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Published Online March 5, 2009
Science DOI: 10.1126/science.1171202

Brevia

Submitted on January 21, 2009
Accepted on February 20, 2009

Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene

Siân Jones 1, Ralph H. Hruban 2, Mihoko Kamiyama 3, Michael Borges 3, Xiaosong Zhang 1, D. Williams Parsons 1, Jimmy Cheng-Ho Lin 1, Emily Palmisano 4, Kieran Brune 4, Elizabeth M. Jaffee 2, Christine A. Iacobuzio-Donahue 2, Anirban Maitra 2, Giovanni Parmigiani 2, Scott E Kern 2, Victor E. Velculescu 5, Kenneth W. Kinzler 5, Bert Vogelstein 1, James R. Eshleman 2{dagger}, Michael Goggins 6{dagger}, Alison P. Klein 2{dagger}*

1 Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Baltimore, MD 21231, USA.; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
2 Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.; Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
3 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
4 Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
5 Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Baltimore, MD 21231, USA.
6 Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.; Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.; Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

* To whom correspondence should be addressed.
Alison P. Klein , E-mail: aklein1{at}jhmi.edu

{dagger}These authors contributed equally to this work.

Through complete sequencing of the protein-coding genes in a patient with familial pancreatic cancer, we identified a germline, truncating mutation in PALB2 that appeared responsible for this patient’s predisposition to the disease. Analysis of 96 additional patients with familial pancreatic cancer revealed three distinct protein-truncating mutations, thereby validating the role of PALB2 as a susceptibility gene for pancreatic cancer. PALB2 mutations have been previously reported in patients with familial breast cancer and, interestingly, the PALB2 protein is a binding partner for BRCA2. These results illustrate that complete, unbiased sequencing of protein-coding genes can lead to the discovery of a gene responsible for a hereditary disease.


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Science. ISSN 0036-8075 (print), 1095-9203 (online)