ATM mutations in patients with hereditary pancreatic cancer

Nicholas Roberts, Yuchen Jiao, Jun Yu, Levy Kopelovich, Gloria M. Petersen, Melissa L. Bondy, Steven Gallinger, Ann G. Schwartz, Sapna Syngal, Michele L. Cote, Jennifer Axilbund, Richard Schulick, Syed Z Ali, James Eshleman, Victor E Velculescu, Michael S Goggins, Bert Vogelstein, Nickolas Papadopoulos, Ralph H Hruban, Kenneth W Kinzler & 1 others Alison Klein

Research output: Contribution to journalArticle

Abstract

Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with >200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated (ATM) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls (P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families (P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition. SIGNIFICANCE: The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes.

Original languageEnglish (US)
Pages (from-to)41-46
Number of pages6
JournalCancer Discovery
Volume2
Issue number1
DOIs
StatePublished - Jan 2012

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Ataxia Telangiectasia
Pancreatic Neoplasms
Mutation
Genes
Adenocarcinoma
Genome
Exome
Neoplasms
Western World
Spouses
Sequence Analysis
Alleles

ASJC Scopus subject areas

  • Oncology

Cite this

ATM mutations in patients with hereditary pancreatic cancer. / Roberts, Nicholas; Jiao, Yuchen; Yu, Jun; Kopelovich, Levy; Petersen, Gloria M.; Bondy, Melissa L.; Gallinger, Steven; Schwartz, Ann G.; Syngal, Sapna; Cote, Michele L.; Axilbund, Jennifer; Schulick, Richard; Ali, Syed Z; Eshleman, James; Velculescu, Victor E; Goggins, Michael S; Vogelstein, Bert; Papadopoulos, Nickolas; Hruban, Ralph H; Kinzler, Kenneth W; Klein, Alison.

In: Cancer Discovery, Vol. 2, No. 1, 01.2012, p. 41-46.

Research output: Contribution to journalArticle

Roberts, Nicholas ; Jiao, Yuchen ; Yu, Jun ; Kopelovich, Levy ; Petersen, Gloria M. ; Bondy, Melissa L. ; Gallinger, Steven ; Schwartz, Ann G. ; Syngal, Sapna ; Cote, Michele L. ; Axilbund, Jennifer ; Schulick, Richard ; Ali, Syed Z ; Eshleman, James ; Velculescu, Victor E ; Goggins, Michael S ; Vogelstein, Bert ; Papadopoulos, Nickolas ; Hruban, Ralph H ; Kinzler, Kenneth W ; Klein, Alison. / ATM mutations in patients with hereditary pancreatic cancer. In: Cancer Discovery. 2012 ; Vol. 2, No. 1. pp. 41-46.
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AU - Gallinger, Steven

AU - Schwartz, Ann G.

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AU - Axilbund, Jennifer

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AU - Ali, Syed Z

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AU - Velculescu, Victor E

AU - Goggins, Michael S

AU - Vogelstein, Bert

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