Letter

Germline mutations in the ribonuclease L gene in families showing linkage with HPC1

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Abstract

Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States1,2, little is known about inherited factors that influence its genetic predisposition3,4,5. Here we report that germline mutations in the gene encoding 2′-5′-oligoadenylate(2-5A)–dependent RNase L (RNASEL)6,7,8 segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24–25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene10,11,12. We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.

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Acknowledgements

We wish to thank the affected individuals and their family members who made this study possible. We thank D. Freije, H. Suzuki, E. Wilkens, A. Kibel, G. Bova, S. Gregory and T. Bonner for contributions to earlier phases of this work; F. S. Collins for input and comments; J. Qian for FISH analyses; M. Emmert-Buck for help in laser-capture microdissection; J. Hicks for immunohistochemistry; and J.R. Okicki for synthesizing the fluorescein-tagged 2-5A.This work was supported in part by grants from the PHS (SPORE), DOD, CaPCURE (W.I.) and the Fund for Research and Progress in Urology, the Johns Hopkins University, the Swedish Cancer Society and the SSF Genome Program (H.G.), the V Foundation for Cancer Research (J.S.), the Finnish Cultural Foundation, the Helsingin Sanomat Foundation, the Paulo Foundation, the Ella & Georg Ehrnrooth Foundation and the Maud Kuistila Foundation (N.N.), the NIH (R.J. and R.H.S.), and DOD (J.X.).

Author information

Affiliations

  1. Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.

    • J. Carpten
    • , N. Nupponen
    • , R. Sood
    • , C. Robbins
    • , M. Faruque
    • , T. Moses
    • , E. Gillanders
    • , P. Hu
    • , D. Gildea
    • , G. Hostetter
    • , O.-P. Kallioniemi
    • , P. Meltzer
    •  & J. Trent
  2. Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

    • S. Isaacs
    • , C. Ewing
    • , P. Bujnovszky
    • , D. Faith
    • , K. Wiley
    • , B. Kelly
    • , A. De Marzo
    • , P. Walsh
    •  & W. Isaacs
  3. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

    • J. Xu
    •  & D. Meyers
  4. Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.

    • I. Makalowska
  5. Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.

    • A. Baffoe-Bonnie
    •  & J. Bailey-Wilson
  6. Division of Population Sciences, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

    • A. Baffoe-Bonnie
  7. Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee, USA.

    • J. Smith
  8. Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.

    • D. Stephan
  9. Laboratory of Genetics, National Institute of Mental Health, NIH, Bethesda, Maryland, USA.

    • M. Brownstein
  10. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

    • R. Jenkins
  11. Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland.

    • M. Matikainen
    •  & J. Schleutker
  12. Genzyme Molecular Oncology, Framingham, Massachusetts, USA.

    • K. Klinger
    •  & T. Connors
  13. Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.

    • Y. Xiang
    • , Z. Wang
    •  & R. Silverman
  14. Institute of Cancer Genetics, Department of Pathology, Columbia University, New York, New York, USA.

    • N. Papadopoulos
  15. Department of Microbiology and Immunology, Albert Einstein School of Medicine, Yeshiva University, Bronx, New York, USA.

    • R. Burk
  16. Department of Oncology, Umeå University, Umeå, Sweden.

    • H. Grönberg

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to J. Trent.

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