Germline Mutation in RNASEL Predicts Increased Risk of Head and Neck, Uterine Cervix and Breast Cancer

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.

Immunotherapy for SV40 T/t antigen-induced breast cancer by recombinant adeno-associated virus serotype 2 carrying interleukin-15 in mice

“…SV40 T/t antigens have been shown to be related to the biological behavior and prognosis of breast cancer (1)(2)(3). In this study, we successfully established SV40 T/t antigen-induced breast cancer transgenic mice.…”

“…Although breast cancer is complex and highly variable in its clinical course, studies have indicated that SV40 T/t antigens are related to the biological behavior and prognosis of breast cancer (1)(2)(3). Previous studies have indicated that interleukins (IL1, IL2, IL12, IL15, IL18, IL24), tumor necrosis factor-α (TNF-α), and the interferon-γ (IFN-γ) can control the immune response and play an important role in breast cancer immunotherapy (4)(5)(6).…”

High-Resolution Melting Analysis for Mutation Screening of RGSL1, RGS16, and RGS8 in Breast Cancer

“…Because of steroid hormone regulation of prostate and breast cancers (16), we also considered implication of the genes within 1q25.3 in breast cancer development. Because mutation screening of RNASEL has not pointed at its unambiguous involvement in breast cancer, we have focused on the group of RGS genes from the region of interest (17,18). The novel family of RGS proteins plays an essential role in regulating GPCR-induced signaling by enhancing the GTPase activity, thereby attenuating the G protein-dependent activation cycle (19)(20)(21).…”

Towards identifying New Human Ribonucleases that Cleave microRNA Using a High-Throughput Method.

“…RNase L also contributes to tumor suppressor activities such as stress mediated apoptosis cell proliferation and regulation of protein synthesis (Liang et al 2006, Madsen et al 2008. Mutated RNase L was related to the increased risk of head and neck, uterine cervix, breast and prostate cancer (Madsen et al, 2008;Carpten et al, 2002).…”

“…Mutated RNase L was related to the increased risk of head and neck, uterine cervix, breast and prostate cancer (Madsen et al, 2008;Carpten et al, 2002).…”