Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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
References
Wooster, R. & Weber, B. L. Breast and ovarian cancer. N. Engl. J. Med. 348, 2339–2347 (2003)
Seal, S. et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nature Genet. 38, 1239–1241 (2006)
Renwick, A. et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nature Genet. 38, 873–875 (2006)
Xia, B. et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell 22, 719–729 (2006)
Shivji, M. K. & Venkitaraman, A. R. DNA recombination, chromosomal stability and carcinogenesis: insights into the role of BRCA2. DNA Repair (Amst.) 3, 835–843 (2004)
King, M. C., Marks, J. H. & Mandell, J. B. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302, 643–646 (2003)
Howlett, N. G. et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297, 606–609 (2002)
Syrjäkoski, K. et al. Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients. J. Natl Cancer Inst. 92, 1529–1531 (2000)
Sarantaus, L. et al. Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland. Eur. J. Hum. Genet. 8, 757–763 (2000)
Borg, Å. Molecular and pathological characterization of inherited breast cancer. Semin. Cancer Biol. 11, 375–385 (2001)
Hedenfalk, I. et al. Molecular classification of familial non-BRCA1/BRCA2 breast cancer. Proc. Natl Acad. Sci. USA 100, 2532–2537 (2003)
Xia, B. et al. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nature Genet. advance online publication, doi:10.1038/ng1942 (2006)
Reid, S. et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nature Genet. advance online publication, doi:10.1038/ng1947 (2006)
Alter, B. P., Rosenberg, P. S. & Brody, L. C. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J. Med. Genet. 44, 1–9 (2007)
Ganguly, A., Rock, M. J. & Prockop, D. J. Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes. Proc. Natl Acad. Sci. USA 90, 10325–10329 (1993)
Körkkö, J., Annunen, S., Pihlajamaa, T., Prockop, D. J. & Ala-Kokko, L. Conformation sensitive gel electrophoresis for simple and accurate detection of mutations: comparison with denaturing gradient gel electrophoresis and nucleotide sequencing. Proc. Natl Acad. Sci. USA 95, 1681–1685 (1998)
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
Supplementary information
Supplementary Information
This file contains Supplementary Methods, Supplementary Tables 1-2 and additional references. (PDF 267 kb)
Rights and permissions
About this article
Cite this article
Erkko, H., Xia, B., Nikkilä, J. et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature 446, 316–319 (2007). https://doi.org/10.1038/nature05609
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature05609
This article is cited by
-
Tight junction protein cingulin variant is associated with cancer susceptibility by overexpressed IQGAP1 and Rac1-dependent epithelial-mesenchymal transition
Journal of Experimental & Clinical Cancer Research (2024)
-
Prevalence of BRCA1, BRCA2, and PALB2 genomic alterations among 924 Taiwanese breast cancer assays with tumor-only targeted sequencing: extended data analysis from the VGH-TAYLOR study
Breast Cancer Research (2023)
-
Common hotspots of cancer chemotherapy
Genome Instability & Disease (2023)
-
Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition
Familial Cancer (2023)
-
Activation of recombinational repair in Ewing sarcoma cells carrying EWS-FLI1 fusion gene by chromosome translocation
Scientific Reports (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.