Germline Variants and Risk for Pancreatic Cancer: A Systematic Review and Emerging Concepts

Abstract

Pancreatic cancer requires many genetic mutations. Combinations of underlying germline variants and environmental factors may increase the risk of cancer and accelerate the oncogenic process. We systematically reviewed, annotated, and classified previously reported pancreatic cancer-associated germline variants in established risk genes. Variants were scored using multiple criteria and binned by evidence for pathogenicity, then annotated with published functional studies and associated biological systems/pathways. Twenty-two previously identified pancreatic cancer risk genes and 337 germline variants were identified from 97 informative studies that met our inclusion criteria. Fifteen of these genes contained 66 variants predicted to be pathogenic (APC, ATM, BRCA1, BRCA2, CDKN2A, CFTR, CHEK2, MLH1, MSH2, NBN, PALB2, PALLD, PRSS1, SPINK1, TP53). Pancreatic cancer risk genes were organized into key biological mechanisms that promote pancreatic oncogenesis within an oncogenic model. Development of precision medicine approaches requires updated variant information within the framework of an oncogenic progression model. Complex risk modeling may improve interpretation of early biomarkers and guide pathway-specific treatment for pancreatic cancer in the future. Precision medicine is within reach.

FIGURE 1.

Progression model of PDAC oncogenesis. The probability that a person develops pancreatic cancer is dependent on progression through multiple stages, each of which requires changes to different robust biological systems. Prior knowledge of the biological function of key genes and pathogenic stresses allows for organization and integration of risk factors and their effects over time. Adapted from Whitcomb et al 2015.

FIGURE 2.

Flow chart describing the search and filter results of Query 2.