|Grant Number:||5R01CA154823-02 Interpret this number|
|Primary Investigator:||Klein, Alison|
|Organization:||Johns Hopkins University|
|Project Title:||Validation and Fine-Scale Mapping of Pancreatic Cancer Susceptibility Loci|
DESCRIPTION (provided by applicant): Pancreatic cancer is the 4th leading cause of cancer death in the United States. This is in large part due to the rapidly fatal course of this disease, as the vast majority of patients die within months of diagnosis and the five- year survival rate is less than 5%. Like all cancers, pancreatic cancer is a fundamentally genetic disease caused by inherited and acquired genetic mutations. Two genome-wide association studies of pancreatic cancer, PanScan I and PanScan II, have recently been completed. These studies have identified four promising regions involved in pancreatic cancer susceptibility: ABO rs505922 (P=4.3.10-6), two correlated SNPs on chromosome 13q22.1, rs9543325 (P=3.3.10-11) and rs9564966 (P=5.9.10-8), rs3790844 (P=2.4.10-10) on chromosome 1q32.1, and rs401681 (P=3.7.10-7) on 5p15.33. The goal of this project is to conduct fine-mapping and large-scale validation genotyping of the potential pancreatic cancer susceptibility variants identified in the recently completed PanScan I and PanScan II studies, in an independent set of 4,000 cases and 4,000 controls from over 10 studies. This will be the first well-powered large-scale replication of these findings. Joint-analysis of these data with the data from PanScanI and II will also be conducted. We will also determine known risk factors for pancreatic cancer including, cigarette smoking and diabetes modify these associations. PUBLIC HEALTH RELEVANCE: Genome-wide association studies (GWAS) are powerful tools to identify changes in DNA associated with diseases. These studies have identified many genes that play an important role in breast, prostate and colon cancers but the first of these studies have only recently been completed for pancreatic cancer. Before the findings of these studies can be translated into the patient setting, replication of the initial findings needs to be conducted to establish that changes in DNA are "truly" associated with pancreatic cancer, not false findings. Furthermore, follow-up GWA studies also have the potential to identify novel associations. Therefore the goal of this study will be to validate the initial pancreatic cancer GWAS findings and identify novel DNA changes that may be associated with pancreatic cancer.
TERT gene harbors multiple variants associated with pancreatic cancer susceptibility.
Authors: Campa D, Rizzato C, Stolzenberg-Solomon R, Pacetti P, Vodicka P, Cleary SP, Capurso G, Bueno-de-Mesquita HB, Werner J, Gazouli M, Butterbach K, Ivanauskas A, Giese N, Petersen GM, Fogar P, Wang Z, Bassi C, Ryska M, Theodoropoulos GE, Kooperberg C, Li D, Greenhalf W, Pasquali C, Hackert T, Fuchs CS, Mohelnikova-Duchonova B, Sperti C, Funel N, Dieffenbach AK, Wareham NJ, Buring J, Holcátová I, Costello E, Zambon CF, Kupcinskas J, Risch HA, Kraft P, Bracci PM, Pezzilli R, Olson SH, Sesso HD, Hartge P, Strobel O, Ma?ecka-Panas E, Visvanathan K, Arslan AA, Pedrazzoli S, Sou?ek P, Gioffreda D, Key TJ, Talar-Wojnarowska R, Scarpa A, Mambrini A, Jacobs EJ, Jamroziak K, Klein A, Tavano F, Bambi F, Landi S, Austin MA, Vodickova L, Brenner H, Chanock SJ, Delle Fave G, Piepoli A, Cantore M, Zheng W, Wolpin BM, Amundadottir LT, Canzian F
Source: Int J Cancer, 2015 Nov 1;137(9), p. 2175-83.
EPub date: 2015 Jun 19.
Genes-environment interactions in obesity- and diabetes-associated pancreatic cancer: a GWAS data analysis.
Authors: Tang H, Wei P, Duell EJ, Risch HA, Olson SH, Bueno-de-Mesquita HB, Gallinger S, Holly EA, Petersen GM, Bracci PM, McWilliams RR, Jenab M, Riboli E, Tjřnneland A, Boutron-Ruault MC, Kaaks R, Trichopoulos D, Panico S, Sund M, Peeters PH, Khaw KT, Amos CI, Li D
Source: Cancer Epidemiol Biomarkers Prev, 2014 Jan;23(1), p. 98-106.
EPub date: 2013 Oct 17.
An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population.
Authors: Klein AP, Lindström S, Mendelsohn JB, Steplowski E, Arslan AA, Bueno-de-Mesquita HB, Fuchs CS, Gallinger S, Gross M, Helzlsouer K, Holly EA, Jacobs EJ, Lacroix A, Li D, Mandelson MT, Olson SH, Petersen GM, Risch HA, Stolzenberg-Solomon RZ, Zheng W, Amundadottir L, Albanes D, Allen NE, Bamlet WR, Boutron-Ruault MC, Buring JE, Bracci PM, Canzian F, Clipp S, Cotterchio M, Duell EJ, Elena J, Gaziano JM, Giovannucci EL, Goggins M, Hallmans G, Hassan M, Hutchinson A, Hunter DJ, Kooperberg C, Kurtz RC, Liu S, Overvad K, Palli D, Patel AV, Rabe KG, Shu XO, Slimani N, Tobias GS, Trichopoulos D, Van Den Eeden SK, Vineis P, Virtamo J, Wactawski-Wende J, Wolpin BM, Yu H, Yu K, Zeleniuch-Jacquotte A, Chanock SJ, Hoover RN, Hartge P, Kraft P
Source: PLoS One, 2013;8(9), p. e72311.
EPub date: 2013 Sep 13.
Recent progress in pancreatic cancer.
Authors: Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, Hruban RH
Source: CA Cancer J Clin, 2013 Sep;63(5), p. 318-48.
EPub date: 2013 Jul 15.
Identifying people at a high risk of developing pancreatic cancer.
Authors: Klein AP
Source: Nat Rev Cancer, 2013 Jan;13(1), p. 66-74.
EPub date: 2012 Dec 6.
Genome-wide sequencing to identify the cause of hereditary cancer syndromes: with examples from familial pancreatic cancer.
Authors: Roberts NJ, Klein AP
Source: Cancer Lett, 2013 Nov 1;340(2), p. 227-33.
EPub date: 2012 Nov 27.