Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer

Nicholas Roberts, Alexis L. Norris, Gloria M. Petersen, Melissa L. Bondy, Randall Brand, Steven Gallinger, Robert C. Kurtz, Sara H. Olson, Anil K. Rustgi, Ann G. Schwartz, Elena Stoffel, Sapna Syngal, George Zogopoulos, Syed Z Ali, Jennifer Axilbund, Kari G. Chaffee, Yun Ching Chen, Michele L. Cote, Erica J. Childs, Christopher DouvilleFernando S Goes, Joseph M. Herman, Christine Iacobuzio-Donahue, Melissa Kramer, Alvin Makohon-Moore, Richard W. McCombie, Kevin Wyatt McMahon, Noushin Niknafs, Jennifer Parla, Mehdi Pirooznia, James Bennett Potash, Andrew D. Rhim, Alyssa L. Smith, Yuxuan Wang, Christopher Wolfgang, Laura Delong Wood, Peter P Zandi, Michael S Goggins, Rachel Karchin, James Eshleman, Nickolas Papadopoulos, Kenneth W Kinzler, Bert Vogelstein, Ralph H Hruban, Alison Klein

Research output: Contribution to journalArticle

Abstract

Pancreatic cancer is projected to become the second leading cause of cancerrelated 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 identification 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 signifi cant implications for the management of patients with familial pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)166-175
Number of pages10
JournalCancer Discovery
Volume6
Issue number2
DOIs
StatePublished - Feb 1 2016

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Genetic Heterogeneity
Pancreatic Neoplasms
Genome
Exome
Inborn Genetic Diseases
Neoplasm Genes
Disease Susceptibility
Hematopoiesis
Genetic Predisposition to Disease
Point Mutation
Genes
Cause of Death
Neoplasms
Adenocarcinoma

ASJC Scopus subject areas

  • Oncology

Cite this

Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. / Roberts, Nicholas; Norris, Alexis L.; Petersen, Gloria M.; Bondy, Melissa L.; Brand, Randall; Gallinger, Steven; Kurtz, Robert C.; Olson, Sara H.; Rustgi, Anil K.; Schwartz, Ann G.; Stoffel, Elena; Syngal, Sapna; Zogopoulos, George; Ali, Syed Z; Axilbund, Jennifer; Chaffee, Kari G.; Chen, Yun Ching; Cote, Michele L.; Childs, Erica J.; Douville, Christopher; Goes, Fernando S; Herman, Joseph M.; Iacobuzio-Donahue, Christine; Kramer, Melissa; Makohon-Moore, Alvin; McCombie, Richard W.; McMahon, Kevin Wyatt; Niknafs, Noushin; Parla, Jennifer; Pirooznia, Mehdi; Potash, James Bennett; Rhim, Andrew D.; Smith, Alyssa L.; Wang, Yuxuan; Wolfgang, Christopher; Wood, Laura Delong; Zandi, Peter P; Goggins, Michael S; Karchin, Rachel; Eshleman, James; Papadopoulos, Nickolas; Kinzler, Kenneth W; Vogelstein, Bert; Hruban, Ralph H; Klein, Alison.

In: Cancer Discovery, Vol. 6, No. 2, 01.02.2016, p. 166-175.

Research output: Contribution to journalArticle

Roberts, N, Norris, AL, Petersen, GM, Bondy, ML, Brand, R, Gallinger, S, Kurtz, RC, Olson, SH, Rustgi, AK, Schwartz, AG, Stoffel, E, Syngal, S, Zogopoulos, G, Ali, SZ, Axilbund, J, Chaffee, KG, Chen, YC, Cote, ML, Childs, EJ, Douville, C, Goes, FS, Herman, JM, Iacobuzio-Donahue, C, Kramer, M, Makohon-Moore, A, McCombie, RW, McMahon, KW, Niknafs, N, Parla, J, Pirooznia, M, Potash, JB, Rhim, AD, Smith, AL, Wang, Y, Wolfgang, C, Wood, LD, Zandi, PP, Goggins, MS, Karchin, R, Eshleman, J, Papadopoulos, N, Kinzler, KW, Vogelstein, B, Hruban, RH & Klein, A 2016, 'Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer', Cancer Discovery, vol. 6, no. 2, pp. 166-175. https://doi.org/10.1158/2159-8290.CD-15-0402
Roberts, Nicholas ; Norris, Alexis L. ; Petersen, Gloria M. ; Bondy, Melissa L. ; Brand, Randall ; Gallinger, Steven ; Kurtz, Robert C. ; Olson, Sara H. ; Rustgi, Anil K. ; Schwartz, Ann G. ; Stoffel, Elena ; Syngal, Sapna ; Zogopoulos, George ; Ali, Syed Z ; Axilbund, Jennifer ; Chaffee, Kari G. ; Chen, Yun Ching ; Cote, Michele L. ; Childs, Erica J. ; Douville, Christopher ; Goes, Fernando S ; Herman, Joseph M. ; Iacobuzio-Donahue, Christine ; Kramer, Melissa ; Makohon-Moore, Alvin ; McCombie, Richard W. ; McMahon, Kevin Wyatt ; Niknafs, Noushin ; Parla, Jennifer ; Pirooznia, Mehdi ; Potash, James Bennett ; Rhim, Andrew D. ; Smith, Alyssa L. ; Wang, Yuxuan ; Wolfgang, Christopher ; Wood, Laura Delong ; Zandi, Peter P ; Goggins, Michael S ; Karchin, Rachel ; Eshleman, James ; Papadopoulos, Nickolas ; Kinzler, Kenneth W ; Vogelstein, Bert ; Hruban, Ralph H ; Klein, Alison. / Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. In: Cancer Discovery. 2016 ; Vol. 6, No. 2. pp. 166-175.
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abstract = "Pancreatic cancer is projected to become the second leading cause of cancerrelated 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 identification 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 signifi cant implications for the management of patients with familial pancreatic cancer.",
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AU - Roberts, Nicholas

AU - Norris, Alexis L.

AU - Petersen, Gloria M.

AU - Bondy, Melissa L.

AU - Brand, Randall

AU - Gallinger, Steven

AU - Kurtz, Robert C.

AU - Olson, Sara H.

AU - Rustgi, Anil K.

AU - Schwartz, Ann G.

AU - Stoffel, Elena

AU - Syngal, Sapna

AU - Zogopoulos, George

AU - Ali, Syed Z

AU - Axilbund, Jennifer

AU - Chaffee, Kari G.

AU - Chen, Yun Ching

AU - Cote, Michele L.

AU - Childs, Erica J.

AU - Douville, Christopher

AU - Goes, Fernando S

AU - Herman, Joseph M.

AU - Iacobuzio-Donahue, Christine

AU - Kramer, Melissa

AU - Makohon-Moore, Alvin

AU - McCombie, Richard W.

AU - McMahon, Kevin Wyatt

AU - Niknafs, Noushin

AU - Parla, Jennifer

AU - Pirooznia, Mehdi

AU - Potash, James Bennett

AU - Rhim, Andrew D.

AU - Smith, Alyssa L.

AU - Wang, Yuxuan

AU - Wolfgang, Christopher

AU - Wood, Laura Delong

AU - Zandi, Peter P

AU - Goggins, Michael S

AU - Karchin, Rachel

AU - Eshleman, James

AU - Papadopoulos, Nickolas

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AU - Vogelstein, Bert

AU - Hruban, Ralph H

AU - Klein, Alison

PY - 2016/2/1

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