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

Date:	2018 Sep
PMID:	30113427
Category:	2
Authors:	Wei Zhan, Celeste A Shelton, Phil J Greer 1, Randall E Brand, David C Whitcomb
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.

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Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, the National Institute of Health, or the National Institute of Diabetes and Digestive and Kidney Diseases.

The Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Diseases under the following award numbers:

Project Number:	Awardee Organization
U01DK108326	Baylor College of Medicine
U01DK108314	Cedars-Sinai Medical Center
U01DK108332	Indiana University
U01DK108323	Kaiser Foundation Research Institute
U01DK108288	Mayo Clinic
U01DK108327	Ohio State University
U01DK108300	Stanford University
U01DK108320	University of Florida
U01DK108306	University of Pittsburgh
U01DK108328	University of Texas MD Anderson Cancer Center