Elevated lung cancer risk is associated with deficiencies in cell cycle checkpoints: genotype and phenotype analyses from a case-control study.
Cell cycle checkpoints play critical roles in the maintenance of genomic integrity and inactivation of checkpoint genes are frequently perturbed in most cancers. In a case-control study of 299 non-small cell lung cancer cases and 550 controls in Baltimore, we investigated the association between gamma-radiation-induced G(2)/M arrest in cultured blood lymphocytes and lung cancer risk, and examined genotype-phenotype correlations between genetic polymorphisms of 20 genes involving in DNA repair and cell cycle control and gamma-radiation-induced G(2)/M arrest. The study was specifically designed to examine race and gender differences in risk factors. Our data indicated that a less efficient DNA damage-induced G(2)/M checkpoint was associated with an increased risk of lung cancer in African American women with an adjusted odds ratio (OR) of 2.63 (95% CI = 1.01-7.26); there were no statistically significant associations for Caucasians, or African American men. When the African American women were categorized into quartiles, a significant reverse trend of decreased G(2)/M checkpoint function and increased lung cancer risk was present, with lowest-vs.-highest quartile OR of 13.72 (95% CI = 2.30-81.92, p(trend) < 0.01). Genotype-phenotype correlation analysis indicated that polymorphisms in ATM, CDC25C, CDKN1A, BRCA2, ERCC6, TP53, and TP53BP1 genes were significantly associated with the gamma-radiation-induced G(2)/M arrest phenotype. This study provides evidence that a less efficient G(2)/M checkpoint is significantly associated with lung cancer risk in African American women. The data also suggested that the function of G(2)/M checkpoint is modulated by genetic polymorphisms in genes involved in DNA repair and cell cycle control.
Zheng
Yun-Ling
YL
Cancer Genetics and Epidemiology Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA.
Kosti
Ourania
O
Loffredo
Christopher A
CA
Bowman
Elise
E
Mechanic
Leah
L
Perlmutter
Donna
D
Jones
Raymond
R
Shields
Peter G
PG
Harris
Curtis C
CC
D000368:Aged; D016022:Case-Control Studies; D002455:Cell Division; D004260:DNA Repair; D005260:Female; D016195:G2 Phase; D018816:Genes, cdc / Q000502:physiology*; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors