Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant.
Ribonuclease L (RNase L) is an important effector of the innate antiviral response. Mutations or variants that impair function of RNase L, particularly R462Q, have been proposed as susceptibility factors for prostate cancer. Given the role of this gene in viral defense, we sought to explore the poss...
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Public Library of Science (PLoS)
2006
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oai:doaj.org-article:fe3f8c4939fb4609b265344ee8a99a5d2021-11-25T05:46:26ZIdentification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant.1553-73661553-737410.1371/journal.ppat.0020025https://doaj.org/article/fe3f8c4939fb4609b265344ee8a99a5d2006-03-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.0020025https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Ribonuclease L (RNase L) is an important effector of the innate antiviral response. Mutations or variants that impair function of RNase L, particularly R462Q, have been proposed as susceptibility factors for prostate cancer. Given the role of this gene in viral defense, we sought to explore the possibility that a viral infection might contribute to prostate cancer in individuals harboring the R462Q variant. A viral detection DNA microarray composed of oligonucleotides corresponding to the most conserved sequences of all known viruses identified the presence of gammaretroviral sequences in cDNA samples from seven of 11 R462Q-homozygous (QQ) cases, and in one of eight heterozygous (RQ) and homozygous wild-type (RR) cases. An expanded survey of 86 tumors by specific RT-PCR detected the virus in eight of 20 QQ cases (40%), compared with only one sample (1.5%) among 66 RQ and RR cases. The full-length viral genome was cloned and sequenced independently from three positive QQ cases. The virus, named XMRV, is closely related to xenotropic murine leukemia viruses (MuLVs), but its sequence is clearly distinct from all known members of this group. Comparison of gag and pol sequences from different tumor isolates suggested infection with the same virus in all cases, yet sequence variation was consistent with the infections being independently acquired. Analysis of prostate tissues from XMRV-positive cases by in situ hybridization and immunohistochemistry showed that XMRV nucleic acid and protein can be detected in about 1% of stromal cells, predominantly fibroblasts and hematopoietic elements in regions adjacent to the carcinoma. These data provide to our knowledge the first demonstration that xenotropic MuLV-related viruses can produce an authentic human infection, and strongly implicate RNase L activity in the prevention or clearance of infection in vivo. These findings also raise questions about the possible relationship between exogenous infection and cancer development in genetically susceptible individuals.Anatoly UrismanRoss J MolinaroNicole FischerSarah J PlummerGraham CaseyEric A KleinKrishnamurthy MalathiCristina Magi-GalluzziRaymond R TubbsDon GanemRobert H SilvermanJoseph L DeRisiPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 2, Iss 3, p e25 (2006) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Anatoly Urisman Ross J Molinaro Nicole Fischer Sarah J Plummer Graham Casey Eric A Klein Krishnamurthy Malathi Cristina Magi-Galluzzi Raymond R Tubbs Don Ganem Robert H Silverman Joseph L DeRisi Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. |
| description |
Ribonuclease L (RNase L) is an important effector of the innate antiviral response. Mutations or variants that impair function of RNase L, particularly R462Q, have been proposed as susceptibility factors for prostate cancer. Given the role of this gene in viral defense, we sought to explore the possibility that a viral infection might contribute to prostate cancer in individuals harboring the R462Q variant. A viral detection DNA microarray composed of oligonucleotides corresponding to the most conserved sequences of all known viruses identified the presence of gammaretroviral sequences in cDNA samples from seven of 11 R462Q-homozygous (QQ) cases, and in one of eight heterozygous (RQ) and homozygous wild-type (RR) cases. An expanded survey of 86 tumors by specific RT-PCR detected the virus in eight of 20 QQ cases (40%), compared with only one sample (1.5%) among 66 RQ and RR cases. The full-length viral genome was cloned and sequenced independently from three positive QQ cases. The virus, named XMRV, is closely related to xenotropic murine leukemia viruses (MuLVs), but its sequence is clearly distinct from all known members of this group. Comparison of gag and pol sequences from different tumor isolates suggested infection with the same virus in all cases, yet sequence variation was consistent with the infections being independently acquired. Analysis of prostate tissues from XMRV-positive cases by in situ hybridization and immunohistochemistry showed that XMRV nucleic acid and protein can be detected in about 1% of stromal cells, predominantly fibroblasts and hematopoietic elements in regions adjacent to the carcinoma. These data provide to our knowledge the first demonstration that xenotropic MuLV-related viruses can produce an authentic human infection, and strongly implicate RNase L activity in the prevention or clearance of infection in vivo. These findings also raise questions about the possible relationship between exogenous infection and cancer development in genetically susceptible individuals. |
| format |
article |
| author |
Anatoly Urisman Ross J Molinaro Nicole Fischer Sarah J Plummer Graham Casey Eric A Klein Krishnamurthy Malathi Cristina Magi-Galluzzi Raymond R Tubbs Don Ganem Robert H Silverman Joseph L DeRisi |
| author_facet |
Anatoly Urisman Ross J Molinaro Nicole Fischer Sarah J Plummer Graham Casey Eric A Klein Krishnamurthy Malathi Cristina Magi-Galluzzi Raymond R Tubbs Don Ganem Robert H Silverman Joseph L DeRisi |
| author_sort |
Anatoly Urisman |
| title |
Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. |
| title_short |
Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. |
| title_full |
Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. |
| title_fullStr |
Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. |
| title_full_unstemmed |
Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. |
| title_sort |
identification of a novel gammaretrovirus in prostate tumors of patients homozygous for r462q rnasel variant. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2006 |
| url |
https://doaj.org/article/fe3f8c4939fb4609b265344ee8a99a5d |
| work_keys_str_mv |
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| _version_ |
1718414498010759168 |