Hereditary pancreatic cancer syndromes

Pancreatic tumours encompass both exocrine carcinomas, predominantly pancreatic ductal adenocarcinoma (PDAC), and pancreatic neuroendocrine tumours (PNET) arising from islet-cell precursors. PDAC typically presents in adulthood, with median age at diagnosis in the seventh decade, and hereditary forms often present earlier, frequently before age 50-55. Hereditary disease occurs both within recognised cancer-predisposition syndromes, where syndromic features such as breast and ovarian cancer, melanoma, , neuroendocrine tumours of other organs, and as familial pancreatic cancer kindreds with two or more affected first-degree relatives but no syndromic phenotype. PNETs in hereditary settings most commonly arise within multisystem syndromes with characteristic extrapancreatic manifestations.

Hereditary syndromes and familial pancreatic cancer kindreds account for approximately 10% of cases.

The genetic conditions associated with pancreatic tumours follow autosomal dominant inheritance, Both syndromic forms (within cancer-predisposition syndromes) and non-syndromic familial pancreatic cancer kindreds segregate in this manner.

To date, no major gene locus has been identified for familial pancreatic cancer, but a large number of genes have been associated with pancreatic tumours. The genetic forms can be grouped into PDAC-predisposing and PNET-predisposing syndromes. Frequently identified causes include the following examples. In hereditary PDAC, BRCA2 is most frequently identified. PDAC-predisposing forms include (BRCA2) and (CDKN2A). PNET-predisposing forms include (MEN1)

• Where pancreatic tumours are suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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• Liu J, Mroczek M, Mach A, Stępień M, Aplas A, Pronobis-Szczylik B, et al. Genetics, Genomics and Emerging Molecular Therapies of Pancreatic Cancer. Cancers. 2023;15(3). doi: 10.3390/cancers15030779. PMID: . PMCID: PMC9913594.