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Grant Details

Grant Number: 5U01CA247283-03 Interpret this number
Primary Investigator: Klein, Alison
Organization: Johns Hopkins University
Project Title: Multi-Ancestry Mapping of Pancreatic Cancer Susceptibility Loci
Fiscal Year: 2022


The goal of this application is to improve our understanding of the genetic basis of pancreatic cancer. Pancreatic cancer is currently the 3rd leading cause of cancer death in the United States and it is projected there will be 56,770 new pancreatic cancer diagnosed in the United States in 2019. Over the past decade the incidence of pancreatic cancer has been steadily increasing. Despite the fact that pancreatic cancer incidence rates are higher among African Americans compared to the US White population there have been no large- scale genetic studies of pancreatic cancer in African Americans conducted to date. Furthermore, the relative rarity of pancreatic ductal adenocarcinoma cancer (PDAC) and the rapidly fatal disease course has resulted in limited samples sizes for all prior genome-wide association studies regardless of ancestral population. As such many common PDAC loci have yet to be identified due to limited statistical power. Large-scale, diverse collaborative studies of PDAC, are needed to dramatically increase our understanding of the inherited basis of this deadly disease. Our proposal is designed to specifically address this need. First, we will conduct the first genetic study of pancreatic cancer risk specifically focused on African Americans through whole genome sequencing. As part of this study we are bringing together African American pancreatic cancer patients and controls from our two, large established, successful pancreatic cancer consortiums, the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case Control Consortium (PanC4). Secondly, we also expand our power to detect pancreatic cancer association across all ethnic groups by doubling the size of prior GWAS studies and conducting the first multi-ethnic genetic study of pancreatic cancer risk. We will conduct both ancestry stratified and ancestry-informed analysis including both single variant and gene-based tests of association of pancreatic cancer patients and controls. In addition, we will conduct gene x environment interaction analysis with known risk factors of smoking, BMI, diabetes, and alcohol intake. The specific aims of the project are to: Aim 1: To identify pancreatic cancer susceptibility loci in the African American population, Aim 2: To identify novel pancreatic cancer loci through multi-ethnic GWAS analyses; Aim 3: To fine-map regions associated with pancreatic cancer risk. In summary, this application seeks to identify novel pancreatic cancer loci, conduct the first genetic analysis of pancreatic cancer in individuals of African Ancestry, and leverage cross population genetic diversity to fine-map known pancreatic cancer susceptibility loci. !


Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases: Workshop Proceedings.
Authors: Mastracci T.L. , Apte M. , Amundadottir L.T. , Alvarsson A. , Artandi S. , Bellin M.D. , Bernal-Mizrachi E. , Caicedo A. , Campbell-Thompson M. , Cruz-Monserrate Z. , et al. .
Source: Diabetes, 2023-04-01; 72(4), p. 433-448.
PMID: 36940317
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Association Between Polycystic Ovary Syndrome and Risk of Pancreatic Cancer.
Authors: Peeri N.C. , Landicino M.V. , Saldia C.A. , Kurtz R.C. , Rolston V.S. , Du M. .
Source: JAMA oncology, 2022-12-01; 8(12), p. 1845-1847.
PMID: 36201203
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Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases: Workshop Proceedings.
Authors: Mastracci T.L. , Apte M. , Amundadottir L.T. , Alvarsson A. , Artandi S. , Bellin M.D. , Bernal-Mizrachi E. , Caicedo A. , Campbell-Thompson M. , Cruz-Monserrate Z. , et al. .
Source: Pancreas, 2022-10-01; 51(9), p. 1061-1073.
PMID: 37078927
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Pancreatic Adenocarcinoma: Trends in Epidemiology, Risk Factors, and Outcomes.
Authors: Afghani E. , Klein A.P. .
Source: Hematology/oncology clinics of North America, 2022 Oct; 36(5), p. 879-895.
EPub date: 2022-09-23.
PMID: 36154788
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The age-dependent association of risk factors with pancreatic cancer.
Authors: Yuan C. , Kim J. , Wang Q.L. , Lee A.A. , Babic A. , PanScan/PanC4 I-III Consortium , Amundadottir L.T. , Klein A.P. , Li D. , McCullough M.L. , et al. .
Source: Annals of oncology : official journal of the European Society for Medical Oncology, 2022 Jul; 33(7), p. 693-701.
EPub date: 2022-04-06.
PMID: 35398288
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A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO.
Authors: Blackford A.L. , Childs E.J. , Porter N. , Petersen G.M. , Rabe K.G. , Gallinger S. , Borgida A. , Syngal S. , Cote M.L. , Schwartz A.G. , et al. .
Source: British journal of cancer, 2021 Dec; 125(12), p. 1712-1717.
EPub date: 2021-10-26.
PMID: 34703010
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A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer.
Authors: Jermusyk A. , Zhong J. , Connelly K.E. , Gordon N. , Perera S. , Abdolalizadeh E. , Zhang T. , O'Brien A. , Hoskins J.W. , Collins I. , et al. .
Source: American journal of human genetics, 2021-10-07; 108(10), p. 1852-1865.
EPub date: 2021-09-23.
PMID: 34559995
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Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.
Authors: Julián-Serrano S. , Yuan F. , Wheeler W. , Benyamin B. , Machiela M.J. , Arslan A.A. , Beane-Freeman L.E. , Bracci P.M. , Duell E.J. , Du M. , et al. .
Source: The American journal of clinical nutrition, 2021-10-04; 114(4), p. 1408-1417.
PMID: 34258619
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Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.
Authors: Chen H. , Majumdar A. , Wang L. , Kar S. , Brown K.M. , Feng H. , Turman C. , Dennis J. , Easton D. , Michailidou K. , et al. .
Source: HGG advances, 2021-07-08; 2(3), p. 100041.
EPub date: 2021-06-12.
PMID: 34355204
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Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors.
Authors: Klein A.P. .
Source: Nature reviews. Gastroenterology & hepatology, 2021 Jul; 18(7), p. 493-502.
EPub date: 2021-05-17.
PMID: 34002083
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Two-Sample Mendelian Randomization Analysis of Associations Between Periodontal Disease and Risk of Cancer.
Authors: Corlin L. , Ruan M. , Tsilidis K.K. , Bouras E. , Yu Y.H. , Stolzenberg-Solomon R. , Klein A.P. , Risch H.A. , Amos C.I. , Sakoda L.C. , et al. .
Source: JNCI cancer spectrum, 2021 Jun; 5(3), .
EPub date: 2021-04-19.
PMID: 34222791
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Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3.
Authors: Mocci E. , Kundu P. , Wheeler W. , Arslan A.A. , Beane-Freeman L.E. , Bracci P.M. , Brennan P. , Canzian F. , Du M. , Gallinger S. , et al. .
Source: Cancer research, 2021-06-01; 81(11), p. 3134-3143.
EPub date: 2021-02-11.
PMID: 33574088
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A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.
Authors: López de Maturana E. , Rodríguez J.A. , Alonso L. , Lao O. , Molina-Montes E. , Martín-Antoniano I.A. , Gómez-Rubio P. , Lawlor R. , Carrato A. , Hidalgo M. , et al. .
Source: Genome medicine, 2021-02-01; 13(1), p. 15.
EPub date: 2021-02-01.
PMID: 33517887
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A pooled genome-wide association study identifies pancreatic cancer susceptibility loci on chromosome 19p12 and 19p13.3 in the full-Jewish population.
Authors: Streicher S.A. , Klein A.P. , Olson S.H. , Kurtz R.C. , Amundadottir L.T. , DeWan A.T. , Zhao H. , Risch H.A. .
Source: Human genetics, 2021 Feb; 140(2), p. 309-319.
EPub date: 2020-07-15.
PMID: 32671597
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Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.
Authors: Ghoneim D.H. , Zhu J. , Zheng W. , Long J. , Murff H.J. , Ye F. , Setiawan V.W. , Wilkens L.R. , Khankari N.K. , Haycock P. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2020 Dec; 29(12), p. 2735-2739.
EPub date: 2020-09-23.
PMID: 32967863
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Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk.
Authors: Yuan F. , Hung R.J. , Walsh N. , Zhang H. , Platz E.A. , Wheeler W. , Song L. , Arslan A.A. , Beane Freeman L.E. , Bracci P. , et al. .
Source: Cancer research, 2020-09-15; 80(18), p. 4004-4013.
EPub date: 2020-07-08.
PMID: 32641412
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