Geographical, ethnic, and genetic differences in pancreatic cancer predisposition

Pancreatic cancer remains a leading cause of cancer-related mortality worldwide. Treatment outcomes remain largely dismal despite significant medical advancements. This lends urgency to the need to understand its risk factors in order to guide early detection and improve outcomes. There are both modifiable and non-modifiable risk factors, the more established of such being that of age, smoking, obesity, diabetes mellitus (DM), alcohol and certain genetic predisposition syndromes with underlying germline mutations. Some genetic predisposition syndromes such as BRCA1/2, PALB2, ATM, and CDKN2A are well-established, arising from germline mutations that result in carcinogenesis through mechanisms such as cell injury, dysregulation of cell growth, dysfunctional DNA repair, and disruption of cell mobility and adhesion. There is also a significant proportion of familial pancreatic cancer (FPC) for which the underlying predisposing genetic mechanism is not yet understood. Nuances have emerged in the ethnic and geographical differences of pancreatic cancer predisposition, and these may be attributed to differences in lifestyle, standard of living, socioeconomic factors, and genetics. This review describes in detail the factors contributing to pancreatic cancer with focus on ethnic and geographical differences and hereditary genetic syndromes. Greater insight into the interplay of these factors can guide clinicians and healthcare authorities in addressing modifiable risk factors, implementing measures for early detection in high-risk individuals, initiating early treatment of pancreatic cancer, and directing future research towards existing knowledge deficits, in order to improve survival outcomes.