Abstract
The BackgroundRibonuclease L (RNASEL), encoding the 2′-5′-oligoadenylate (2-5A)-dependent RNase L, is a key enzyme in the interferon induced antiviral and anti-proliferate pathway. Mutations in RNASEL segregate with the disease in prostate cancer families and specific genotypes are associated with an increased risk of prostate cancer.Infection by human papillomavirus (HPV) is the major risk factor for uterine cervix cancer and for a subset of head and neck squamous cell carcinomas (HNSCC). HPV, Epstein Barr virus (EBV) and sequences from mouse mammary tumor virus (MMTV) have been detected in breast tumors, and the presence of integrated SV40 T/t antigen in breast carcinomas correlates with an aggressive phenotype and poor prognosis.A genetic predisposition could explain why some viral infections persist and induce cancer, while others disappear spontaneously. This points at RNASEL as a strong susceptibility gene.Methodology/Principal FindingsTo evaluate the implication of an abnormal activity of RNase L in the onset and development of viral induced cancers, the study was initiated by searching for germline mutations in patients diagnosed with uterine cervix cancer. The rationale behind is that close to 100% of the cervix cancer patients have a persistent HPV infection, and if a defective RNase L were responsible for the lack of ability to clear the HPV infection, we would expect to find a wide spectrum of mutations in these patients, leading to a decreased RNase L activity. The HPV genotype was established in tumor DNA from 42 patients diagnosed with carcinoma of the uterine cervix and somatic tissue from these patients was analyzed for mutations by direct sequencing of all coding and regulatory regions of RNASEL. Fifteen mutations, including still uncharacterized, were identified. The genotype frequencies of selected single nucleotide polymorphisms (SNPs) established in the cervix cancer patients were compared between 382 patients with head and neck squamous cell carcinomas (HNSCC), 199 patients with primary unilateral breast cancer and 502 healthy Danish control individuals. We found that the genotype frequencies of only one of the 15 mutations, the yet uncharacterized 5′UTR mutation rs3738579 differed significantly between cancer patients and control individuals (P-value: 4.43×10−5).Conclusion/SignificanceIn conclusion, we have discovered an increased risk, a heterozygous advantage and thereby a protective effect linked to the RNASEL SNP rs3738579. This effect is found for patients diagnosed with carcinoma of the uterine cervix, HNSCC, and breast cancer thus pointing at RNASEL as a general marker for cancer risk and not restricted to familial prostate cancer.
Highlights
Ribonuclease L (RNASEL) encoding the versatile endoribonuclease RNase L is a key enzyme in the interferon induced antiviral and anti-proliferate pathway, involved in cellular viral defense, single-stranded RNA cleavage and tumor suppressor activities as stress mediated apoptosis, cell proliferation and regulation of protein synthesis [1,2,3,4,5].RNase L is activated in response to viral infection and the presence of virally encoded dsRNA mobilizes the type I interferons (IFN), which activate a family of 29-59 oligoadenylate synthetases (OAS) [6,7]
Mutational spectrum of RNASEL in cervical carcinomas As viral infection is implicated in close to 100% of all uterine cervix cancer cases, we hypothesized that if a defective RNase L is responsible for the lack of ability to clear a viral infection, patients with cervix cancer would carry a wide spectrum of mutations affecting the activity or expression level of RNase L
single nucleotide polymorphisms (SNPs) rs3738579 is located within the 59UTR region and may be implicated in posttranscriptional regulation or a mediator of an existing low penetrant mutation
Summary
Ribonuclease L (RNASEL) encoding the versatile endoribonuclease RNase L is a key enzyme in the interferon induced antiviral and anti-proliferate pathway, involved in cellular viral defense, single-stranded RNA cleavage and tumor suppressor activities as stress mediated apoptosis, cell proliferation and regulation of protein synthesis [1,2,3,4,5].RNase L is activated in response to viral infection and the presence of virally encoded dsRNA mobilizes the type I interferons (IFN), which activate a family of 29-59 oligoadenylate synthetases (OAS) [6,7]. Ribonuclease L (RNASEL) encoding the versatile endoribonuclease RNase L is a key enzyme in the interferon induced antiviral and anti-proliferate pathway, involved in cellular viral defense, single-stranded RNA cleavage and tumor suppressor activities as stress mediated apoptosis, cell proliferation and regulation of protein synthesis [1,2,3,4,5]. 59-phosphorylated 29-59 linked oligoadenylates (2-5A), which activate RNase L by binding to the ankyrin repeats and inducing dimerization, essential for the endonuclease activity of RNase L [8]. The ankyrin repeats are known to be involved in protein/protein interactions, but the RNase L ankyrin repeats (2 to 4) bind the 25A molecule, which initiates the conformational change of RNase L leading to dimerization and thereby activation of the enzyme [9,10].
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