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A recurrent mutation in PALB2 in Finnish cancer families

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BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer1,2,3. 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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Figure 1: PALB2 protein structure and assessment of functional consequences of the c.1592delT and 3433GC sequence alterations.
Figure 2: Examples of pedigrees of breast cancer families exhibiting the c.1592delT allele.
Figure 3: Pedigree of a prostate cancer family segregating the PALB2 c.1592delT truncation allele.

Change history

  • 15 March 2007

    In the AOP version of this Letter, an incorrect version of Figure 1 was published online on 7 February 2007, with errors in panel 1b. This Figure has now been corrected for both print and online publication on 15 March 2007


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We thank J. Ignatius, E. Nieminen, K. Mononen, H. Konola, O. Kajula, M. Vahera, K. Holli, T. Tammela, K. Rouhento, L. Enroth, R. Vaalavuo and S. Marttinen for help in sample and data collection and technical assistance. We also thank the Finnish Red Cross Blood Service for help with collection of population control blood samples, the Finnish Cancer Registry for information on cancer occurrence, and all patients and their family members for volunteering to participate in these studies. This study was supported by the Foundation for the Finnish Cancer Institute, the Academy of Finland, the Ida Montin Foundation, the Cancer Foundation of Northern Finland, the University of Oulu, Oulu University Hospital, the Reino Lahtikari Foundation, the Sigrid Juselius Foundation, Competitive Research Funding of the Pirkanmaa Hospital District, and grants to D.M.L. from the National Cancer Institute. This work was also supported by a grant from the Shapiro Family Foundation. D.M.L. is a scientific consultant to and a grant recipient of The Novartis Institute for Biomedical Research.

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Correspondence to David M. Livingston or Robert Winqvist.

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Erkko, H., Xia, B., Nikkilä, J. et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature 446, 316–319 (2007).

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