Journal Article

Prevalence of germline variants in Brazilian pancreatic carcinoma patients

Fridman, Cintia, Lopes, Edia Filomena di Tullio, Segatelli, Vanderlei, Estevez-Diz, Maria del Pilar, Serio, Pedro Adolpho de Menezes Pacheco, Leite, Luiz Antonio Senna, Rodrigues, Lívia Munhoz, Katayama, Maria Lucia Hirata, Barros, Luciana Rodrigues Carvalho, Rocha, Vinícius Marques, Ribeiro Junior, Ulysses, Guindalini, Rodrigo Santa Cruz, Gonçalves, Fernanda Toledo, Lopez, Rossana Veronica Mendoza, Maistro, Simone, Folgueira, Maria Aparecida Azevedo Koike

2024

Overview

We evaluated the prevalence of pathogenic/likely pathogenic germline variants (PGV) in Brazilian pancreatic adenocarcinoma (PC) patients, that represent a multiethnic population, in a cross-sectional study. We included 192 PC patients unselected for family history of cancer. We evaluated a panel of 113 cancer genes, through genomic DNA sequencing and 46 ancestry-informative markers, through multiplex PCR. The median age was 61 years; 63.5% of the patients presented disease clinical stages III or IV; 8.3% reported personal history of cancer; 4.7% and 16.1% reported first-degree relatives with PC or breast and/or prostate cancer, respectively. Although the main ancestry was European, there was considerable genetic composition admixture. Twelve patients (6.25%) were PGV carriers in PC predisposition genes ( ATM , BRCA1 , BRCA2 , CDKN2A , MSH2 , PALB2 ) and another 25 (13.0%) were PGV carriers in genes with a limited association or not previously associated with PC ( ACD , BLM , BRIP1 , CHEK2 , ERCC4 , FANCA , FANCE , FANCM , GALNT12 , MITF , MRE11 , MUTYH , POLE , RAD51B , RAD51C , RECQL4 , SDHA , TERF2IP) . The most frequently affected genes were CHEK2 , ATM and FANC . In tumor samples from PGV carriers in ACD , BRIP1 , MRE11 , POLE , SDHA , TERF2IP , which were examined through exome sequencing, the main single base substitutions (SBS) mutational signature was SBS1+5+18, probably associated with age, tobacco smoking and reactive oxygen species. SBS3 associated with homologous repair deficiency was also represented, but on a lower scale. There was no difference in the frequency of PGV carriers between: (a) patients with or without first-degree relatives with cancer; and (b) patients with admixed ancestry versus those with predominantly European ancestry. Furthermore, there was no difference in overall survival between PGV carriers and non-carriers. Therefore, genetic testing should be offered to all Brazilian pancreatic cancer patients, regardless of their ancestry. Genes with limited or previously unrecognized associations with pancreatic cancer should be further investigated to clarify their role in cancer risk.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/337 / 631/67 / Adenocarcinoma / Adenocarcinoma - genetics / Adult / Aged / Aged, 80 and over / Brazil - epidemiology / BRCA1 protein / BRCA2 protein / Breast cancer / Cross-Sectional Studies / DNA sequencing / Female / Genealogy / Genetic ancestry / Genetic Predisposition to Disease / Genetic screening / Genetics / Germ-Line Mutation / Germline variants / Health risks / Humanities and Social Sciences / Humans / Male / Middle Aged / MRE11 protein / MSH2 protein / multidisciplinary / Pancreatic cancer / Pancreatic carcinoma / Pancreatic Neoplasms - epidemiology / Pancreatic Neoplasms - genetics / Population studies / Prevalence / Prostate cancer / Reactive oxygen species / Science / Science (multidisciplinary) / Tobacco smoking / Whole genome sequencing