Abstract 1007: Screening pathogenic germline variants in prostate cancer predisposition genes in an ethnically diverse cohort of unselected prostate cancer patients
Authors: Vinícius Marques Rocha, Vitoria Pelegrino do Val, Maria Lucia Hirata Katayama, Tais Vaz, Simone Maistro, Isabela Arcanjo Nunez Arcanjo Nunez, Luciane Sussuchi da Silva, Fernando Marcon Passos, Jaqueline Wang, Rosimeire Aparecida Roela, Fátima Solange Pasini, Gláucia Fernanda de Lima Pereira, Rossana Veronica Mendonza Lopez, José Pontes Júnior, Fabio Pescarmona Gallucci, Juliana Macedo dos Santos, Leticia Montanha de Assis, Elisa Mei Utsunomiya, Beatriz Fernandes de Souza, Rafael Lara Nohmi, Gabriel Ficagna Zaccaron, Luiz Antonio Senna Leite, Maria del Pilar Estevez-Diz, Cristovam Scapulatempo Neto, Roger Chammas, William Carlos Nahas, Guilherme Lopes Yamamoto, Maria Aparecida Azevedo Koike Folgueira
Journal: Cancer Research (2025)

Abstract Introduction: There is limited data on the heritability of PrCa in Brazil, a country with a miscegenated ethnic composition. We enrolled participants in a case-control study aimed at calibrating a polygenic risk score. We now present preliminary results of 557 PrCa patients whose samples were analyzed using whole genome sequencing (WGS). We estimate genetic ancestry and assess the prevalence of pathogenic genetic variants (PGVs) in PrCa-related genes. Methods: We included unselected PrCa patients. Previously we performed in silico random downsampling of WGS data initially at 30x depth to 15x, using samples from 3 Brazilian people, to estimate percentages of variant similarities and rare variants missed due to lower coverage. Only high-quality, rare variants (≤ 1% in population databases), likely functional (exonic or splicing regions) were considered, excluding chromosomes X, Y, and mitochondrial DNA. Sequencing at 15x depth identified 94.2% to 97.1% of heterozygous variants detected at 30x, with a mean expected variant loss of 4.3%. Subsequently, we performed WGS at 15x depth on 557 samples of PrCa patients using Illumina technology. We screened data for germline mutations in a panel of 16 genes (including HOXB13) associated with high/moderate risk for PrCa. Ancestry admixture proportions were also estimated. Results: A total of 557 PrCa patients were included. The median age at diagnosis was 64.6 years (41—90y). Self-reported skin color consisted of White (44.8%), Brown (37.4%), and Black (13.2%). Most patients were diagnosed with clinical stages II (32.8%) and III (43.1%), and ISUP grades 2 (40.2%) and 3 (22.9%). There was significant ancestry admixture, with predominant EUR genetic composition (61.4%), followed by AFR (24.6%), INDIG (7.7%), Asian (1.6%), and Middle Eastern (4.7%). PGVs in high/moderate risk genes for PrCa were identified in 29 out of 557 patients (5.2%), including BRCA2 (n=8), CHEK2 (n=5), ATM, BRCA1, BRIP1, MLH1, PALB2, PMS2 (n=2 each), and MSH2, MSH6, NBN, RAD51C, and TP53 (n=1 each). One patient carried PGVs in both PALB2 and TP53. Variants included 9 frameshift, 4 splice site, and 17 missense mutations. All these variants will be confirmed in subsequent evaluations. Conclusion: In a predominantly mixed-population setting, WGS at 15x depth appears appropriate for screening high-risk variants. Although there is a small chance (∼5%) of missing rare PGVs or detecting false positives, from a population perspective, downsampling seems to be acceptable, comparing the benefits of sequencing at 15x twice the number of samples than 30x. Preliminary data suggest that the prevalence of PGVs in high/moderate-risk genes in PrCa patients is similar to other populations worldwide. The PGV spectrum identified is consistent with those described in Brazilian cancer patients. Supported by CNPQ Citation Format: Vinícius Marques Rocha, Vitoria Pelegrino do Val, Maria Lucia Hirata Katayama, Tais Vaz, Simone Maistro, Isabela Arcanjo Nunez Arcanjo Nunez, Luciane Sussuchi da Silva, Fernando Marcon Passos, Jaqueline Wang, Rosimeire Aparecida Roela, Fátima Solange Pasini, Gláucia Fernanda de Lima Pereira, Rossana Veronica Mendonza Lopez, José Pontes Júnior, Fabio Pescarmona Gallucci, Juliana Macedo dos Santos, Leticia Montanha de Assis, Elisa Mei Utsunomiya, Beatriz Fernandes de Souza, Rafael Lara Nohmi, Gabriel Ficagna Zaccaron, Luiz Antonio Senna Leite, Maria del Pilar Estevez-Diz, Cristovam Scapulatempo Neto, Roger Chammas, William Carlos Nahas, Guilherme Lopes Yamamoto, Maria Aparecida Azevedo Koike Folgueira. Screening pathogenic germline variants in prostate cancer predisposition genes in an ethnically diverse cohort of unselected prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1007.