Elevated lung cancer risk is associated with deficiencies in cell cycle checkpoints: genotype and phenotype analyses from a case‐control study
Open Access
- 22 July 2009
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 126 (9), 2199-2210
- https://doi.org/10.1002/ijc.24771
Abstract
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 γ‐radiation‐induced G2/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 γ‐radiation‐induced G2/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 G2/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 G2/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 γ‐radiation‐induced G2/M arrest phenotype. This study provides evidence that a less efficient G2/M checkpoint is significantly associated with lung cancer risk in African American women. The data also suggested that the function of G2/M checkpoint is modulated by genetic polymorphisms in genes involved in DNA repair and cell cycle control.Keywords
This publication has 51 references indexed in Scilit:
- Genotypes and haplotypes of ERCC1 and ERCC2/XPD genes predict levels of benzo[a]pyrene diol epoxide-induced DNA adducts in cultured primary lymphocytes from healthy individuals: a genotype-phenotype correlation analysisCarcinogenesis: Integrative Cancer Research, 2008
- Cancer Statistics, 2008CA: A Cancer Journal for Clinicians, 2008
- Common Genetic Variation in TP53 Is Associated with Lung Cancer Risk and Prognosis in African Americans and Somatic Mutations in Lung TumorsCancer Epidemiology, Biomarkers & Prevention, 2007
- Racial and ethnic differences in lung cancer incidence: how much is explained by differences in smoking patterns? (United States)Cancer Causes & Control, 2006
- Nucleotide excision repair as a marker for susceptibility to tobacco-related cancers: A review of molecular epidemiological studiesMolecular Carcinogenesis, 2005
- ATM: A mediator of multiple responses to genotoxic stressOncogene, 1999
- The role of ATM in DNA damage responses and cancerOncogene, 1998
- X‐ray‐induced chromatid damage in relation to dna repair and cancer incidence in family membersInternational Journal of Cancer, 1993
- Increased Radiosensitivity and the Basic Defect in Ataxia TelangiectasiaInternational Journal of Radiation Biology, 1989
- Effects of X-irradiation on cell-cycle progression, induction of chromosomal aberrations and cell killing in ataxia telangiectasia (AT) fibroblastsMutation research. Reviews in mutation research, 1985