Skip to main content
Grant Details

Grant Number: 5R01CA154823-07 Interpret this number
Primary Investigator: Klein, Alison
Organization: Johns Hopkins University
Project Title: Validation and Fine-Scale Mapping of Pancreatic Cancer Susceptibility Loci (STUDY)
Fiscal Year: 2018
Back to top


Abstract

? DESCRIPTION (provided by applicant): Inherited genetic factors play an important role in pancreatic cancer risk with up to 10% of patients with pancreatic cancer reporting a family history of disease. Despite our past successes in identifying low-risk common pancreatic cancer susceptibility loci using genome-wide association approaches or high-penetrance genes using genomic sequencing. Much of the genetic basis of pancreatic cancer remains unexplained. Therefore, we hypothesize that by bringing together these two unique datasets (GWAS and whole-genome sequencing) we will be able to address some of the limitations of our previous analyses and identify novel pancreatic cancer susceptibility loci. Furthermore, leveraging our whole genome sequencing data we will be able to fine-map recently associated regions and develop a prioritized list of variants for future functional studies. We will accomplish these goal first conducting association analysis of whole genome sequencing data from 638 patients in 593 familial pancreatic cancer kindreds compared to 818 controls. We then use this genomic sequencing data to impute these variants into 9,220 pancreatic cancer patients and 12,567 controls followed by association analysis of the imputed data. We will also use this imputed data to fine-map previously established pancreatic cancer susceptibility loci. Candidate variants will then be directly genotyped in approximately 6,000 pancreatic cancer patients and 5,500 controls. We anticipate this work will identify novel pancreatic cancer susceptibility variants as well as identify putatively functional variants that may underlie some of the recently reported association signals. This will pave the way for identification of functional variants responsible fr these association signals and how environmental factors interact with the variants, which in turn will improve our understanding of the etiology of pancreatic cancer.

Back to top


Publications

Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance.
Authors: Canto M.I. , Almario J.A. , Schulick R.D. , Yeo C.J. , Klein A. , Blackford A. , Shin E.J. , Sanyal A. , Yenokyan G. , Lennon A.M. , et al. .
Source: Gastroenterology, 2018-05-24 00:00:00.0; , .
EPub date: 2018-05-24 00:00:00.0.
PMID: 29803839
Related Citations

are associated with pancreatic cancer.
Authors: Tamura K. , Yu J. , Hata T. , Suenaga M. , Shindo K. , Abe T. , MacGregor-Das A. , Borges M. , Wolfgang C.L. , Weiss M.J. , et al. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2018-05-01 00:00:00.0; 115(18), p. 4767-4772.
EPub date: 2018-04-18 00:00:00.0.
PMID: 29669919
Related Citations

Genetic variants in the platelet-derived growth factor subunit B gene associated with pancreatic cancer risk.
Authors: Duan B. , Hu J. , Liu H. , Wang Y. , Li H. , Liu S. , Xie J. , Owzar K. , Abbruzzese J. , Hurwitz H. , et al. .
Source: International Journal Of Cancer, 2018-04-01 00:00:00.0; 142(7), p. 1322-1331.
EPub date: 2017-12-04 00:00:00.0.
PMID: 29168174
Related Citations

Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.
Authors: Klein A.P. , Wolpin B.M. , Risch H.A. , Stolzenberg-Solomon R.Z. , Mocci E. , Zhang M. , Canzian F. , Childs E.J. , Hoskins J.W. , Jermusyk A. , et al. .
Source: Nature Communications, 2018-02-08 00:00:00.0; 9(1), p. 556.
EPub date: 2018-02-08 00:00:00.0.
PMID: 29422604
Related Citations

Inherited pancreatic cancer.
Authors: Chen F. , Roberts N.J. , Klein A.P. .
Source: Chinese Clinical Oncology, 2017 Dec; 6(6), p. 58.
PMID: 29307198
Related Citations

Quantifying the genetic correlation between multiple cancer types.
Authors: Lindström S. , Finucane H. , Bulik-Sullivan B. , Schumacher F.R. , Amos C.I. , Hung R.J. , Rand K. , Gruber S.B. , Conti D. , Permuth J.B. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2017-06-21 00:00:00.0; , .
EPub date: 2017-06-21 00:00:00.0.
PMID: 28637796
Related Citations

Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148.
Authors: Fang J. , Jia J. , Makowski M. , Xu M. , Wang Z. , Zhang T. , Hoskins J.W. , Choi J. , Han Y. , Zhang M. , et al. .
Source: Nature Communications, 2017-05-02 00:00:00.0; 8, p. 15034.
EPub date: 2017-05-02 00:00:00.0.
PMID: 28447668
Related Citations

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.
PMID: 28036406
Related Citations

Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression.
Authors: Hoskins J.W. , Ibrahim A. , Emmanuel M.A. , Manmiller S.M. , Wu Y. , O'Neill M. , Jia J. , Collins I. , Zhang M. , Thomas J.V. , et al. .
Source: Human Molecular Genetics, 2016-11-01 00:00:00.0; 25(21), p. 4726-4738.
PMID: 28172817
Related Citations

Circulating Tumor Cells Expressing Markers Of Tumor Initiating Cells Predict Poor Survival And Cancer Recurrence In Patients With Pancreatic Ductal Adenocarcinoma
Authors: Poruk K.E. , Blackford A.L. , Weiss M.J. , Cameron J.L. , He J. , Goggins M.G. , Rasheed Z. , Wolfgang C.L. , Wood L.D. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2016-10-27 00:00:00.0; , .
PMID: 27789528
Related Citations

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.
PMID: 27579533
Related Citations

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.
PMID: 27197284
Related Citations

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.
EPub date: 2016-06-13 00:00:00.0.
PMID: 27291797
Related Citations

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.
PMID: 26658419
Related Citations

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.
PMID: 26464424
Related Citations

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.
PMID: 25940397
Related Citations

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.
PMID: 26098869
Related Citations

Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.
Authors: Wang Z. , Zhu B. , Zhang M. , Parikh H. , Jia J. , Chung C.C. , Sampson J.N. , Hoskins J.W. , Hutchinson A. , Burdette L. , et al. .
Source: Human Molecular Genetics, 2014-12-15 00:00:00.0; 23(24), p. 6616-33.
EPub date: 2014-12-15 00:00:00.0.
PMID: 25027329
Related Citations

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.
PMID: 24136929
Related Citations

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.
PMID: 23196058
Related Citations

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.
PMID: 23222481
Related Citations

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.
PMID: 24058443
Related Citations

Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer.
Authors: Li D. , Duell E.J. , Yu K. , Risch H.A. , Olson S.H. , Kooperberg C. , Wolpin B.M. , Jiao L. , Dong X. , Wheeler B. , et al. .
Source: Carcinogenesis, 2012 Jul; 33(7), p. 1384-90.
PMID: 22523087
Related Citations




Back to Top