Cyclin D1 genotype, response to biochemoprevention, and progression rate to upper aerodigestive tract cancer.
BACKGROUND
Altered cyclin D1 expression in advanced preinvasive lesions of the upper aerodigestive tract (UADT) is associated with an increased risk of developing cancer and histologic progression during and after combination biochemopreventive therapy (13-cis-retinoic acid, alpha-interferon, and alpha-tocopherol). Both alleles of the adenine (A)/guanine (G) cyclin D1 polymorphism located at nucleotide 870 encode two alternatively spliced transcripts, but the A allele preferentially encodes a protein with an extended half-life. We investigated whether the cyclin D1 genotype at nucleotide 870 was associated with baseline levels of cyclin D1 protein, post-treatment modulation of cyclin D1 protein levels, histologic response to treatment, and the outcome for subjects with preinvasive UADT lesions after biochemopreventive therapy.


METHODS
UADT tissue biopsy samples were obtained before and 6 and 12 months after biochemopreventive treatment from 31 individuals with advanced preinvasive UADT lesions. Tissues were examined for cyclin D1 genotype (by DNA single-strand conformation polymorphism analysis), for cyclin D1 protein expression (by immunohistochemistry), and for cyclin D1 gene copy number (by fluorescence in situ hybridization). Associations of cyclin D1 genotype with histologic response to therapy and time to progression to a higher degree of dysplasia or invasive cancer were investigated. All statistical tests were two-sided.


RESULTS
The A allele was associated with increased baseline cyclin D1 expression in the parabasal epithelial layer (16 of 18 AA/AG subjects versus four of nine GG subjects; P =.02), decreased histologic response to biochemopreventive treatment (six of 21 AA/AG subjects versus four of 10 GG subjects; P =.70), decreased favorable modulation of cyclin D1 expression by the treatment (seven of 18 AA/AG subjects versus eight of nine GG subjects; P =.02), and shorter progression-free survival (P =.05).


CONCLUSIONS
The cyclin D1 A allele was associated with a diminished modulation of normal physiologic and treatment-induced decreased expression of cyclin D1, a decreased likelihood of response to biochemopreventive intervention, and an increased rate of progression to cancer development, findings that require validation in a larger cohort.
Izzo
Julie G
JG
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. jizzo@mdanderson.org
Papadimitrakopoulou
Vassiliki A
VA
Liu
Diane D
DD
den Hollander
Petra L C
PL
Babenko
Ilona M
IM
Keck
Jamie
J
El-Naggar
Adel K
AK
Shin
Dong M
DM
Lee
J Jack
JJ
Hong
Waun K
WK
Hittelman
Walter N
WN
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019938:Cyclin D1 / Q000097:blood / Q000235:genetics*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000627:therapeutic use; D017404:In Situ Hybridization, Fluorescence; D016898:Interferon-alpha / Q000008:administration & dosage; D015474:Isotretinoin / Q000008:administration & dosage; D007822:Laryngeal Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D009062:Mouth Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011446:Prospective Studies; D016896:Treatment Outcome; D024502:alpha-Tocopherol / Q000008:administration & dosage
D007155:Immunologic Factors; D016898:Interferon-alpha; D019938:Cyclin D1; D015474:Isotretinoin; D024502:alpha-Tocopherol