Determination of the spectrum and frequency of germline mutations in cancer predisposition genes in patients with pancreatic cancer

Author(s)

Lívia Munhoz Rodrigues

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
• Defense date: 2024-07-19

Examining board members

Maria Aparecida Azevedo Koike Folgueira; Taisa Manuela Bonfim Machado Lopes; Maria Aparecida Nagai; José Cláudio Casali da Rocha

• Advisor: Maria Aparecida Azevedo Koike Folgueira

Abstract

We evaluated the spectrum and frequency of pathogenic germline variants in a cohort of Brazilian pancreatic adenocarcinoma patients that represents a multiethnic population. METHODS: We included 192 pancreatic cancer patients unselected for family history of cancer. We used genomic DNA sequencing to evaluate a panel of 113 cancer genes and multiplex PCR of 46 ancestry-informative markers to determine genetic ancestry. RESULTS: The median age was 61 years; 63% presented advanced disease; 8.3% reported personal history of cancer; 4.7% and 16.1% reported a first-degree relative with pancreatic cancer or breast and/or prostate cancer, respectively. Although the main ancestry was European, there was considerable genetic composition admixture. Thirty-seven patients (19%) carried pathogenic germline variants in 24 genes, of which 6% were in predisposition genes (ATM, BRCA1, BRCA2, CDKN2A, MSH2, PALB2) and the other 13% in genes with limited or no association previously associated with pancreatic cancer (ACD, BLM, BRIP1, CHEK2, ERCC4, FANCA, FANCE, FANCM, GALNT12, MITF, MRE11, MUTYH, POLE, RAD51B, RAD51C, RECQL4, SDHA, TERF2IP), with 28 (14.5%) variants in genes related to the homologous DNA repair pathway.. The most frequently affected genes were CHEK2, ATM and FANC family. There was no difference in pathogenic germline variants frequency between: patients reporting or not first-degree relatives with cancer; patients with European or non-European ancestry predominance. There was no difference in overall survival for pathogenic germline variants carriers versus non-carriers, considering all genes and homologous DNA repair genes. CONCLUSIONS: In a cohort of admixed ancestry patients with pancreatic cancer, 19% were pathogenic/likely germline variant carriers. Genetic testing should be offered to all Brazilian patients with pancreatic cancer, regardless of their family history of cancer. Genes with limited or previously unrecognized association with pancreatic cancer should be further investigated to clarify their role in cancer risk (AU)

• FAPESP's process: 18/04712-9 - Determination of the spectrum and frequency of germline mutations in Cancer predisposing genes in patients with Pancreatic Cancer
• Grantee: Lívia Munhoz Rodrigues
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)