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Originally published in Science Express on 5 March 2009
Science 10 April 2009:
Vol. 324. no. 5924, p. 217
DOI: 10.1126/science.1171202
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Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene

Siân Jones,1,2 Ralph H. Hruban,2,3 Mihoko Kamiyama,3 Michael Borges,3 Xiaosong Zhang,1,2 D. Williams Parsons,1,2 Jimmy Cheng-Ho Lin,1,2 Emily Palmisano,2 Kieran Brune,2 Elizabeth M. Jaffee,2,3 Christine A. Iacobuzio-Donahue,2,3 Anirban Maitra,2,3 Giovanni Parmigiani,2,3 Scott E Kern,2,3 Victor E. Velculescu,1 Kenneth W. Kinzler,1 Bert Vogelstein,1,2 James R. Eshleman,2,3* Michael Goggins,2,3,4* Alison P. Klein2,3*{dagger}

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 the PALB2 protein is a binding partner for BRCA2. These results illustrate that complete, unbiased sequencing of protein-coding genes can lead to the identification of a gene responsible for a hereditary disease.

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

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: aklein1{at}jhmi.edu

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