TY - JOUR
T1 - Cyclin D1 and p16 alterations in advanced premalignant lesions of the upper aerodigestive tract
T2 - Role in response to chemoprevention and cancer development
AU - Papadimitrakopoulou, Vassiliki A.
AU - Keck, Jamie
AU - Hamilton, David
AU - Dong Moon Shin, Dong
AU - Hong, Waun K.
AU - Izzo, Julie
AU - Den Hollander, Petra
AU - Hittelman, Walter N.
AU - Mao, Li
AU - El-Naggar, Adel
AU - Liu, Diane
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
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M3 - Article
C2 - 11595705
AN - SCOPUS:0034791377
SN - 1078-0432
VL - 7
SP - 3127
EP - 3134
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 10
ER -