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

J. Carpten, N. Nupponen, S. Isaacs, R. Sood, C. Robbins, J. Xu, M. Faruque, T. Moses, C. Ewing, E. Gillanders, P. Hu, P. Bujnovszky, I. Makalowska, A. Baffoe-Bonnie, D. Faith, J. Smith, D. Stephan, K. Wiley, M. Brownstein, D. Gildea & 21 others B. Kelly, R. Jenkins, G. Hostetter, M. Matikainen, J. Schleutker, K. Klinger, T. Connors, Y. Xiang, Z. Wang, A. De Marzo, N. Papadopoulos, O. P. Kallioniemi, Robert D. Burk, D. Meyers, H. Grönberg, P. Meltzer, R. Silverman, J. Bailey-Wilson, P. Walsh, W. Isaacs, J. Trent

Research output: Contribution to journalArticle

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Abstract

Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States, little is known about inherited factors that influence its genetic predisposition. Here we report that germline mutations in the gene encoding 2′-5′-oligoadenylate(2-5A)-dependent RNase L (RNASEL) 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 gene. 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.

Original languageEnglish (US)
Pages (from-to)181-184
Number of pages4
JournalNature Genetics
Volume30
Issue number2
DOIs
StatePublished - Feb 2002

Fingerprint

Germ-Line Mutation
Ribonucleases
Genes
Prostatic Neoplasms
Alleles
Initiator Codon
2-5A-dependent ribonuclease
Familial Prostate cancer
Nonsense Codon
Loss of Heterozygosity
Genetic Predisposition to Disease
Tumor Suppressor Genes
Interferons
Organism Cloning
Neoplasms
Cell Proliferation
Apoptosis
Mutation

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Carpten, J., Nupponen, N., Isaacs, S., Sood, R., Robbins, C., Xu, J., ... Trent, J. (2002). Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nature Genetics, 30(2), 181-184. https://doi.org/10.1038/ng823

Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. / Carpten, J.; Nupponen, N.; Isaacs, S.; Sood, R.; Robbins, C.; Xu, J.; Faruque, M.; Moses, T.; Ewing, C.; Gillanders, E.; Hu, P.; Bujnovszky, P.; Makalowska, I.; Baffoe-Bonnie, A.; Faith, D.; Smith, J.; Stephan, D.; Wiley, K.; Brownstein, M.; Gildea, D.; Kelly, B.; Jenkins, R.; Hostetter, G.; Matikainen, M.; Schleutker, J.; Klinger, K.; Connors, T.; Xiang, Y.; Wang, Z.; De Marzo, A.; Papadopoulos, N.; Kallioniemi, O. P.; Burk, Robert D.; Meyers, D.; Grönberg, H.; Meltzer, P.; Silverman, R.; Bailey-Wilson, J.; Walsh, P.; Isaacs, W.; Trent, J.

In: Nature Genetics, Vol. 30, No. 2, 02.2002, p. 181-184.

Research output: Contribution to journalArticle

Carpten, J, Nupponen, N, Isaacs, S, Sood, R, Robbins, C, Xu, J, Faruque, M, Moses, T, Ewing, C, Gillanders, E, Hu, P, Bujnovszky, P, Makalowska, I, Baffoe-Bonnie, A, Faith, D, Smith, J, Stephan, D, Wiley, K, Brownstein, M, Gildea, D, Kelly, B, Jenkins, R, Hostetter, G, Matikainen, M, Schleutker, J, Klinger, K, Connors, T, Xiang, Y, Wang, Z, De Marzo, A, Papadopoulos, N, Kallioniemi, OP, Burk, RD, Meyers, D, Grönberg, H, Meltzer, P, Silverman, R, Bailey-Wilson, J, Walsh, P, Isaacs, W & Trent, J 2002, 'Germline mutations in the ribonuclease L gene in families showing linkage with HPC1', Nature Genetics, vol. 30, no. 2, pp. 181-184. https://doi.org/10.1038/ng823
Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J et al. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nature Genetics. 2002 Feb;30(2):181-184. https://doi.org/10.1038/ng823
Carpten, J. ; Nupponen, N. ; Isaacs, S. ; Sood, R. ; Robbins, C. ; Xu, J. ; Faruque, M. ; Moses, T. ; Ewing, C. ; Gillanders, E. ; Hu, P. ; Bujnovszky, P. ; Makalowska, I. ; Baffoe-Bonnie, A. ; Faith, D. ; Smith, J. ; Stephan, D. ; Wiley, K. ; Brownstein, M. ; Gildea, D. ; Kelly, B. ; Jenkins, R. ; Hostetter, G. ; Matikainen, M. ; Schleutker, J. ; Klinger, K. ; Connors, T. ; Xiang, Y. ; Wang, Z. ; De Marzo, A. ; Papadopoulos, N. ; Kallioniemi, O. P. ; Burk, Robert D. ; Meyers, D. ; Grönberg, H. ; Meltzer, P. ; Silverman, R. ; Bailey-Wilson, J. ; Walsh, P. ; Isaacs, W. ; Trent, J. / Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. In: Nature Genetics. 2002 ; Vol. 30, No. 2. pp. 181-184.
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abstract = "Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States, little is known about inherited factors that influence its genetic predisposition. Here we report that germline mutations in the gene encoding 2′-5′-oligoadenylate(2-5A)-dependent RNase L (RNASEL) 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 gene. 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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AU - Nupponen, N.

AU - Isaacs, S.

AU - Sood, R.

AU - Robbins, C.

AU - Xu, J.

AU - Faruque, M.

AU - Moses, T.

AU - Ewing, C.

AU - Gillanders, E.

AU - Hu, P.

AU - Bujnovszky, P.

AU - Makalowska, I.

AU - Baffoe-Bonnie, A.

AU - Faith, D.

AU - Smith, J.

AU - Stephan, D.

AU - Wiley, K.

AU - Brownstein, M.

AU - Gildea, D.

AU - Kelly, B.

AU - Jenkins, R.

AU - Hostetter, G.

AU - Matikainen, M.

AU - Schleutker, J.

AU - Klinger, K.

AU - Connors, T.

AU - Xiang, Y.

AU - Wang, Z.

AU - De Marzo, A.

AU - Papadopoulos, N.

AU - Kallioniemi, O. P.

AU - Burk, Robert D.

AU - Meyers, D.

AU - Grönberg, H.

AU - Meltzer, P.

AU - Silverman, R.

AU - Bailey-Wilson, J.

AU - Walsh, P.

AU - Isaacs, W.

AU - Trent, J.

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