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.

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

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Multipoint linkage analysis assuming heterogeneity on 91 high-risk prostate cancer families suggests HPC1 maps to D1S2883D1S158D1S422.
Figure 2: Deficiences in RNase L in tumor tissue and lymphoblasts from HPC1-affected individuals.

References

  1. 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).

    CAS  Article  Google Scholar 

  2. 2

    Dennis, L.K. & Resnick, M.I. Analysis of recent trends in prostate cancer incidence and mortality. Prostate 42, 247–252 (2000).

    CAS  Article  Google Scholar 

  3. 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).

    CAS  Article  Google Scholar 

  4. 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).

    CAS  Article  Google Scholar 

  5. 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).

    CAS  Article  Google Scholar 

  6. 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).

    CAS  Article  Google Scholar 

  7. 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).

    CAS  Article  Google Scholar 

  8. 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).

    CAS  Article  Google Scholar 

  9. 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).

    CAS  Article  Google Scholar 

  10. 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).

    CAS  Article  Google Scholar 

  11. 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).

    CAS  Article  Google Scholar 

  12. 12

    Lengyel, P. Tumor-suppressor genes: news about the interferon connection. Proc. Natl Acad. Sci. USA 90, 5893–5895 (1993).

    CAS  Article  Google Scholar 

  13. 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).

    CAS  Article  Google Scholar 

  14. 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).

    CAS  Article  Google Scholar 

  15. 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).

    CAS  Article  Google Scholar 

  16. 16

    Sherman, F., McKnight, G. & Stewart, J.W. AUG is the only initiation codon in eukaryotes. Biochim. Biophys. Acta. 609, 343–346 (1980).

    CAS  Article  Google Scholar 

  17. 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).

    CAS  Article  Google Scholar 

  18. 18

    Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    CAS  Article  Google Scholar 

  19. 19

    Dong, B. & Silverman, R.H. 2-5A-dependent RNase molecules dimerize during activation by 2-5A. J. Biol. Chem. 270, 4133–4137 (1995).

    CAS  Article  Google Scholar 

  20. 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. 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).

    CAS  Article  Google Scholar 

  22. 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. 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 

Download references

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

Authors

Corresponding author

Correspondence to J. Trent.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

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