers), younger at first cancer (mean 42.3 <i>v</i> 47.3 years in NT), and more likely to have multiple primaries. Colorectal cancer predominated across genes; endometrial tumors were more frequent in <i>MLH1/MSH2</i>, and urothelial tumors clustered in <i>MSH2</i> (descriptive). After false discovery rate control across LS-spectrum sites, site-wise multigene contrasts were not significant. Carriers showed earlier onset and higher multiplicity, with gene-linked patterns consistent with LS heterogeneity. Low testing uptake broadened observed spectra among NT relatives, supporting cascade testing and genotype-tailored surveillance.