Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant.
Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant.
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DOI：
10.1371/journal.ppat.0020025
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发表时间：
2006-03
期刊：
影响因子：
6.7
通讯作者：
DeRisi JL
中科院分区：
文献类型：
--
作者：
Urisman A;Molinaro RJ;Fischer N;Plummer SJ;Casey G;Klein EA;Malathi K;Magi-Galluzzi C;Tubbs RR;Ganem D;Silverman RH;DeRisi JL
核糖核酸酶L(核糖核酸酶L)是先天抗病毒反应的重要效应者。核糖核酸酶L功能受损的突变或变异，特别是R462Q，已被认为是前列腺癌的易感因素。鉴于该基因在病毒防御中的作用，我们试图探索病毒感染可能导致携带R462Q变异的个体患前列腺癌的可能性。由已知病毒中最保守的序列组成的寡核苷酸组成的病毒检测DNA微阵列在11例R462Q纯合(QQ)病例中的7例和8例杂合(RQ)和纯合野生型(RR)病例的cDNA样本中发现存在伽玛逆转录病毒序列。通过特异性RT-PCR对86个肿瘤的扩大调查，在20例QQ病例中有8例(40%)检测到病毒，而在66例RQ和RR病例中只有1例(1.5%)检测到病毒。从3例QQ阳性病例中独立克隆了病毒的全长基因组并进行了测序。该病毒名为XMRV，与异嗜性小鼠白血病病毒(MuLV)关系密切，但其序列明显不同于这一组的所有已知成员。对不同肿瘤分离株的Gag和Poll序列的比较表明，所有病例都感染了相同的病毒，但序列变异与感染是独立获得的一致。对XMRV阳性病例的前列腺组织进行原位杂交和免疫组织化学分析，发现约1%的间质细胞中可检测到XMRV核酸和蛋白，主要是癌旁区域的成纤维细胞和造血细胞。据我们所知，这些数据首次证明了异嗜性MULV相关病毒可以产生真实的人类感染，并强烈暗示核糖核酸酶L在体内预防或清除感染方面的活性。这些发现还提出了一些问题，即外源性感染与遗传易感个体的癌症发展之间的可能关系。前列腺癌是美国50岁以上男性最常见的癌症，也是癌症死亡的第二大原因。一些遗传因素被认为是前列腺癌发生的潜在风险因素，其中包括一种名为RNASEL的病毒防御基因。该基因的一种常见遗传变异R462Q最近与高达13%的前列腺癌病例有关。鉴于RNASE的抗病毒作用，作者试图检查与R462Q变异相关的前列腺癌中是否存在病毒。使用设计用于检测所有已知病毒家族的DNA微阵列，作者在前列腺癌样本的一个子集中识别出一种新的病毒，名为XMRV。对86例前列腺癌进行的XMRV聚合酶链式反应检测显示，病毒的存在与R462Q变异体的纯合之间存在强烈的关联。对该病毒的克隆和测序表明，XMRV是几种已知的异嗜性小鼠白血病病毒的近亲。这份报告介绍了首次记录的人类感染异嗜性逆转录病毒的病例。未来的工作将解决XMRV感染和R462Q RNASE变异患者前列腺癌风险增加之间的潜在联系。
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. Prostate cancer is the most frequent cancer and the second leading cause of cancer deaths in US men over the age of 50. Several genetic factors have been proposed as potential risk factors for the development of prostate cancer, including a viral defense gene called RNASEL. A common genetic variant in this gene, R462Q, was recently implicated in up to 13% of prostate cancer cases. Given the antiviral role of RNASEL, the authors sought to examine if a virus might be present in prostate cancers associated with the R462Q variant. Using a DNA microarray designed to detect all known viral families, the authors identified a novel virus, named XMRV, in a subset of prostate tumor samples. Polymerase chain reaction testing of 86 prostate tumors for the presence of XMRV revealed a strong association between the presence of the virus and being homozygous for the R462Q variant. Cloning and sequencing of the virus showed that XMRV is a close relative of several known xenotropic murine leukemia viruses. This report presents the first documented cases of human infection with a xenotropic retrovirus. Future work will address the potential connection between XMRV infection and the increased prostate cancer risk in patients with the R462Q RNASEL variant.
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影响因子：
3.8
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通讯作者：
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56.9
作者：
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