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Showing content from https://www.ncbi.nlm.nih.gov/pubmed/22585167 below:

ATM mutations in patients with hereditary pancreatic cancer

doi: 10.1158/2159-8290.CD-11-0194. Epub 2011 Dec 29. ATM mutations in patients with hereditary pancreatic cancer Nicholas J Roberts¹, 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 R Eshleman, Victor E Velculescu, Michael Goggins, Bert Vogelstein, Nickolas Papadopoulos, Ralph H Hruban, Kenneth W Kinzler, Alison P Klein

Affiliations

Affiliation

¹ Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA.

PMID: 22585167
PMCID: PMC3676748
DOI: 10.1158/2159-8290.CD-11-0194

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ATM mutations in patients with hereditary pancreatic cancer

Nicholas J Roberts et al. Cancer Discov. 2012 Jan.

doi: 10.1158/2159-8290.CD-11-0194. Epub 2011 Dec 29. Authors Nicholas J Roberts¹, 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 R Eshleman, Victor E Velculescu, Michael Goggins, Bert Vogelstein, Nickolas Papadopoulos, Ralph H Hruban, Kenneth W Kinzler, Alison P Klein Affiliation

¹ Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA.

PMID: 22585167
PMCID: PMC3676748
DOI: 10.1158/2159-8290.CD-11-0194

Item in Clipboard

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.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

Under agreements between the Johns Hopkins University, Inostics, PGDx and Qiagen, N.P., B.V., K.W.K. and V.E.V are entitled to a share of the royalties received by the University on sales of products related to genes and technologies described in this manuscript. N.P., B.V., K.W.K. and V.E.V are a co-founders of Inostics and Personal Genome Diagnostics are members of their Scientific Advisory Boards, and own stock in Inostics and PGDx, which is subject to certain restrictions under Johns Hopkins University policy. The terms of these arrangements are managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.

Figures
Figure 1. Pedigrees of familial pancreatic cancer…

Figure 1. Pedigrees of familial pancreatic cancer families FPC-A and FPC-B

I. Family FPC-A. Individuals…

Figure 1. Pedigrees of familial pancreatic cancer families FPC-A and FPC-B

I. Family FPC-A. Individuals interrogated with whole-genome sequencing. Individuals with an ATM mutation indicated with K2756X. II. Family FPC-B. Individuals interrogated with whole exome sequencing. Individuals an ATM mutation indicated with W57X.

Figure 2. Chromatograms from IV-1 of family…

Figure 2. Chromatograms from IV-1 of family FPC-A

I. Peripheral blood lymphocytes of IV-1 demonstrating…

Figure 2. Chromatograms from IV-1 of family FPC-A

I. Peripheral blood lymphocytes of IV-1 demonstrating heterozygosity for the ATM inactivating mutant c.8266A>AT; p.K1756X. II. Laser capture microdissected pancreatic tumor of IV-1 showing loss of heterozygosity with retention of the ATM inactivating mutant c.8266A>T; p.K1756X.