Cyclin D1 splice variants

Polymorphism, risk, and isoform-specific regulation in prostate cancer

Clay E S Comstock, Michael A. Augello, Ruth Pe Benito, Jason Karch, Thai H. Tran, Fransiscus E. Utama, Elizabeth A. Tindall, Ying Wang, Craig J. Burd, Eric M. Groh, Hoa N. Hoang, Graham G. Giles, Gianluca Severi, Vanessa M. Hayes, Brian E. Henderson, Loic Le Marchand, Laurence N. Kolonel, Christopher A. Haiman, Raffaele Baffa, Leonard G. Gomella & 5 others Erik S. Knudsen, Hallgeir Rui, Susan M. Henshall, Robert L. Sutherland, Karen E. Knudsen

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5338-5349
Number of pages12
JournalClinical Cancer Research
Volume15
Issue number17
DOIs
StatePublished - Sep 1 2009

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Cyclins
Cyclin D1
Prostatic Neoplasms
Protein Isoforms
Prostate
Neoplasms
Carcinogenesis
Cyclin D
Alternative Splicing
Androgens
Case-Control Studies
Adenocarcinoma
Research Design
Alleles
Hormones

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Comstock, C. E. S., Augello, M. A., Pe Benito, R., Karch, J., Tran, T. H., Utama, F. E., ... Knudsen, K. E. (2009). Cyclin D1 splice variants: Polymorphism, risk, and isoform-specific regulation in prostate cancer. Clinical Cancer Research, 15(17), 5338-5349. https://doi.org/10.1158/1078-0432.CCR-08-2865

Cyclin D1 splice variants : Polymorphism, risk, and isoform-specific regulation in prostate cancer. / Comstock, Clay E S; Augello, Michael A.; Pe Benito, Ruth; Karch, Jason; Tran, Thai H.; Utama, Fransiscus E.; Tindall, Elizabeth A.; Wang, Ying; Burd, Craig J.; Groh, Eric M.; Hoang, Hoa N.; Giles, Graham G.; Severi, Gianluca; Hayes, Vanessa M.; Henderson, Brian E.; Le Marchand, Loic; Kolonel, Laurence N.; Haiman, Christopher A.; Baffa, Raffaele; Gomella, Leonard G.; Knudsen, Erik S.; Rui, Hallgeir; Henshall, Susan M.; Sutherland, Robert L.; Knudsen, Karen E.

In: Clinical Cancer Research, Vol. 15, No. 17, 01.09.2009, p. 5338-5349.

Research output: Contribution to journalArticle

Comstock, CES, Augello, MA, Pe Benito, R, Karch, J, Tran, TH, Utama, FE, Tindall, EA, Wang, Y, Burd, CJ, Groh, EM, Hoang, HN, Giles, GG, Severi, G, Hayes, VM, Henderson, BE, Le Marchand, L, Kolonel, LN, Haiman, CA, Baffa, R, Gomella, LG, Knudsen, ES, Rui, H, Henshall, SM, Sutherland, RL & Knudsen, KE 2009, 'Cyclin D1 splice variants: Polymorphism, risk, and isoform-specific regulation in prostate cancer', Clinical Cancer Research, vol. 15, no. 17, pp. 5338-5349. https://doi.org/10.1158/1078-0432.CCR-08-2865
Comstock, Clay E S ; Augello, Michael A. ; Pe Benito, Ruth ; Karch, Jason ; Tran, Thai H. ; Utama, Fransiscus E. ; Tindall, Elizabeth A. ; Wang, Ying ; Burd, Craig J. ; Groh, Eric M. ; Hoang, Hoa N. ; Giles, Graham G. ; Severi, Gianluca ; Hayes, Vanessa M. ; Henderson, Brian E. ; Le Marchand, Loic ; Kolonel, Laurence N. ; Haiman, Christopher A. ; Baffa, Raffaele ; Gomella, Leonard G. ; Knudsen, Erik S. ; Rui, Hallgeir ; Henshall, Susan M. ; Sutherland, Robert L. ; Knudsen, Karen E. / Cyclin D1 splice variants : Polymorphism, risk, and isoform-specific regulation in prostate cancer. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 17. pp. 5338-5349.
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abstract = "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.",
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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.

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