|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.
Winner's Curse Correction And Variable Thresholding Improve Performance Of Polygenic Risk Modeling Based On Genome-wide Association Study Summary-level Data
Authors: Shi J. , Park J.H. , Duan J. , Berndt S.T. , Moy W. , Yu K. , Song L. , Wheeler W. , Hua X. , Silverman D. , et al. .
Source: Plos Genetics, 2016 Dec; 12(12), p. e1006493.
Three New Pancreatic Cancer Susceptibility Signals Identified On Chromosomes 1q32.1, 5p15.33 And 8q24.21
Authors: Zhang M. , Wang Z. , Obazee O. , Jia J. , Childs E.J. , Hoskins J. , Figlioli G. , Mocci E. , Collins I. , Chung C.C. , et al. .
Source: Oncotarget, 2016-10-11 00:00:00.0; 7(41), p. 66328-66343.
Association Of Common Susceptibility Variants Of Pancreatic Cancer In Higher-risk Patients: A Pacgene Study
Authors: Childs E.J. , Chaffee K.G. , Gallinger S. , Syngal S. , Schwartz A.G. , Cote M.L. , Bondy M.L. , Hruban R.H. , Chanock S.J. , Hoover R.N. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2016 Jul; 25(7), p. 1185-91.
Female Chromosome X Mosaicism Is Age-related And Preferentially Affects The Inactivated X Chromosome
Authors: Machiela M.J. , Zhou W. , Karlins E. , Sampson J.N. , Freedman N.D. , Yang Q. , Hicks B. , Dagnall C. , Hautman C. , Jacobs K.B. , et al. .
Source: Nature Communications, 2016-06-13 00:00:00.0; 7, p. 11843.
Whole Genome Sequencing Defines The Genetic Heterogeneity Of Familial Pancreatic Cancer
Authors: Roberts N.J. , Norris A.L. , Petersen G.M. , Bondy M.L. , Brand R. , Gallinger S. , Kurtz R.C. , Olson S.H. , Rustgi A.K. , Schwartz A.G. , et al. .
Source: Cancer Discovery, 2016 Feb; 6(2), p. 166-75.
Analysis Of Heritability And Shared Heritability Based On Genome-wide Association Studies For Thirteen Cancer Types
Authors: Sampson J.N. , Wheeler W.A. , Yeager M. , Panagiotou O. , Wang Z. , Berndt S.I. , Lan Q. , Abnet C.C. , Amundadottir L.T. , Figueroa J.D. , et al. .
Source: Journal Of The National Cancer Institute, 2015 Dec; 107(12), p. djv279.
Tert Gene Harbors Multiple Variants Associated With Pancreatic Cancer Susceptibility
Authors: Campa D. , Rizzato C. , Stolzenberg-Solomon R. , Pacetti P. , Vodicka P. , Cleary S.P. , Capurso G. , Bueno-de-Mesquita H.B. , Werner J. , Gazouli M. , et al. .
Source: International Journal Of Cancer, 2015-11-01 00:00:00.0; 137(9), p. 2175-83.
Common Variation At 2p13.3, 3q29, 7p13 And 17q25.1 Associated With Susceptibility To Pancreatic Cancer
Authors: Childs E.J. , Mocci E. , Campa D. , Bracci P.M. , Gallinger S. , Goggins M. , Li D. , Neale R.E. , Olson S.H. , Scelo G. , et al. .
Source: Nature Genetics, 2015 Aug; 47(8), p. 911-6.
Brca1, Brca2, Palb2, And Cdkn2a Mutations In Familial Pancreatic Cancer: A Pacgene Study
Authors: Zhen D.B. , Rabe K.G. , Gallinger S. , Syngal S. , Schwartz A.G. , Goggins M.G. , Hruban R.H. , Cote M.L. , McWilliams R.R. , Roberts N.J. , et al. .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2015 Jul; 17(7), p. 569-77.
Genes-environment Interactions In Obesity- And Diabetes-associated Pancreatic Cancer: A Gwas Data Analysis
Authors: Tang H. , Wei P. , Duell E.J. , Risch H.A. , Olson S.H. , Bueno-de-Mesquita H.B. , Gallinger S. , Holly E.A. , Petersen G.M. , Bracci P.M. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2014 Jan; 23(1), p. 98-106.
Genome-wide Sequencing To Identify The Cause Of Hereditary Cancer Syndromes: With Examples From Familial Pancreatic Cancer
Authors: Roberts N.J. , Klein A.P. .
Source: Cancer Letters, 2013-11-01 00:00:00.0; 340(2), p. 227-33.
Recent Progress In Pancreatic Cancer
Authors: Wolfgang C.L. , Herman J.M. , Laheru D.A. , Klein A.P. , Erdek M.A. , Fishman E.K. , Hruban R.H. .
Source: Ca: A Cancer Journal For Clinicians, 2013 Sep; 63(5), p. 318-48.
Identifying People At A High Risk Of Developing Pancreatic Cancer
Authors: Klein A.P. .
Source: Nature Reviews. Cancer, 2013 Jan; 13(1), p. 66-74.
An Absolute Risk Model To Identify Individuals At Elevated Risk For Pancreatic Cancer In The General Population
Authors: Klein A.P. , Lindström S. , Mendelsohn J.B. , Steplowski E. , Arslan A.A. , Bueno-de-Mesquita H.B. , Fuchs C.S. , Gallinger S. , Gross M. , Helzlsouer K. , et al. .
Source: Plos One, 2013; 8(9), p. e72311.
Identification Of Germline Genomic Copy Number Variation In Familial Pancreatic Cancer
Authors: Al-Sukhni W. , Joe S. , Lionel A.C. , Zwingerman N. , Zogopoulos G. , Marshall C.R. , Borgida A. , Holter S. , Gropper A. , Moore S. , et al. .
Source: Human Genetics, 2012 Sep; 131(9), p. 1481-94.