Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A recurrent mutation in PALB2 in Finnish cancer families

This article has been updated

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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

References

  1. Wooster, R. & Weber, B. L. Breast and ovarian cancer. N. Engl. J. Med. 348, 2339–2347 (2003)

    CAS  Article  Google Scholar 

  2. 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)

    CAS  Article  Google Scholar 

  3. Renwick, A. et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nature Genet. 38, 873–875 (2006)

    CAS  Article  Google Scholar 

  4. Xia, B. et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell 22, 719–729 (2006)

    CAS  Article  Google Scholar 

  5. 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)

    CAS  Article  Google Scholar 

  6. 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)

    ADS  CAS  Article  Google Scholar 

  7. Howlett, N. G. et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297, 606–609 (2002)

    ADS  CAS  Article  Google Scholar 

  8. 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)

    Article  Google Scholar 

  9. 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)

    CAS  Article  Google Scholar 

  10. Borg, Å. Molecular and pathological characterization of inherited breast cancer. Semin. Cancer Biol. 11, 375–385 (2001)

    CAS  Article  Google Scholar 

  11. Hedenfalk, I. et al. Molecular classification of familial non-BRCA1/BRCA2 breast cancer. Proc. Natl Acad. Sci. USA 100, 2532–2537 (2003)

    ADS  CAS  Article  Google Scholar 

  12. 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)

  13. 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)

  14. 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)

    CAS  Article  Google Scholar 

  15. 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)

    ADS  CAS  Article  Google Scholar 

  16. 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)

    ADS  Article  Google Scholar 

Download references

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

Authors

Corresponding authors

Correspondence to David M. Livingston or Robert Winqvist.

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

Reprints 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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05609

Further reading

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.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing