TY - JOUR
T1 - Association of polymorphisms in the Cyclin D1 and XPD genes and susceptibility to cancers of the upper aero-digestive tract
AU - Buch, Shama
AU - Zhu, Bing
AU - Davis, Autumn Gaither
AU - Odom, Dominic
AU - Siegfried, Jill M.
AU - Grandis, Jennifer R.
AU - Romkes, Marjorie
PY - 2005/4
Y1 - 2005/4
N2 - DNA repair enzyme genetic polymorphisms have been postulated to increase the risk of certain cancers in the presence of tobacco carcinogen exposures. The XPD protein is an important component of the TFIIH transcription factor complex. XPD genetic polymorphisms resulting in amino acids substitutions may lead to alterations in TFIIH helicase activity, resulting in repair and transcription defects. Cyclin D1 is a key regulatory protein for the transition of cells from the G1-S cell cycle phase. The CCND1 G870A polymorphism has been reported to enhance alternate splicing of a stable mRNA variant, which may result in the bypass of the G1/S cell cycle checkpoint. In this study, XPD G23591A (Asp312Asn) and A35931C (Lys751Gln) polymorphisms and the CCND1 G870A splice variant frequencies were determined in 273 upper aero-digestive tract cancer cases and 269 controls. The XPD Asp312Asn variant frequency was significantly different among cases and controls and conferred an odds ratio (OR) of 1.3 (95% CI 1.0-1.8). However, individuals with the CCND1 G870A and XPD Lys751Gln variants had higher age adjusted ORs of 3.2 (95% CI 2.2-4.6) and 2.2 (95% CI 1.5-3.2), respectively. Furthermore, a significant gene-gene interaction was observed among cases with at least two variant alleles for both CCND1 and XPD genes [OR 7.09 (95% CI 4.03-12.5)]. Smokers with a combination of at least one variant allele of both CCND1 and XPD genes also had an elevated risk as compared to nonsmokers. This is the first study to suggest an associative interaction between XPD and CCND1 genetic polymorphisms, tobacco exposure, and cancer risk.
AB - DNA repair enzyme genetic polymorphisms have been postulated to increase the risk of certain cancers in the presence of tobacco carcinogen exposures. The XPD protein is an important component of the TFIIH transcription factor complex. XPD genetic polymorphisms resulting in amino acids substitutions may lead to alterations in TFIIH helicase activity, resulting in repair and transcription defects. Cyclin D1 is a key regulatory protein for the transition of cells from the G1-S cell cycle phase. The CCND1 G870A polymorphism has been reported to enhance alternate splicing of a stable mRNA variant, which may result in the bypass of the G1/S cell cycle checkpoint. In this study, XPD G23591A (Asp312Asn) and A35931C (Lys751Gln) polymorphisms and the CCND1 G870A splice variant frequencies were determined in 273 upper aero-digestive tract cancer cases and 269 controls. The XPD Asp312Asn variant frequency was significantly different among cases and controls and conferred an odds ratio (OR) of 1.3 (95% CI 1.0-1.8). However, individuals with the CCND1 G870A and XPD Lys751Gln variants had higher age adjusted ORs of 3.2 (95% CI 2.2-4.6) and 2.2 (95% CI 1.5-3.2), respectively. Furthermore, a significant gene-gene interaction was observed among cases with at least two variant alleles for both CCND1 and XPD genes [OR 7.09 (95% CI 4.03-12.5)]. Smokers with a combination of at least one variant allele of both CCND1 and XPD genes also had an elevated risk as compared to nonsmokers. This is the first study to suggest an associative interaction between XPD and CCND1 genetic polymorphisms, tobacco exposure, and cancer risk.
KW - CCND1
KW - DNA repair
KW - Genetic epidemiology
KW - Upper aero-digestive tract cancer
KW - XPD
UR - http://www.scopus.com/inward/record.url?scp=17044423360&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=17044423360&partnerID=8YFLogxK
U2 - 10.1002/mc.20086
DO - 10.1002/mc.20086
M3 - Article
C2 - 15754315
AN - SCOPUS:17044423360
VL - 42
SP - 222
EP - 228
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
SN - 0899-1987
IS - 4
ER -