Cyclin D1 and p16 alterations in advanced premalignant lesions of the upper aerodigestive tract: Role in response to chemoprevention and cancer development

Vassiliki A. Papadimitrakopoulou, Jamie Keck, David Hamilton, Dong Dong Moon Shin, Waun K. Hong, Julie Izzo, Petra Den Hollander, Walter N. Hittelman, Li Mao, Adel El-Naggar, Diane Liu

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Purpose: To better understand the role of G1-S transition regulator abnormalities in the pathogenesis of advanced premalignant lesions of the upper aerodigestive tract and the biological effects of chemoprevention, we studied biopsies obtained sequentially from participants in a prospective trial using 13-cis retinoic acid, IFN-α, and α-tocopherol for 12 months. Experimental design: Cyclin D1 and p16 expression were analyzed by immunohistochemistry, loss of heterozygosity by polymerse chain reacting amplification, and then electrophoretic separation of the products, methylation of the p16 promoter by methylation-speciffc polymerase chain reacting, and cyclin D1 gene amplification by fluorescence in situ hybridization. Results: Baseline dysregulation of cyclin D1 expression was found in 50% (14 of 28) and was reversed in 6 of 14 cases, whereas p16 expression was lost in 46% (13 of 28) and regained in 2 of 13 cases. Loss of heterozygosity at 9p21 occurred in 68% and p16INK4a promoter methylation occurred in 75% of cases, with increasing frequency from mild to severe dysplasia. Cyclin D1 gene amplification was identiffed in two cases. Cyclin D1 protein dysregulation at last follow-up alone and in combination with p16 loss was associated with histological progression and cancer development (P<0.01). Conclusions: Additional study of these alterations in a larger sample and exploration of the upstream signaling partners of these cell cycle regulators in vivo is warranted to identify cancer risk profiles that would be meaningful targets for chemopreventive intervention.

Original languageEnglish (US)
Pages (from-to)3127-3134
Number of pages8
JournalClinical Cancer Research
Volume7
Issue number10
StatePublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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