Dataset Information

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

ABSTRACT: 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.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.Cyclin D1b is induced in tumors, and a significant subset expressed this isoform in the absence of detectable cyclin D1a. Accordingly, the isoforms showed noncorrelated 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.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.

SUBMITTER: Comstock CE

PROVIDER: S-EPMC2849314 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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

Comstock Clay E S CE Augello Michael A MA Benito Ruth Pe RP Karch Jason J Tran Thai H TH Utama Fransiscus E FE Tindall Elizabeth A EA Wang Ying Y Burd Craig J CJ Groh Eric M EM Hoang Hoa N HN Giles Graham G GG Severi Gianluca G Hayes Vanessa M VM Henderson Brian E BE Le Marchand Loic L Kolonel Laurence N LN Haiman Christopher A CA Baffa Raffaele R Gomella Leonard G LG Knudsen Erik S ES Rui Hallgeir H Henshall Susan M SM Sutherland Robert L RL Knudsen Karen E KE

Clinical cancer research : an official journal of the American Association for Cancer Research 20090825 17

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 ...[more]

PMID: 19706803

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Project description:BackgroundCyclin D1 (CCND1) G870A polymorphism may be associated with hepatocellular carcinoma (HCC) risk, but the results of previous studies were inconsistent. Available evidence was meta-analyzed to assess their potential association.MethodsDatabases PubMed, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature database, China National Knowledge Infrastructure, and Google Scholar were systematically searched. Meta-analyses were performed to investigate the association of G870A polymorphism with HCC risk by calculating odds ratios (ORs) and 95% confidence intervals (CIs) from the data of relevant case-control studies.ResultsResults of this meta-analysis of six case-control studies involving 1,030 cases and 1,683 controls indicate that G870A polymorphism was not associated with HCC risk in any of the five genetic models tested (recessive model: AA vs GG + AG: OR =1.38, 95% CI =0.95-2.00, P=0.09; dominant model: AG + AA vs GG: OR =1.38, 95% CI =0.87-2.20, P=0.17; homozygous model: AA vs GG: OR =1.60, 95% CI =0.87-2.94, P=0.13; heterozygous model: AG vs GG: OR =1.24, 95% CI =0.86-1.79, P=0.25; allelic model: A vs G: OR =1.30, 95% CI =0.95-1.80, P=0.10). Subgroup analyses according to ethnicity showing marginally significant association between this single nucleotide polymorphism and HCC risk indicate that G870A may be significantly associated with HCC risk in Caucasian populations (recessive model: AA vs GG + AG: OR =2.34, 95% CI =1.60-3.42, P<0.0001; dominant model: AG + AA vs GG: OR =2.44, 95% CI =1.19-4.97, P=0.01; homozygous model: AA vs GG: OR =3.42, 95% CI =1.80-6.50, P=0.0002; allelic model: A vs G: OR =2.06, 95% CI =1.31-3.24, P=0.002), but not in Asian populations.ConclusionAvailable evidence suggests that no significant association between G870A polymorphism and HCC risk was found in either total populations or Asian populations. However, significant association was found in Caucasian populations. These results should be verified and extended in further detailed and well-designed studies involving larger, multiethnic samples.

Dataset Information

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

Publications

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

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