METHODOLOGY/PRINCIPAL FINDINGS: To 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: 4.43x10(-5)).
CONCLUSION/SIGNIFICANCE: In 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.