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Abstract
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.
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1 Universidade de Sao Paulo, FMUSP, Departamento de Radiologia e Oncologia, Comprehensive Center for Precision Oncology - C2PO, Centro de Investigação Translacional em Oncologia (CTO), Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Sao Paulo, Brazil (GRID:grid.11899.38) (ISNI:0000 0004 1937 0722)
2 Universidade de Sao Paulo, FMUSP, Registro Hospitalar de Cancer, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, São Paulo, Brazil (GRID:grid.11899.38) (ISNI:0000 0004 1937 0722)
3 Universidade de Sao Paulo, FMUSP, Departamento de Medicina Legal, Bioetica, Medicina do Trabalho e Medicina Física e Reabilitação, Faculdade de Medicina, Sao Paulo, Brazil (GRID:grid.11899.38) (ISNI:0000 0004 1937 0722)
4 Genesis Genomics, Sao Paulo, Brazil (GRID:grid.11899.38)
5 Universidade de Sao Paulo, FMUSP, Departamento de Radiologia e Oncologia, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Sao Paulo, Brazil (GRID:grid.11899.38) (ISNI:0000 0004 1937 0722)
6 Universidade de Sao Paulo, FMUSP, Departamento de Patologia Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Sao Paulo, Brazil (GRID:grid.11899.38) (ISNI:0000 0004 1937 0722)
7 Instituto D’or de Pesquisa e Ensino (IDOR), Salvador, Brazil (GRID:grid.472984.4)
8 Universidade de Sao Paulo FMUSP, Division of Digestive Surgery, Department of Gastroenterology, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Sao Paulo, Brazil (GRID:grid.11899.38) (ISNI:0000 0004 1937 0722)