TY - JOUR
T1 - Cyclin D1 splice variants
T2 - Polymorphism, risk, and isoform-specific regulation in prostate cancer
AU - Comstock, Clay E.S.
AU - Augello, Michael A.
AU - Pe Benito, Ruth
AU - Karch, Jason
AU - Tran, Thai H.
AU - Utama, Fransiscus E.
AU - Tindall, Elizabeth A.
AU - Wang, Ying
AU - Burd, Craig J.
AU - Groh, Eric M.
AU - Hoang, Hoa N.
AU - Giles, Graham G.
AU - Severi, Gianluca
AU - Hayes, Vanessa M.
AU - Henderson, Brian E.
AU - Le Marchand, Loic
AU - Kolonel, Laurence N.
AU - Haiman, Christopher A.
AU - Baffa, Raffaele
AU - Gomella, Leonard G.
AU - Knudsen, Erik S.
AU - Rui, Hallgeir
AU - Henshall, Susan M.
AU - Sutherland, Robert L.
AU - Knudsen, Karen E.
PY - 2009/9/1
Y1 - 2009/9/1
N2 - Purpose: Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged. Experimental Design: First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas. Second, relevance of the androgen axis was determined. Third, minigenes were created to interrogate the role of the G/A870 polymorphism (within the splice site), and findings were validated in primary tissue. Fourth, the effect of G/A870 on cancer risk was assessed in two large case-control studies. Results: Cyclin D1b is induced in tumors, and a significant subset expressed this isoform in the absence of detectable cyclin D1a. Accordingly, the isoforms showed non-correlated expression patterns, and hormone status did not alter splicing. Whereas G/A870 was not independently predictive of cancer risk, A870 predisposed for transcript-b production in cells and in normal prostate. The influence of A870 on overall transcript-b levels was relieved in tumors, indicating that aberrations in tumorigenesis likely alter the influence of the polymorphism. Conclusions: These studies reveal that cyclin D1b is specifically elevated in prostate tumorigenesis. Cyclin D1b expression patterns are distinct from that observed with cyclin D1a. The A870 allele predisposes for transcript-b production in a context-specific manner. Although A870 does not independently predict 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 potential modifiers of the G/A870 polymorphism.
AB - Purpose: Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged. Experimental Design: First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas. Second, relevance of the androgen axis was determined. Third, minigenes were created to interrogate the role of the G/A870 polymorphism (within the splice site), and findings were validated in primary tissue. Fourth, the effect of G/A870 on cancer risk was assessed in two large case-control studies. Results: Cyclin D1b is induced in tumors, and a significant subset expressed this isoform in the absence of detectable cyclin D1a. Accordingly, the isoforms showed non-correlated expression patterns, and hormone status did not alter splicing. Whereas G/A870 was not independently predictive of cancer risk, A870 predisposed for transcript-b production in cells and in normal prostate. The influence of A870 on overall transcript-b levels was relieved in tumors, indicating that aberrations in tumorigenesis likely alter the influence of the polymorphism. Conclusions: These studies reveal that cyclin D1b is specifically elevated in prostate tumorigenesis. Cyclin D1b expression patterns are distinct from that observed with cyclin D1a. The A870 allele predisposes for transcript-b production in a context-specific manner. Although A870 does not independently predict 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 potential modifiers of the G/A870 polymorphism.
UR - http://www.scopus.com/inward/record.url?scp=65049089363&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-08-2865
DO - 10.1158/1078-0432.CCR-08-2865
M3 - Article
C2 - 19706803
AN - SCOPUS:65049089363
SN - 1078-0432
VL - 15
SP - 5338
EP - 5349
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -