title: Cyclin D1 splice variants: polymorphism, risk, and isoform-specific regulation in prostate cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 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.
  
  
  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.
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Clay E S
authors.initials: CE
authors.lastname: Comstock
authors.forename: Michael A
authors.initials: MA
authors.lastname: Augello
authors.forename: Ruth Pe
authors.initials: RP
authors.lastname: Benito
authors.forename: Jason
authors.initials: J
authors.lastname: Karch
authors.forename: Thai H
authors.initials: TH
authors.lastname: Tran
authors.forename: Fransiscus E
authors.initials: FE
authors.lastname: Utama
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Tindall
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Burd
authors.forename: Eric M
authors.initials: EM
authors.lastname: Groh
authors.forename: Hoa N
authors.initials: HN
authors.lastname: Hoang
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Gianluca
authors.initials: G
authors.lastname: Severi
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hayes
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Raffaele
authors.initials: R
authors.lastname: Baffa
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Gomella
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.forename: Susan M
authors.initials: SM
authors.lastname: Henshall
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
mesh_terms: D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics*; D016022:Case-Control Studies; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D020033:Protein Isoforms; D019938:Cyclin D1
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