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DOI: 10.1055/s-0045-1807911
Paired normal-tumor exome sequencing in metastatic prostate cancer: interplay between germline and somatic data
Authors
Introduction: Metastatic castration-resistant prostate tumors with mutations in homologous recombination repair (HRR) genes are vulnerable to the action of poly-ADP ribose polymerase inhibitors. Germline and somatic variations are intricately connected and together shape tumor initiation and progression, but their role in cancer, especially in a mixed ancestry population, remains poorly characterized.
Aim: We performed a large-scale prospective exome sequencing of matched tumor-blood samples from 193 Brazilian patients diagnosed with metastatic prostate cancer (PC), coupled with clinical annotation and genetic ancestry, to define the germline and somatic genomic landscape in our population.
Methods: This is a multicenter study, approved by the ethics committees, encompassing men with metastatic PC from all Brazilian regions. Germline DNA was extracted from blood and tumor DNA from formalin-fixed paraffin-embedded (FFPE) tissue. Whole-exome sequencing was performed, and genetic variants were interpreted according to specific guidelines.
Results: Pathogenic (PV) and likely pathogenic (LPV) germline variants were identified in 14.5% of patients, of which 5.7% were in genes significantly associated to higher risk for PC. PV and LPV in CHEK2, ATM, BRCA2 and PALB2 genes were the most common, all representing 18.1% of the mutated genes. The median age at diagnosis was 3 years earlier in PV and LPV carriers (61 years, 60.0-70.5) compared to non-carriers (64 years, 55.0-63.7) (p-value=0.032). Likely clonal hematopoiesis of indeterminate potential variants were identified in 7.8% (n = 15), mainly affecting DNMT3A and TET2 genes. In contrast to germline data, somatic results were obtained in 61(31.6%) of the samples. The most frequently mutated genes were TP53 (27.9%), SPOP (14.8%), GNAQ (11.5%), APC (8.2%), ATM (8.2%) and PTEN (8.2%), being mainly mutually exclusive. Overall, HRR mutations were identified in 18.2% of the cases, most of them showed the inactivation of the second allele within the tumor. The mean tumor mutational burden was 3.7 (±4.5) mutations/Mb and 8.3% (n = 5) samples showed more than 10 mutations/Mb.
Conclusion: To our knowledge, this is the first Brazilian study to perform comprehensive genomic analyses in patients with metastatic prostate cancer from different regions of the country. Our data demonstrate a low prevalence of PV and LPV in genes associated to PC risk and highlight the difficulties when working with exome on FFPE samples.
Corresponding author: Gabriel Souza Macedo (e-mail: gmacedoufrgs@gmail.com).
No conflict of interest has been declared by the author(s).
Publication History
Article published online:
06 May 2025
© 2025. 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/)
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Gabriel de Souza Macedo, Jaqueline Bohrer Schuch, Angélica Cerveira de Baumont, Giovana Dallaio Curzel, Claudia Bordignon, Mahira Lopes Rosa, Nathan Araujo Cadore, Juliana Sena de Souza, Daniela Lacerda Costa Louzeiro, Lilian Arruda do Rego Barros, Alessandra Notari, Aline Bobato Lara Gongora, Vitor Fiorin de Vasconcellos, Williams Fernandes Barra, Henrique Guesser Ascenco, Daniel D'Almeida Preto, Juliana Janoski de Menezes, Edilmar de Moura Santos, Gustavo Werutski, Pedro Emanuel Rubini Liedke, Gláucio Antônio Bertollo, Eduardo Kowalski Neto, André Luiz Campos Mancini, Marina Bessel, Daniela Dornelles Rosa. Paired normal-tumor exome sequencing in metastatic prostate cancer: interplay between germline and somatic data. Brazilian Journal of Oncology 2025; 21.
DOI: 10.1055/s-0045-1807911