Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer

被引：280

作者：

Roberts, Nicholas J. ^{[1
,2
,3
]}

Norris, Alexis L. ^{[1
]}

Petersen, Gloria M. ^{[4
]}

Bondy, Melissa L. ^{[5
]}

Brand, Randall ^{[6
]}

Gallinger, Steven ^{[7
]}

Kurtz, Robert C. ^{[8
]}

Olson, Sara H. ^{[9
]}

Rustgi, Anil K. ^{[10
,11
]}

Schwartz, Ann G. ^{[12
]}

Stoffel, Elena ^{[13
]}

Syngal, Sapna ^{[14
,15
]}

Zogopoulos, George ^{[16
,17
]}

Ali, Syed Z. ^{[1
]}

Axilbund, Jennifer ^{[1
]}

Chaffee, Kari G. ^{[4
]}

Chen, Yun-Ching ^{[18
]}

Cote, Michele L. ^{[12
]}

Childs, Erica J. ^{[19
]}

Douville, Christopher ^{[18
]}

Goes, Fernando S. ^{[20
]}

Herman, Joseph M. ^{[21
]}

Iacobuzio-Donahue, Christine ^{[22
]}

Kramer, Melissa ^{[23
]}

Makohon-Moore, Alvin ^{[1
]}

McCombie, Richard W. ^{[23
]}

McMahon, K. Wyatt ^{[2
,3
]}

Niknafs, Noushin ^{[18
]}

Parla, Jennifer ^{[23
,24
]}

Pirooznia, Mehdi ^{[20
]}

Potash, James B. ^{[25
]}

Rhim, Andrew D. ^{[10
,11
,26
]}

Smith, Alyssa L. ^{[16
,17
]}

Wang, Yuxuan ^{[2
,3
]}

Wolfgang, Christopher L. ^{[27
]}

Wood, Laura D. ^{[1
,21
]}

Zandi, Peter P. ^{[20
]}

Goggins, Michael ^{[1
,21
,28
]}

Karchin, Rachel

Eshleman, James R. ^{[1
,21
]}

Papadopoulos, Nickolas ^{[2
,3
]}

Kinzler, Kenneth W. ^{[2
,3
]}

Vogelstein, Bert ^{[2
,3
]}

Hruban, Ralph H. ^{[1
,21
]}

Klein, Alison P. ^{[1
,19
,21
]}

机构：

[1] Johns Hopkins Med Inst, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA

[2] Johns Hopkins Med Inst, Ludwig Ctr, 1650 Orleans St, Baltimore, MD 21231 USA

[3] Johns Hopkins Med Inst, Howard Hughes Med Inst, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA

[4] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

[5] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA

[6] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA

[7] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, 600 Univ Ave, Toronto, ON M5G 1X5, Canada

[8] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[9] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[10] Univ Penn, Perelman Sch Med, Pancreat Canc Translat Ctr Excellence, Abramson Canc Ctr,Div Gastroenterol,Dept Med, Philadelphia, PA 19104 USA

[11] Univ Penn, Perelman Sch Med, Pancreat Canc Translat Ctr Excellence, Abramson Canc Ctr,Div Gastroenterol,Dept Genet, Philadelphia, PA 19104 USA

[12] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI USA

[13] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[14] Dana Farber Canc Inst, Populat Sci Div, Boston, MA 02115 USA

[15] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA

[16] McGill Univ, Res Inst, Ctr Hlth, Montreal, PQ, Canada

[17] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ, Canada

[18] Johns Hopkins Univ, Dept Biomed Engn, Inst Computat Med, Baltimore, MD USA

[19] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[20] Johns Hopkins Med Inst, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA

[21] Johns Hopkins Med Inst, Dept Oncol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA

[22] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[23] Cold Spring Harbor Lab, Stanley Inst Cognit Genom, POB 100, Cold Spring Harbor, NY 11724 USA

[24] InGenious Targeting Lab, Ronkonkoma, NY USA

[25] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA

[26] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA

[27] Johns Hopkins Med Inst, Sol Goldman Pancreat Canc Res Ctr, Dept Surg, Baltimore, MD 21205 USA

[28] Johns Hopkins Med Inst, Dept Med, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA

来源：

CANCER DISCOVERY | 2016年 / 6卷 / 02期

关键词：

INCREASED RISK; MUTATIONS; PREDISPOSITION; SUSCEPTIBILITY; ALIGNMENT; VARIANTS;

D O I：

10.1158/2159-8290.CD-15-0402

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identifi cation of susceptibility genes in other common cancer types. SIGNIFICANCE: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer. (C) 2015 AACR.

引用

页码：166 / 175

页数：10

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