Cyclin D1 and p16 alterations in advanced premalignant lesions of the upper aerodigestive tract: role in response to chemoprevention and cancer development.
OBJECTIVE
To better understand the role of G(1)-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-alpha, and alpha-tocopherol for 12 months.


METHODS
Cyclin D1 and p16 expression were analyzed by immunohistochemistry, loss of heterozygosity by polymerase chain reacting amplification, and then electrophoretic separation of the products, methylation of the p16 promoter by methylation-specific 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 p16(INK4a) promoter methylation occurred in 75% of cases, with increasing frequency from mild to severe dysplasia. Cyclin D1 gene amplification was identified 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.
Papadimitrakopoulou
V A
VA
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1500 Holcombe Boulevard, Houston, TX 77030, USA. vpapadim@mdanderson.org
Izzo
J
J
Mao
L
L
Keck
J
J
Hamilton
D
D
Shin
D M
DM
El-Naggar
A
A
den Hollander
P
P
Liu
D
D
Hittelman
W N
WN
Hong
W K
WK
D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins / Q000502:physiology; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D056741:Cyclin D; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D005786:Gene Expression Regulation; D006258:Head and Neck Neoplasms / Q000473:pathology* / Q000517:prevention & control; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
D018797:Cell Cycle Proteins; D056741:Cyclin D; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D004247:DNA