Germline Mutation in RNASEL Predicts Increased Risk of Head and Neck, Uterine Cervix and Breast CancerReport as inadecuate




Germline Mutation in RNASEL Predicts Increased Risk of Head and Neck, Uterine Cervix and Breast Cancer - Download this document for free, or read online. Document in PDF available to download.

The Background

Ribonuclease 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 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: 4.43×10−5.

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.



Author: Bo Eskerod Madsen, Eliana Marisa Ramos, Mathieu Boulard, Katarzyna Duda, Jens Overgaard, Marianne Nordsmark, Carsten Wiuf, Lise L

Source: http://plos.srce.hr/



DOWNLOAD PDF




Related documents