1. Department of Clinical Genetics,
2. Department of Surgery,
3. Department of Oncology,
4. Department of Pathology, University of Oulu and Oulu University Hospital, FIN-90029 OYS, Finland
5. Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
6. Laboratory of Cancer Genetics, Institute of Medical Technology, FIN-33520 University of Tampere and Tampere University Hospital, Finland
7. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Kuopio and Department of Clinical Pathology, Kuopio University Hospital, FIN-70211 Kuopio, Finland
8. Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA
9. Department of Medical Genetics, University of Helsinki and Biomedicum Helsinki, FIN-00014 HY, Finland
10. Department of Biosciences and Nutrition, and Clinical Research Centre, Karolinska Institutet, SE-17177 Huddinge, Sweden
11. Institute of Clinical Medicine, Oncology, University of Kuopio and Department of Oncology, Kuopio University Hospital, FIN-70211 Kuopio, Finland
12. These authors contributed equally to the work.
13. Present address: National Human Genome Research Institute/NIH, Bethesda, Maryland 20892, USA.

Correspondence to: David M. Livingston⁵Robert Winqvist¹ Correspondence and requests for materials should be addressed to R.W. (Email: robert.winqvist@oulu.fi) or D.M.L. (Email: david_livingston@dfci.harvard.edu).

Abstract

BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer^{1, 2, 3}. Other relevant genes therefore remain to be discovered. Recently a new BRCA2-binding protein, PALB2, was identified⁴. The BRCA2–PALB2 interaction is crucial for certain key BRCA2 DNA damage response functions as well as its tumour suppression activity⁴. Here we show, by screening for PALB2 mutations in Finland that a frameshift mutation, c.1592delT, is present at significantly elevated frequency in familial breast cancer cases compared with ancestry-matched population controls. The truncated PALB2 protein caused by this mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair. Further screening of c.1592delT in unselected breast cancer individuals revealed a roughly fourfold enrichment of this mutation in patients compared with controls. Most of the mutation-positive unselected cases had a familial pattern of disease development. In addition, one multigenerational prostate cancer family that segregated the c.1592delT truncation allele was observed. These results indicate that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development.

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