Germline Variants in Patients with Multiple Primary Malignancies: Uncommon Presentations Beyond Classical Hereditary Syndromes

Le résumé fourni par la source

All articles of this category (opens in new window) Address for correspondence Mariana de Moura de Souza (marisdemoura@gmail.com) Background: Inherited genetic alterations may contribute to the development of multiple primary malignancies, even in individuals who do not fulfill the criteria for established hereditary syndromes. This study aimed to investigate associations between pathogenic variants in patients with multiple primary tumors. Methods: We retrospectively reviewed clinical and genomic data from patients diagnosed with two or more distinct primary malignancies, one being a solid tumor. All patients underwent next-generation sequencing using multigene panels with at least 136 genes between June 2018 and April 2024. Results: A total of 206 patients were evaluated, with a mean age of 64 years (SD: 14), 122 (59%) were female, and 122 (59%) self-identified as white. A positive family history of cancer was reported in 163 patients (79%). A notable subset (12%) presented with both hematologic and solid tumors. Frequent tumor pairings included breast and thyroid (7%), breast and gynecologic (7%), breast and cutaneous non-melanoma (6%), breast and lower gastrointestinal tract (4%), prostate and lung (3%), and prostate and urinary tract (3%). We identified 68 heterozygous pathogenic or likely pathogenic germline variants and 411 Variant of Uncertain Significance (VUS) across 121 genes. The most frequently altered high-penetrance genes were BRCA1, BRCA2, and TP53, each present in 2% of patients. All individuals with a BRCA1 mutation, except one (with gynecologic and thyroid cancers), had tumor combinations involving breast cancer. Among those with a BRCA2 mutation, half had tumors involving the upper gastrointestinal tract, and half had urinary tract tumors. Only one BRCA2 patient had both breast and gynecologic cancers, and one patient had three distinct primary tumors (upper gastrointestinal tract, urinary tract, and melanoma). Among individuals with a TP53 mutation, 75% carried the p.R337H variant. Half had metachronous tumors involving sarcomas, and the remaining half had central nervous system neoplasms. Additionally, 75% of TP53-mutated individuals had prostate cancer in combination with another malignancy. Notably, none of the patients with TP53 mutations had breast cancer. Conclusions: Individuals with multiple primary cancers and pathogenic germline variants often have uncommon tumor presentations. These findings support the potential utility of universal germline genetic testing in cancer patients, even in the absence of classic hereditary syndrome indicators. Publication History Article published online: 26 June 2026 © 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda. Rua Rego Freitas, 175, loja 1, República, São Paulo, SP, CEP 01220-010, Brazil Bibliographical Record Mariana de Moura de Souza, Ana Luiza Spina Nagy, Maria Fernanda Botelho Teixeira, Diego Lopes Paim Miranda, Isabela Prado Checchio, Fernando Moura, Uelson Donizeti Rocioli Junior, Fernanda Tereza de Lima, Pedro Luiz Serrano Uson Junior. Germline Variants in Patients with Multiple Primary Malignancies: Uncommon Presentations Beyond Classical Hereditary Syndromes. Brazilian Journal of Oncology 2026; 22. DOI: 10.1055/s-0046-1825390

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.