Germline mutations in the ribonuclease L gene in families showing linkage with HPC1 (original) (raw)

• Letter
• Published: 22 January 2002
• N. Nupponen1,
• S. Isaacs2,
• R. Sood1,
• C. Robbins1,
• J. Xu3,
• M. Faruque1,
• T. Moses1,
• C. Ewing2,
• E. Gillanders1,
• P. Hu1,
• P. Bujnovszky2,
• I. Makalowska4,
• A. Baffoe-Bonnie5,6,
• D. Faith2,
• J. Smith7,
• D. Stephan8,
• K. Wiley2,
• M. Brownstein9,
• D. Gildea1,
• B. Kelly2,
• R. Jenkins10,
• G. Hostetter1,
• M. Matikainen11,
• J. Schleutker11,
• K. Klinger12,
• T. Connors12,
• Y. Xiang13,
• Z. Wang13,
• A. De Marzo2,
• N. Papadopoulos14,
• O.-P. Kallioniemi1,
• R. Burk15,
• D. Meyers3,
• H. Grönberg16,
• P. Meltzer1,
• R. Silverman13,
• J. Bailey-Wilson5,
• P. Walsh2,
• W. Isaacs2 &
• …
• J. Trent1

Nature Genetics volume 30, pages 181–184 (2002)Cite this article

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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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References

1. Hankey, B.F. et al. Cancer surveillance series: interpreting trends in prostate cancer—part I: evidence of the effects of screening in recent prostate cancer incidence, mortality, and survival rates. J. Natl Cancer Inst. 91, 1017–1024 (1999).
   Article CAS Google Scholar
2. Dennis, L.K. & Resnick, M.I. Analysis of recent trends in prostate cancer incidence and mortality. Prostate 42, 247–252 (2000).
   Article CAS Google Scholar
3. Steinberg, G.D., Carter, B.S., Beaty, T.H., Childs, B. & Walsh, P.C. Family history and the risk of prostate cancer. Prostate 17, 337–347 (1990).
   Article CAS Google Scholar
4. Carter, B.S., Beaty, T.H., Steinberg, G.D., Childs, B. & Walsh, P.C. Mendelian inheritance of familial prostate cancer. Proc. Natl Acad. Sci. USA 89, 3367–3371 (1992).
   Article CAS Google Scholar
5. Ostrander, E.A. & Stanford, J.L. Genetics of prostate cancer: too many loci, too few genes. Am. J. Hum. Genet. 67, 1367–1375 (2000).
   Article CAS Google Scholar
6. Clemens, M.J. & Williams, B.R. Inhibition of cell-free protein synthesis by pppA2′p5′A2′p5′A: a novel oligonucleotide synthesized by interferon-treated L cell extracts. Cell 13, 565–572 (1978).
   Article CAS Google Scholar
7. Floyd-Smith, G., Slattery, E. & Lengyel, P. Interferon action: RNA cleavage pattern of a (2′-5′)oligoadenylate-dependent endonuclease. Science 212, 1030–1032 (1981).
   Article CAS Google Scholar
8. Zhou, A., Hassel, B.A. & Silverman, R.H. Expression cloning of 2-5A-dependent RNAase: a uniquely regulated mediator of interferon action. Cell 72, 753–765 (1993).
   Article CAS Google Scholar
9. Smith, J.R. et al. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 274, 1371–1374 (1996).
   Article CAS Google Scholar
10. Hassel, B.A., Zhou, A., Sotomayor, C., Maran, A. & Silverman, R.H. A dominant negative mutant of 2-5A-dependent RNase suppresses antiproliferative and antiviral effects of interferon. EMBO J. 12, 3297–3304 (1993).
    Article CAS Google Scholar
11. Zhou A., et al. Interferon action and apoptosis are defective in mice devoid of 2′,5′- oligoadenylate-dependent RNase L. EMBO J. 16, 6355–6363 (1997).
    Article CAS Google Scholar
12. Lengyel, P. Tumor-suppressor genes: news about the interferon connection. Proc. Natl Acad. Sci. USA 90, 5893–5895 (1993).
    Article CAS Google Scholar
13. Carpten, J.D. et al. A 6-Mb high-resolution physical and transcription map encompassing the hereditary prostate cancer 1 (HPC1) region. Genomics 64, 1–14 (2000).
    Article CAS Google Scholar
14. Sood, R. et al. Cloning and characterization of 13 novel transcripts and the human rgs8 gene from the 1q25 region encompassing the hereditary prostate cancer (hpc1) locus. Genomics 73, 211–222 (2001).
    Article CAS Google Scholar
15. Kerr, I.M. & Brown, R.E. pppA2′p5′A2′p5′A: an inhibitor of protein synthesis synthesized with an enzyme fraction from interferon-treated cells. Proc. Natl Acad. Sci. USA 75, 256–260 (1978).
    Article CAS Google Scholar
16. Sherman, F., McKnight, G. & Stewart, J.W. AUG is the only initiation codon in eukaryotes. Biochim. Biophys. Acta. 609, 343–346 (1980).
    Article CAS Google Scholar
17. Hartge, P., Struewing, J.P., Wacholder, S., Brody, L.C. & Tucker, M.A. The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am. J. Hum. Genet. 64, 963–970 (1999).
    Article CAS Google Scholar
18. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).
    Article CAS Google Scholar
19. Dong, B. & Silverman, R.H. 2-5A-dependent RNase molecules dimerize during activation by 2-5A. J. Biol. Chem. 270, 4133–4137 (1995).
    Article CAS Google Scholar
20. Silverman, R.H., Skehel, J.J., James, T.C., Wreschner, D.H. & Kerr, I.M. rRNA cleavage as an index of ppp(A2′p)nA activity in interferon-treated encephalomyocarditis virus-infected cells. J. Virol. 46, 1051–1055 (1983).
    CAS PubMed PubMed Central Google Scholar
21. Tnani, M. & Bayard, B.A. Lack of 2′,5′-oligoadenylate-dependent RNase expression in the human hepatoma cell line HepG2. Biochim. Biophys. Acta 1402, 139–150 (1998).
    Article CAS Google Scholar
22. Isaacs, J.T., Furuya, Y. & Berges, R. The role of androgen in the regulation of programmed cell death/apoptosis in normal and malignant prostatic tissue. Semin. Cancer Biol. 5, 391–400 (1994).
    CAS PubMed Google Scholar
23. Kaighn, M.E., Narayan, K.S., Ohnuki, Y., Lechner, J.F. & Jones, L.W. Establishment and characterization of a human prostatic carcinoma cell line (PC-3). Invest. Urol. 17, 16–23 (1979).
    CAS PubMed Google Scholar

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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.).

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Authors and Affiliations

1. Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, 20892, Maryland, 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. Department of Pathology, Institute of Cancer Genetics, 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

Authors

1. J. Carpten
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2. N. Nupponen
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3. S. Isaacs
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4. R. Sood
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5. C. Robbins
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6. J. Xu
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7. M. Faruque
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8. T. Moses
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9. C. Ewing
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10. E. Gillanders
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11. P. Hu
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12. P. Bujnovszky
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13. I. Makalowska
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14. A. Baffoe-Bonnie
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15. D. Faith
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16. J. Smith
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17. D. Stephan
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18. K. Wiley
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19. M. Brownstein
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20. D. Gildea
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21. B. Kelly
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22. R. Jenkins
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23. G. Hostetter
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24. M. Matikainen
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25. J. Schleutker
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26. K. Klinger
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27. T. Connors
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28. Y. Xiang
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29. Z. Wang
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30. A. De Marzo
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31. N. Papadopoulos
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32. O.-P. Kallioniemi
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33. R. Burk
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34. D. Meyers
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35. H. Grönberg
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36. P. Meltzer
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37. R. Silverman
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38. J. Bailey-Wilson
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39. P. Walsh
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40. W. Isaacs
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41. J. Trent
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Correspondence toJ. Trent.

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Carpten, J., Nupponen, N., Isaacs, S. et al. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1.Nat Genet 30, 181–184 (2002). https://doi.org/10.1038/ng823

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• Received: 05 November 2001
• Accepted: 16 November 2001
• Published: 22 January 2002
• Issue Date: February 2002
• DOI: https://doi.org/10.1038/ng823