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Cyclin D1 splice variants: polymorphism, risk, and isoform specific regulation in prostate cancer.


Purpose: Alternative splicing of the CCND1 transcript results in cyclin D1b, which has specialized, pro-tumorigenic functions in prostate cells not shared by the cyclin D1a (full-length) isoform. Until now, the frequency of cyclin D1b production, tumor relevance, and mechanisms controlling alternative splicing remained unchallenged. Experimental Design: First, unbiased expression of both cyclin D1 isoforms was quantified in a large cohort of prostate adenocarcinomas. Second, relevance of the androgen axis was determined. Third, minigenes were created to interrogate the role of the G/A870 polymorphism (found within the splice donor site), and findings were validated in primary prostate tissues. Fourth, impact of G/A870 on cancer risk was assessed in two large population based case-controlled studies. Results: Unlike cyclin D1a, cyclin D1b is induced in prostate cancers (p<0.004), and a subset exclusively express this isoform. The two isoforms are independently regulated, and hormone status did not alter alternative splicing. While G/A870 was not independently predictive of prostate cancer risk, A870 predisposed for cyclin D1b production in cells and in normal prostate tissue. The influence of the A-allele was relieved in tumors, indicating that cooperative effects likely occur in tumorigenesis. Conclusions: These studies show for the first time that cyclin D1b (but not cyclin D1a) is a predominant isoform in prostate cancer. Cyclin D1b production is regulated independently of cyclin D1a, but the A870 allele predisposes for cyclin D1b production in a context specific manner. While A870 does not independently predict prostate cancer risk, tumor cells can bypass the influence of the polymorphism. These findings have major implications for the analyses of D-cyclin function in the prostate, and provide the foundation for future studies directed at identifying modifiers of the G/A870 polymorphism.

Type Journal
ISBN 1078-0432 (Print)
Authors Comstock, C.E.S.; Augello, M.A.; PeBenito, R.; Karch, J.; Tran, T.H.; Ultama, F.E.; Tindall, E.; Wang, Y.; Burd, C.J.; Groh, E.M.; Hoang, H.N.; Giles, G.G.; Severi, G.; Hayes, V.M.; Henderson, B.E.; Marchand, L.L.; Kolonel, L.N.; Haiman, C.A.; Baffa, R.; Gomella, L.G.; Knudsen, E.S.; Rui, H.; Henshall, S.M.; Sutherland, R.L.; Knudsen, K.E.
Published Date 2009-09-01
Published Volume 15
Published Issue 17
Published Pages 5338-5348
Status Published in-print
DOI 10.1158/1078-0432.CCR-08-2865
URL link to publisher's version
OpenAccess link to author's accepted manuscript version