From genetic risk to clinical action: universal germline testing and surveillance in pancreatic cancer

Abstract Pancreatic cancer (PCA) can have a hereditary component linked to pathogenic germline variants (PGVs) in multiple cancer predisposition genes in app. 10–20 % of patients. Therefore, international clinical guidelines like NCCN and ASCO recommend genetic testing of patients afflicted with pancreatic ductal adenocarcinoma (PDAC) using a panel of high risk genes. However, recommendations vary regarding the genes to be studied reflecting ongoing uncertainty about their clinical significance. Emerging candidate genes such as BRIP1 show potential associations with PCA but have not yet been included in these guideline recommendations. The German S3-Guideline recommends testing of first degree relatives of PDAC patients only under certain conditions with respect to family history. Genetic testing of PDAC patients themselves remains restricted to therapeutic options regarding BRCA1/2 pathogenic variants. A comparison of germline testing approaches and yields across international guidelines and cohorts showed that while U.S. guidelines support universal testing for all PCA patients, European and German guidelines apply more restrictive family history criteria, thus missing PDAC patients afflicted with a genetic tumor risk syndrome (GENTURIS) carrying a pathogenic/likely pathogenic germline variant (PGV). In a local german cohort of 40 PCA patients tested largely outside of formal criteria, 32.5 % carried PGVs, mainly in PALB2 , ATM , BRCA1/2 , and CHEK2 . A meta-analysis of ten international cohorts comprising over 4,000 patients revealed a median PGV prevalence of 13 % in autosomal dominant genes, with BRIP1 variants identified more frequently than some established mismatch repair genes. These findings highlight the needs to establish routine germline testing for PDAC patients using standardized large gene panels in Europe, to improve data interpretation and reporting for enhancing hereditary risk detection and to implement personalized care for persons at risk for PDAC carrying PGVs.