PT - JOURNAL ARTICLE AU - Roberts, Nicholas J. AU - Jiao, Yuchen AU - Yu, Jun AU - Kopelovich, Levy AU - Petersen, Gloria M. AU - Bondy, Melissa L. AU - Gallinger, Steven AU - Schwartz, Ann G. AU - Syngal, Sapna AU - Cote, Michele L. AU - Axilbund, Jennifer AU - Schulick, Richard AU - Ali, Syed Z. AU - Eshleman, James R. AU - Velculescu, Victor E. AU - Goggins, Michael AU - Vogelstein, Bert AU - Papadopoulos, Nickolas AU - Hruban, Ralph H. AU - Kinzler, Kenneth W. AU - Klein, Alison P. TI - <em>ATM</em> Mutations in Patients with Hereditary Pancreatic Cancer AID - 10.1158/2159-8290.CD-11-0194 DP - 2012 Jan 01 TA - Cancer Discovery PG - 41--46 VI - 2 IP - 1 4099 - http://cancerdiscovery.aacrjournals.org/content/2/1/41.short 4100 - http://cancerdiscovery.aacrjournals.org/content/2/1/41.full SO - Cancer Discov2012 Jan 01; 2 AB - Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with &gt;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. Cancer Discovery; 2(1): 41–6. ©2011 AACR.Read the Commentary on this article by Bakker and de Winter, p. 14This article is highlighted in the In This Issue feature, p. 1