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1.  Genome-Wide Association Study Reveals Novel Genetic Determinants of DNA Repair Capacity in Lung Cancer 
Cancer research  2012;73(1):256-264.
Suboptimal cellular DNA repair capacity (DRC) has been shown to be associated with enhanced cancer risk, but genetic variants affecting the DRC phenotype have not been comprehensively investigated. In this study, with the available DRC phenotype data, we analyzed correlations between the DRC phenotype and genotypes detected by the Illumina 317K platform in 1,774 individuals of European ancestry from a Texas lung cancer genome-wide association study. The discovery phase was followed by a replication in an independent set of 1,374 cases and controls of European ancestry. We applied a generalized linear model with SNPs as predictors and DRC (a continuous variable) as the outcome. Covariates of age, sex, pack-years of smoking, DRC assay-related variables and case-control status of the study participants were adjusted in the model. We validated that reduced DRC was associated with an increased risk of lung cancer in both independent datasets. Several suggestive loci that contributed to the DRC phenotype were defined in ERCC2/XPD, PHACTR2 and DUSP1. In summary, we determined that DRC is an independent risk factor for lung cancer and we defined several genetic loci contributing to DRC phenotype.
PMCID: PMC3537906  PMID: 23108145
DNA repair capacity; genetic susceptibility; genome-wide association; molecular epidemiology
2.  Chromosome Instability and Risk of Squamous Cell Carcinomas of Head and Neck 
Cancer research  2008;68(11):4479-4485.
In 895 subjects with squamous cell carcinoma of the head and neck (SCCHN) and 898 cancer-free controls matched by age, sex, and ethnicity, we validated our previous finding that mutagen sensitivity as measured by the frequency of chromatid breaks in vitro induced by benzo[a]pyrene diol epoxide (BPDE) is an independent risk factor for SCCHN. Using a previously established concentration of 4 μM BPDE to treat short-term cultured primary lymphocytes for 5 hours, we evaluated chromatid breaks in 50 well-spread metaphases for each blood sample. The mean frequency of BPDE-induced chromatid breaks was significantly higher in cases than in controls in non-Hispanic whites (P = 0.0003) but not in other ethnic groups (P = 0.549 for Hispanic Americans and 0.257 for African Americans). The odds ratio associated with risk of SCCHN for the frequency of chromatid breaks greater than median value of controls was 1.56 (95% confidence interval, 1.27–1.91) in non-Hispanic whites (767 cases and 763 controls) after adjustment for age, sex, smoking status, and drinking status. When the quartiles of the controls were used as the cutoff values, there was a dose response between the degree of mutagen sensitivity and risk of SCCHN in non-Hispanic whites (Ptrend = 0.0001). However, none of these associations in non-Hispanic whites was identified in Hispanic Americans (69 cases and 70 controls) or African Americans (59 cases and 65 controls), possibly because of the small samples of these ethnic groups or ethnic difference in genetic variation, which needs to be confirmed in future studies.
PMCID: PMC3079380  PMID: 18519711
mutagen sensitivity; genetic susceptibility; molecular epidemiology; chromosome aberration; head and neck cancer
3.  Deciphering the impact of common genetic variation on lung cancer risk: A genome-wide association study 
Cancer research  2009;69(16):6633-6641.
To explore the impact of common variation on the risk of developing lung cancer we conducted a two-phase genome-wide association (GWA) study. In Phase 1, we compared the genotypes of 511,919 tagging single nucleotide polymorphisms (tagSNPs) in 1,952 cases and 1,438 controls; in Phase 2, 30,568 SNPs were genotyped in 2,465 cases and 3,005 controls. SNP selection was based on best supported P-values from Phase 1 and two other GWA studies of lung cancer. In the combined analysis of Phases 1 and 2, the strongest associations identified were defined by SNPs mapping to 15q25.1 (rs12914385; P = 3.19 × 10−16), 5p15.33 (rs4975616; P = 6.66 × 10−7), and 6p21.33 (rs3117582; P = 9.13 × 10−7). Variation at 15q25.1, but not 5p15.33 or 6p21.33, was strongly associated with smoking behaviour with risk alleles correlated to higher consumption. Variation at 5p15.33 was shown to significantly influence induction of lung cancer histology. Pooling data from the four series provided 21,620 genotypes for 7,560 cases and 8,205 controls. A meta-analysis provided increased support that variation at 15q25.1 (rs8034191; P = 3.24 × 10−26), 5p15.33 (rs4975616; P = 2.99 × 10−9), and 6p21.33 (rs3117582; P = 4.46 × 10−10) influences lung cancer risk. The next best-supported associations were attained at 15q15.2 (rs748404: P = 1.08 × 10−6) and 10q23.31 (rs1926203; P = 1.28 × 10−6). These data indicate few common variants account for 1% of the excess familial risk underscoring the necessity of having additional large sample series for gene discovery.
PMCID: PMC2754318  PMID: 19654303
lung cancer; genome-wide association

Results 1-3 (3)