Abstract IA03: Genetic and non-genetic risk factors of pancreatic cancer

In the United States, incidence and mortality rates of pancreatic cancer (PC) have remained largely unchanged since 1973. During 2005-2009, the incidence rate for Whites was 11.6/105 and for African-Americans, 15.2/105. Mortality rates were 10.7/105 for Whites and 13.8/105 for African-Americans. The 5-year survival has been 4-7% for decades. The absolute number of new cases and deaths due to PC has been increasing steadily since 2004 due to the baby-boomer generation reaching the risk window (where median age at diagnosis is 71 years). By 2030, PC will be the second most common cause of cancer mortality, after lung cancer. Already, in 2016 it is estimated to be the third leading cause of cancer death, surpassing deaths from breast cancer. Though the etiology of PC remains to be fully understood, we have learned much in the past decade in a variety of case-control and cohort studies on non-genetic and genetic risk factors. Non genetic factors: Host and lifestyle factors such as cigarette smoking, high body mass index, and heavy alcohol use, and long-standing type II diabetes mellitus and chronic pancreatitis, are associated with increased risk. The range of increased risks among these factors are two- to three fold increased risk over the general population. Other epidemiological investigations have implicated environmental exposures such as pesticides, asbestos, benzene and chlorinated hydrocarbons, with odds ratios in the range of 1.2 to 1.7. Protective effects of factors have been observed with diets rich in fruits and vegetables, dietary fiber, aspirin use, and history of allergies. Genetic factors account for ~10% of all PC cases. The genetic risk factors for PC have been pursued along two lines of inquiry. The first line of inquiry involves studies of high risk families, particularly those kindreds meeting criteria for familial pancreatic cancer (FPC) by containing at least two affected first degree relatives. Family-based studies and new methods for gene discovery, including next generation sequencing, have significantly increased our understanding of low frequency predisposition mutations, and the proportion of patients who carry mutations in genes such as BRCA1, BRCA2, CDKN2A, PALB2, ATM, mismatch repair genes (Lynch syndrome), and PRSS1 and SPINK2 (hereditary pancreatitis). Novel predisposition genes, among them a host of DNA repair genes, continue to be identified and emphasize the genetic heterogeneity of PC. As sporadic case series are being screened for mutations, we are finding that family history of PC is not a necessary requirement to be a PC mutation carrier. Predisposition genetic testing for individuals in FPC kindreds is feasible, and evolving, but typically will consist of sequencing a panel of multiple genes. The second line of inquiry involves large series of sporadic cases and non-cancer controls who are screened agnostically with thousands of single nucleotide polymorphisms (SNPs) that are studied in genome wide association studies (GWAS). Through this approach, numerous low penetrance but common variants have been implicated as contributing to PC risk, including SNPs in genes or regions such as ABO, NR5A2, CLPTMIL-TERT, LINC-PINT, BCAR1/CTRB1/CTRB2, PDX1, ZNRF3, LINC00673, SUGCT, TP63, and ETAA1. In general, these findings have helped generate new lines of inquiry for further understanding of PC etiology. Ongoing research continues to identify new risk factors and gene-environment interactions. Improvements in risk assessment and preventive interventions are increasingly becoming plausible. Citation Format: Gloria M. Petersen.{Authors}. Genetic and non-genetic risk factors of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA03.