2′‐5′ oligoadenylate synthetase 1 polymorphism is associated with prostate cancer

Abstract

Background 2′ -5′ –oligoadenylate synthetase (2-5 OAS1), an antiviral, pro-apoptotic and anti-proliferative gene converts ATP to a series of 2′ -5′ –oligoadenylates (2-5A). 2-5A in turn activates RNaseL, a candidate hereditary prostate cancer gene. OAS1 polymorphism (rs2660) has been associated with increased susceptibility to infections and various diseases. In general, the low enzyme activity AA genotype promotes susceptibility whereas high enzyme activity GG genotype confers protection. In this study we investigated the association of this functional polymorphism (rs2660) in OAS1 with prostate cancer. Methods Sample size and power was calculated using the PGA software. Genomic DNA from a controls (n=140) and prostate cancer patients (n=164) were used for genotyping SNPs rs2660, rs1131454 and rs34137742 on all samples. Statistical analysis was performed using logistic regression model. Results Significant association was observed between rs2660 genotype (A/G) and prostate cancer. Genotype AA increased the risk whereas GG genotype decreased the risk of prostate cancer. The GG genotype was not observed in the African American samples. The AA genotype also increased the risk of prostate cancer with age. Conclusions OAS1 SNP rs2660 AA genotype is significantly associated with prostate cancer whereas GG genotype protects against prostate cancer. OAS1 rs2660 could be a prostate cancer susceptibility polymorphism, a significant observation especially in a context of the OAS1-RNaseL pathway. Thus a functional defect in OAS1 due to rs2660 SNP can not only attenuate RNaseL function, but can also alter cell growth and apoptosis independent of RNaseL.

Association of the Innate Immunity and Inflammation Pathway with Advanced Prostate Cancer Risk

“…Nonetheless, these agents could possibly induce carcinogenesis through the activation of a chronic inflammatory response [53]. Only one study of the association between prostate cancer and OAS1 was done on a smaller sample size and 3 SNPs different from our selection where an association with rs2660 was found [54].…”

Resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus: Role of type I interferon signaling

“…OAS converts adenosine triphosphate into a series of 20–50 oligoadenylates (2-5A), which activate the latent ribonuclease (RNaseL). The activated OAS-RNaseL system promotes apoptosis, attenuates proliferation, degrades viral and cellular RNA, and inhibits protein synthesis (Justesen et al, 2000; Mandal et al, 2011). Previous studies showed increased expression of OAS in PDA cells resistant to adenoviruses (Monsurro et al, 2010), and human mesothelioma cells resistant to VSV (Saloura et al, 2010).…”

Oligoadenylate synthetase 1 (OAS1) expression in human breast and prostate cancer cases, and its regulation by sex steroid hormones

“…Taking into account that OAS1 levels were lower in both breast and prostate cancers than in normal tissue, that aggressiveness of the tumours correlated positively with lower levels of OAS1 expression, and considering the role of OAS1 in apoptosis, it is liable to speculate that apoptosis induced by the OAS/RNase L pathway may be compromised in these cancers. Recently, several number of polymorphisms in OAS1 gene were identified to be associated with prostate cancer, also suggesting that RNase L can be compromised, and consequently, changing the cell growth and apoptosis rate [30] . Both oestrogens and androgens play crucial roles in the proliferative and apoptotic events in the normal physiological states of mammary gland and prostate, as well as in pathological conditions [21,22] .…”