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1.  Trends in prevalence of prognostic factors and survival in lung cancer patients from 1985 to 2004 at a tertiary care center 
Cancer detection and prevention  2008;32(2):101-108.
After a prolonged period of increasing rates of lung cancer incidence and mortality for both men and women, incidence and mortality rates are decreasing in men and stabilizing in women. The goal of this study was to assess changes over 20 years in the prevalence of known risk factors for lung cancer and to elucidate possible predictors associated with lung cancer survival.
The study included a total of 908 patients with primary lung cancer referred to The University of Texas M. D. Anderson Cancer Center over three study periods 1985–1989 (N=392), 1993–1997 (N= 216), and 2000–2004 (N= 300). Detailed questionnaires were used to collect information from the patients. Hazard ratios were estimated by fitting a Cox proportional hazards model. Using the Kaplan Meier method, survival in months was calculated up to 2 years from the date of diagnosis to achieve comparability in the three groups.
We observed a decrease in the proportion of patients who are current cigarette smokers and an increase in the proportion of patients who present with adenocarcinoma of the lung, are obese and patients who present with localized disease. We also found an increase in the number of patients who report a family history of lung cancer. The overall median survival duration has increased over the years from 12.0 months in 1985–1989 to 17.5 months in 2000–2004. Also, the probability of survival of patients who were alive at 2 years after diagnosis has also increased (26.5% in 1985–1989 to 40.8% in 2000–2004). Overall, women had a better median survival than men.
The results show that the demographic, histologic, clinical, and outcome variables of patients with lung cancer have changed over the past 20 years. Most important, the survival of patients with lung cancer has improved.
PMCID: PMC4287275  PMID: 18639390
Lung cancer survival; time-trends; predictors for lung cancer survival
2.  An Expanded Risk Prediction Model for Lung Cancer 
Risk prediction models are useful in clinical decision making. We have published an internally validated prediction tool for lung cancer based on easily obtainable epidemiologic and clinical data. Because the precision of the model was modest, we now estimate the improvement obtained by adding two markers of DNA repair capacity.
Assay data (host-cell reactivation and mutagen sensitivity) were available for 725 White lung cancer cases and 615 controls, all former or current smokers, a subset of cases and controls from the previous analysis. Multivariable models were constructed from the original variables with addition of the biomarkers separately and together. Pairwise comparisons of the area under the receiver operating characteristic curves (AUC) and 3-fold cross-validations were done.
For former smokers, the AUC and 95% confidence intervals were 0.67 (0.63–0.71) for the baseline model and 0.70 (0.66–0.74) for the expanded model. For current smokers, the comparable AUC values were 0.68 (0.64–0.72) and 0.73 (0.69–0.77). For both groups, the expanded models were statistically significantly better than the baseline models (P = 0.006 and P = 0.0048, respectively), although the increases in the concordance statistics were modest. We also recomputed 1-year absolute risks of lung cancer as described previously for two different risk profiles and showed that individuals who exhibited poor repair capacity or heightened mutagen sensitivity had increased absolute risks of lung cancer.
Addition of biomarker assays improved the sensitivity of the expanded models.
PMCID: PMC2854404  PMID: 19138968
3.  The CHRNA5-A3 Region on Chromosome 15q24-25.1 Is a Risk Factor Both for Nicotine Dependence and for Lung Cancer 
Common variants in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25.1 were associated with lung cancer risk in three recently published independently conducted genome-wide association studies, with no consensus as to the relative impact of the variants on the propensity to smoke vs a direct carcinogenic effect. To further explore our hypothesis that these variants are indeed associated with both cancer causation and nicotine dependence, we performed a more detailed analysis of the association of these putative risk genotypes with smoking phenotype, as well as in lifetime never smokers, and in other smoking-related cancers. We demonstrate a statistically significant association of the variants with both nicotine dependence, as well as lung cancer phenotypes, including earlier age at lung cancer onset. The variants were associated with higher risks of lung cancer in lower smoking-exposed strata, and in individuals with a strong family history of lung or smoking-related cancers. In contrast, we found no evidence that the variants were associated with elevated risks in 547 lifetime never-smoking lung cancer case subjects, nor in other smoking-related cancers (bladder and renal). Thus, we conclude that the variants are implicated both in smoking behavior and more directly in lung cancer risk.
PMCID: PMC2720751  PMID: 18957677
4.  The Influence of Tumor Necrosis Factor-α –308 G/A and IL-6 –174 G/C on Pain and Analgesia Response in Lung Cancer Patients Receiving Supportive Care 
We previously showed that select cytokine gene polymorphisms are a significant predictor for pain reported at initial presentation in 446 white patients newly diagnosed with non–small cell lung cancer. This follow-up study explores the extent to which polymorphisms in tumor necrosis factor-α (TNF- α-308 G/A), interleukin (IL)-6 −174G/C, and IL-8 −251T/A could explain variability in pain and analgesic response among those patients (n = 140) subsequently referred for pain treatment.
Pain severity (0, no pain; 10, worst pain) was assessed at initial consultation and at follow-up visit. The total dose of opioids at the time of first-follow up visit (30 days postconsult) was converted to an equivalent dose of parenteral morphine.
Forty-one percent (57 of 140) of the patients reported severe pain (score >7/10) at initial consultation (mean, 5.5), which significantly decreased to 25% (mean, 4) at first follow-up visit (McNemar = P < 0.001). Polymorphisms in TNF and IL-6 were significantly associated with pain severity (for TNF GG, 4.12; GA, 5.38; AA, 5.50; P = 0.04) and with morphine equivalent daily dose (IL-6 GG, 69.61; GC, 73.17; CC, 181.67; P = 0.004), respectively. Adjusting for demographic and clinical variables, variant alleles in TNFα −308 G/A remained significantly associated with pain severity (b = 0.226; P = 0.036) and carriers of the IL-6 −174C/C genotypes required 4.7 times higher dose of opioids for pain relief (odds ratio, 4.7; 95% confidence interval, 1.2;15.0) relative to GG and GC genotypes.
We provide preliminary evidence of the influence of cytokine genes on pain and response to analgesia in lung cancer patients. Additional studies are needed to validate our findings. The long-term application is to tailored pain therapies.
PMCID: PMC3398799  PMID: 18990769
5.  Prognostic Significance of Ataxia-Telangiectasia Mutated, DNA-dependent Protein Kinase Catalytic Subunit, and Ku Heterodimeric Regulatory Complex 86-kD Subunit Expression in Patients With Nonsmall Cell Lung Cancer 
Cancer  2008;112(12):2756-2764.
The double-strand break (DSB) repair capacity has been implicated in the survival of patients in several cancer types. However, little is known about the prognostic importance of the key DSB repair genes—ataxia-telangiectasia mutated (ATM), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and the Ku heterodimeric regulatory complex 86-kD subunit (Ku80)—in nonsmall cell lung cancer (NSCLC). To address this issue, the authors determined the messenger RNA (mRNA) expression of these genes in patients NSCLC and assessed their prognostic relevance.
mRNA expression levels of ATM, DNA-PKcs, and Ku80 were measured in tumor and adjacent normal tissues from 140 patients with NSCLC by using quantitative real-time polymerase chain reaction analysis. Then, a Cox proportional hazards regression model and Kaplan-Meier plots were used to evaluate the association between the tumor:normal (T/N) expression ratios of the 3 genes and the overall survival rate and duration in patients with NSCLC.
mRNA expression of ATM and DNA-PKcs, but not of Ku80, was significantly higher in tumor tissues than in adjacent normal tissues (P = .003 and P < .001, respectively). The high T/N expression ratios of ATM and DNA-PKcs were associated significantly with a 1.82-fold increased risk of death (95% confidence interval, 1.05–2.70) and a 2.13-fold increased risk of death (95% confidence interval, 1.21–3.76), respectively. However, no significant association with risk was observed for Ku80. Kaplan-Meier analyses revealed that patients with high T/N expression ratios of ATM or DNA-PKcs had notably shorter median survival than patients with low ratios.
The current findings suggested that the T/N expression ratios of ATM and DNA-PKcs may be useful for identifying NSCLC patients with a poor prognosis who may benefit from more aggressive therapy.
PMCID: PMC3384998  PMID: 18457328
DNA repair; DNA double-strand break; nonsmall cell lung cancer; prognosis
6.  Dietary α-, β-, γ- and δ-tocopherols in lung cancer risk 
Studies of vitamin E and cancer have focused on the α-tocopherol form of the vitamin. However, other forms of vitamin E, in particular γ-tocopherol may have unique mechanistic characteristics relevant to lung cancer prevention. In an ongoing study of 1,088 incident lung cancer cases and 1,414 healthy matched controls, we studied the associations between 4 tocopherols (α-, β-, γ-, and δ-tocopherol) in the diet and lung cancer risk. Using multiple logistic regression analysis, the adjusted odds ratios (OR) and 95% confidence intervals (CI) of lung cancer for increasing quartiles of dietary α-tocopherol intake were 1.0, 0.63 (0.50–0.79), 0.58 (0.44–0.76) and 0.39 (0.28–0.53), respectively (p-trend < 0.0001). For dietary intake of β-tocopherol, the OR and 95% CI for all subjects were: 1.0, 0.79 (0.63–0.98), 0.59 (0.45–0.78) and 0.56 (0.42–0.74), respectively (p-trend < 0.0001). Similar results for dietary γ-tocopherol intake were observed: 1.0, 0.84 (0.67–1.06), 0.76 (0.59–0.97) and 0.56 (0.42–0.75), respectively (p- trend = 0.0002). No significant association between δ-tocopherol intake and lung cancer risk was detected. When the 4 tocopherols were summed as total tocopherol intake, a monotonic risk reduction was also observed. When we entered the other tocopherols in our model, only the association with dietary α-tocopherol intake remained significant; i.e., increasing intake of dietary α-tocopherol accounted for 34–53% reductions in lung cancer risk. To the best of our knowledge, this is the first report of the independent associations of the 4 forms of dietary tocopherol (α-, β-, γ- and δ-tocohperol) on lung cancer risk. Given the limitations with case-control studies, these findings need to be confirmed in further investigations.
PMCID: PMC3380426  PMID: 18546288
dietary tocopherols; lung cancer risk; diet and lung cancer; vitamin E and lung cancer
7.  Automated detection of genetic abnormalities combined with cytology in sputum is a sensitive predictor of lung cancer 
Modern Pathology  2008;21(8):950-960.
Detection of lung cancer by sputum cytology has low sensitivity but is noninvasive and, if improved, could be a powerful tool for early lung cancer detection. To evaluate whether the accuracy of diagnosing lung cancer by evaluating sputa for cytologic atypia and genetic abnormalities is greater than that of conventional cytology alone, automated scoring of genetic abnormalities for 3p22.1 and 10q22.3 (SP-A) by fluorescence in situ hybridization (FISH) and conventional cytology was done on sputa from 35 subjects with lung cancer, 25 high-risk smokers, and 6 healthy control subjects. Multivariate analysis was performed to select variables that most accurately predicted lung cancer. A model of probability for the presence of lung cancer was derived for each subject. Cells exfoliated from patients with lung cancer contained genetic aberrations and cytologic atypias at significantly higher levels than in those from control subjects. When combined with cytologic atypia, a model of risk for lung cancer was derived that had 74% sensitivity and 82% specificity to predict the presence of lung cancer, whereas conventional cytology achieved only 37% sensitivity and 87% specificity. For diagnosing lung cancer in sputum, a combination of molecular and cytologic variables was superior to using conventional cytology alone.
PMCID: PMC3377448  PMID: 18500269
surfactant protein A gene; 3p22.1; FISH; cytology; field cancerization effect; sputum
8.  3p22.1 and 10q22.3 Deletions Detected by Fluorescence In Situ Hybridization (FISH) 
Journal of Thoracic Oncology  2008;3(9):979-984.
Our objective was to study the feasibility of detecting chromosomal deletions at 3p22.1 and 10q22.3 by fluorescent in situ hybridization (FISH) and to examine their distribution in different areas of the airway in patients with non-small cell lung cancer.
Brush biopsies from the mainstem bronchus on the normal side contralateral to the tumor (NBB) and mainstem bronchus on the tumor side (TBB) were obtained from 122 patients who underwent surgical resection. Touch preparations from the tumor (TTP), normal lung parenchyma, and bronchi adjacent to the tumor were also obtained. Two FISH assays using probes complementary to 3p22.1 and 10q22.3 were used to detect deletions.
NBB showed a relatively low deletion rate of 3p22.1 and 10q22.3 compared with TTP (p < 0.0001). TBB showed a significantly higher rate of deletions compared with NBB but lower than TTP from the tumor (p < 0.05) for both 3p22.1 and 10q22.3. A significantly higher deletion rate was seen at TTP compared with normal lung parenchyma at both the 3p22.1 and 10 q22.3 (p < 0.0001). Correlations were seen between the deletion rates of TTP and TBB at 3p22.1 (ρ = 0.61, p < 0.0001) and between TTP and bronchi adjacent to the tumor at 10q22.3 (ρ = 0.64, p < 0.0001).
Deletions of the 3p22.1 and 10q22.3 regions can be reliably detected by FISH. As one progresses from the contralateral normal bronchus to the bronchus on the side of tumor and the tumor itself, the percentage of chromosomal deletions increases in a statistically significant fashion. This suggests that, FISH analysis of bronchoscopic brushes may be useful for identifying patients at high risk for developing non-small cell lung cancer.
PMCID: PMC3370669  PMID: 18758299
Lung; Cancer; Non-small cell; Screening; Fluorescent in situ hybridization; Bronchial brushes
9.  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
10.  Cytokinesis-Blocked Micronucleus Cytome Assay Biomarkers Identify Lung Cancer Cases Amongst Smokers 
The multi-endpoint cytokinesis-blocked micronucleus assay is used for assessing chromosome aberrations. We have recently reported that this assay is extremely sensitive to genetic damage caused by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyr-idyl)-1-butanone (NNK) and that the binucleated cells with micronuclei, nucleoplasmic bridges, and nuclear buds in lymphocytes (chromosome damage endpoints measured by the assay) are strong predictors of lung cancer risk. In the current study, we refined our analysis to include toxicity endpoints (micronuclei in mononucleated cells, apoptosis, necrosis, and nuclear division index) to investigate the benefit of including these variables on improving the predictive value of the assay. Baseline and NNK-induced micronuclei in mononucleated cells were significantly higher in patients (n = 139) than controls (n = 130; P < 0.001). Baseline apoptosis was higher among cases; however, the controls showed a significant higher fold increase in NNK-induced apoptosis compared with baseline (P < 0.001). Principal components analysis was used to derive a summary measure for all endpoints and calculate the positive predictive value (PPV) and negative predictive value (NPV) for disease status. First principal component for NNK-induced chromosome damage endpoints (binucleated cells with micronuclei, nucleoplasmic bridges, and nuclear buds) had an area under the curve = 97.9 (95% confidence interval, 95.9-99.0), PPV = 94.8, and NPV = 92.6. The discriminatory power improved when micronuclei in mononucleated cells were included: area under the curve = 99.1 (95% confidence interval, 97.9- 100.0), PPV = 98.7 and NPV = 95.6. The simplicity, rapidity, and sensitivity of the assay together with potential for automation make it a valuable tool for screening and prioritizing potential cases for intensive screening.
PMCID: PMC2854407  PMID: 18483333
11.  Development and Validation of a Lung Cancer Risk Prediction Model for African-Americans 
Because existing risk prediction models for lung cancer were developed in white populations, they may not be appropriate for predicting risk among African-Americans. Therefore, a need exists to construct and validate a risk prediction model for lung cancer that is specific to African-Americans. We analyzed data from 491 African-Americans with lung cancer and 497 matched African-American controls to identify specific risks and incorporate them into a multivariable risk model for lung cancer and estimate the 5-year absolute risk of lung cancer. We performed internal and external validations of the risk model using data on additional cases and controls from the same ongoing multiracial/ethnic lung cancer case-control study from which the model-building data were obtained as well as data from two different lung cancer studies in metropolitan Detroit, respectively. We also compared our African-American model with our previously developed risk prediction model for whites. The final risk model included smoking-related variables [smoking status, pack-years smoked, age at smoking cessation (former smokers), and number of years since smoking cessation (former smokers)], self- reported physician diagnoses of chronic obstructive pulmonary disease or hay fever, and exposures to asbestos or wood dusts. Our risk prediction model for African-Americans exhibited good discrimination [75% (95% confidence interval, 0.67−0.82)] for our internal data and moderate discrimination [63% (95% confidence interval, 0.57−0.69)] for the external data group, which is an improvement over the Spitz model for white subjects. Existing lung cancer prediction models may not be appropriate for predicting risk for African-Americans because (a) they were developed using white populations, (b) level of risk is different for risk factors that African-American share with whites, and (c) unique group-specific risk factors exist for African-Americans. This study developed and validated a risk prediction model for lung cancer that is specific to African-Americans and thus more precise in predicting their risks. These findings highlight the importance of conducting further ethnic-specific analyses of disease risk.
PMCID: PMC2854402  PMID: 19138969
12.  The influence of subjective social status on the relationship between positive outcome expectations and experimentation with cigarettes 
In Texas, Mexican American (MA) adolescents, and in particular boys, are at increased risk of experimenting with cigarettes compared to their black or white counterparts. Positive outcome expectations (POE), the functional social significance ascribed to cigarettes, and subjective social status (SSS), the adolescents’ subjective views of where they lie in the school-based social hierarchy, are independent predictors of smoking. The goal of this study was to test the hypothesis that SSS moderates the relationship between POE and experimentation with cigarettes.
Moderating effects of SSS were examined using a between-subjects 2 by 2 ANOVA and unconditional logistic regression analyses. Using a prospective study design, we followed 1,142 MA adolescents aged 11 to 13. Participants completed a baseline survey at home, which assessed POE, SSS, and smoking and were followed via telephone at 6 monthly intervals over a 12 month period to assess changes in smoking behavior.
At follow-up, there were 99 new experimenters. Consistent with our hypothesis, adolescents who reported moderate-low SSS and who held POE at baseline were more likely to have experimented with cigarettes at either follow-up than their peers with moderate-low SSS who held less POE (OR=1.92, CI: 1.02–3.58). There was no association between outcome expectations and experimenting among adolescents with high SSS (OR=1.79, CI: 0.73–4.36). Low SSS boys were more likely to experiment than girls and high SSS boys.
The results of this study indicate that adolescents with moderate-low SSS hold different outcome expectations about smoking than their higher SSS peers. The results underscore the possibility that moderate-low SSS adolescents view behaviors such as smoking as a way to achieve higher SSS and thereby increase their peer social standing. Our results suggest that, in addition to tailoring intervention efforts by gender, placing adolescents of similar social standing to one another within the school into intervention groups that are led by a peer-nominated peer may increase the overall effectiveness of these peer-led prevention efforts.
PMCID: PMC2705959  PMID: 19306792
13.  Common 5p15.33 and 6p21.33 variants influence lung cancer risk 
Nature genetics  2008;40(12):1407-1409.
We conducted a genome-wide association (GWA) study of lung cancer comparing 511,919 SNP genotypes in 1,952 cases and 1,438 controls. The most significant association was attained at 15q25.1 (rs8042374; P = 7.75 × 10−12), confirming recent observations. Pooling data with two other GWA studies (5,095 cases, 5,200 controls) and with replication in an additional 2,484 cases and 3,036 controls, we identified two newly associated risk loci mapping to 6p21.33 (rs3117582, BAT3-MSH5; Pcombined = 4.97 × 10−10) and 5p15.33 (rs401681, CLPTM1L; Pcombined = 7.90 × 10−9).
PMCID: PMC2695928  PMID: 18978787
14.  Smoking-related Genomic Signatures in Non–Small Cell Lung Cancer 
Rationale: Tobacco smoking is responsible for 85% of all lung cancers. To further our understanding of the molecular pathogenesis of lung cancer, we determined whether smoking history leads to the emergence of specific genomic alterations found in non–small cell lung cancer (NSCLC).
Objectives: To identify gene copy number alterations in NSCLCs associated with smoking history or DNA repair capacity.
Methods: Seventy-five NSCLCs were selected for this study from patients with current, none, or past smoking history, including pack year information. Tissue sections were microdissected, and DNA was extracted, purified, and labeled by random priming before hybridization onto bacterial artificial chromosome (BAC) arrays. Normalized ratios were correlated with smoking history and DNA repair capacity was measured by an in vitro lymphocyte assay in the same patients.
Measurements and Main Results: We identified smoking-related genomic signatures in NSCLCs that could be predicted with an overall 74% accuracy. Lung tumors arising from current-smokers had the greatest number of copy number alterations. The genomic regions most significantly associated with smoking were located within 60 regions and were functionally associated with genes controlling the M phase of the cell cycle, the segregation of chromosomes, and the methylation of DNA. Verification of the data is provided from data in the public domain and by quantitative real-time polymerase chain reaction. The associations between genomic abnormalities and DNA repair capacity did not reach statistical significance.
Conclusions: These findings indicate that smoking history leaves a specific genomic signature in the DNA of lung tumors and suggest that these alterations may reflect new molecular pathways to cancer development.
PMCID: PMC2720147  PMID: 18776155
array comparative genomic hybridization; tobacco; profile; microarray
15.  Genetic Variations in Cell Cycle Pathway and the Risk of Oral Premalignant Lesions 
Cancer  2008;113(9):2488-2495.
Cell-cycle checkpoint regulates cell cycle progression and proliferation. Alterations in cell-cycle control mechanisms are linked to tumorigenesis.
This case-control study included 147 cases and 147 controls. We used a pathway-based approach to assess the association between 10 potential functional single-nucleotide polymorphisms from seven cell-cycle control genes and the risk of oral premalignant lesions (OPLs). We also used classification and regression tree analysis to examine high-order gene-gene and gene-smoking interactions.
Compared with the homozygous wild-type GG genotype of CCND1 P241P, individuals with the AG genotype exhibited an increased risk of OPL (odds ratio, 1.58; 95% confidence interval, 0.89–2.83), and carriers of the AA genotype had a significantly increased risk of OPL (odds ratio, 2.75; 95% confidence interval, 1.33–5.71), with risk increasing significantly with the increasing number of variant alleles (P = 0.006). The risk of OPL increased significantly as the number of unfavorable genotypes in the pathway increased (P = 0.002). The final decision tree in the CART analysis contained five terminal nodes. Compared with the never smokers (the lowest risk group), the odds ratios for terminal nodes 2 through 5 ranged from 1.21 to 5.40.
Our results illustrated the advantage of using a pathway-based approach for analyzing gene-gene and gene-smoking interactions. Specifically, we showed that genetic polymorphisms in cell-cycle control pathway genes may contribute to the risk of OPL.
PMCID: PMC2577230  PMID: 18823025
Cell-cycle pathway; SNP; Oral premalignant lesion; CART
16.  International Lung Cancer Consortium: Pooled Analysis of Sequence Variants in DNA Repair and Cell Cycle Pathways 
The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies.
Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects.
Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79–0.99 and homozygote OR, 0.84; 95% CI, 0.71–1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% CI, 0.89–1.10 and homozygote OR, 1.19; 95% CI, 1.02–1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00–1.29 and homozygote OR, 1.20; 95% CI, 1.02–1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01–1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk.
In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies.
PMCID: PMC2756735  PMID: 18990748
17.  Germline Genetic variations in drug action pathways predict clinical outcomes in advanced lung cancer treated with platinum-based chemotherapy 
Pharmacogenetics and genomics  2008;18(11):955-965.
Genetic polymorphisms contribute to interindividual variation in drug response. However, a single polymorphism is likely to exhibit a modest effect. Therefore, we applied a pathway-based approach to evaluate the cumulative effect of multiple polymorphisms on clinical outcome of patients with non-small cell lung cancer (NSCLC).
We genotyped 25 functional polymorphisms in 16 key genes involved in cisplatin metabolism and action and evaluated their associations with overall survival in 229 NSCLC patients receiving first-line cisplatin-based chemotherapy.
Several biologically plausible main effects were identified in individual analysis. More importantly, when 6 polymorphisms in nucleotide excision repair genes were analyzed jointly, a significant trend of reduced risk of death with decreasing number of putative unfavorable genotypes was observed (P for trend <0.001 and log-rank p<0.001). Survival tree analysis revealed potential higher-order gene-gene interactions and categorized subgroups with dramatically different survival experiences, based on distinct genotype profiles. The median survival time was 78.5 months for terminal node 1 in the low-risk group, 15.1 months for terminal node 10 in the medium-risk group, and 6.7 months for terminal node 9 in the high-risk group (log rank P<0.001). We also constructed a prediction hazard model. The area under the curve (AUC) increased from 0.71 (using clinical variables only) to 0.84 (using clinical, epidemiological, and genetic variations from survival tree analysis).
Our results highlight the clinical potential of taking a pathway-based approach and using survival tree analytic approach to identify subgroups of patients with distinctly differing outcomes.
PMCID: PMC2665725  PMID: 18854777
18.  Familial Aggregation of Common Sequence Variants on 15q24-25.1 in Lung Cancer 
Three recent genome-wide association studies identified associations between markers in the chromosomal region 15q24-25.1 and the risk of lung cancer. We conducted a genome-wide association analysis to investigate associations between single-nucleotide polymorphisms (SNPs) and the risk of lung cancer, in which we used blood DNA from 194 case patients with familial lung cancer and 219 cancer-free control subjects. We identified associations between common sequence variants at 15q24-25.1 (that spanned LOC123688 [a hypothetical gene], PSMA4, CHRNA3, CHRNA5, and CHRNB4) and lung cancer. The risk of lung cancer was more than fivefold higher among those subjects who had both a family history of lung cancer and two copies of high-risk alleles rs8034191 (odds ratio [OR] = 7.20, 95% confidence interval [CI] = 2.21 to 23.37) or rs1051730 (OR = 5.67, CI = 2.21 to 14.60, both of which were located in the 15q24-25.1 locus, than among control subjects. Thus, further research to elucidate causal variants in the 15q24-25.1 locus that are associated with lung cancer is warranted.
PMCID: PMC2538550  PMID: 18780872
19.  Mitochondrial DNA Content: Its Genetic Heritability and Association With Renal Cell Carcinoma 
The extent to which mitochondrial DNA (mtDNA) content (also termed mtDNA copy number) in normal human cells is influenced by genetic factors has yet to be established. In addition, whether inherited variation of mtDNA content in normal cells contributes to cancer susceptibility remains unclear. Renal cell carcinoma accounts for 85% of all renal cancers. No studies have investigated the association between mtDNA content and the risk of renal cell carcinoma.
We first used a classic twin study design to estimate the genetic contribution to the determination of mtDNA content. mtDNA content was measured by quantitative real-time polymerase chain reaction in peripheral blood lymphocytes from 250 monozygotic twins, 92 dizygotic twins, and 33 siblings (ie, individual siblings of a pair of twins). We used biometric genetic modeling to estimate heritability of mtDNA content. We then used a case–control study with 260 case patients with renal cell carcinoma and 281 matched control subjects and multivariable logistic regression analysis to examine the association between mtDNA content in peripheral blood lymphocytes and the risk of renal cell carcinoma. All statistical tests were two-sided.
The heritability (ie, proportion of phenotypic variation in a population that is attributable to genetic variation among individuals) of mtDNA content was 65% (95% confidence interval [CI] = 50% to 72%; P < .001). Case patients with renal cell carcinoma had a statistically significantly lower mtDNA content (1.18 copies) than control subjects (1.29 copies) (difference = 0.11, 95% CI = 0.03 to 0.17; P = .006). Low mtDNA content (ie, less than the median in control subjects) was associated with a statistically significantly increased risk of renal cell carcinoma, compared with high content (odds ratio = 1.53, 95% CI = 1.07 to 2.19). In a trend analysis, a statistically significant dose–response relationship was detected between lower mtDNA content and increasing risk of renal cell carcinoma (P for trend <.001).
mtDNA content appears to have high heritability. Low mtDNA content appears to be associated with increased risk of renal cell carcinoma.
PMCID: PMC2720693  PMID: 18664653
20.  Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1 
Nature genetics  2008;40(5):616-622.
To identify risk variants for lung cancer, we conducted a multistage genome-wide association study. In the discovery phase, we analyzed 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, we evaluated the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P < 1 × 10−17) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. We conclude that variation in a region of 15q25.1 containing nicotinic acetylcholine receptors genes contributes to lung cancer risk.
PMCID: PMC2713680  PMID: 18385676
21.  Genetic Polymorphisms in Double-Strand Break DNA Repair Genes Associate with Risk of Oral Premalignant Lesions 
Oral premalignant lesions (OPLs) are early genetic events en route to oral cancer. To identify individuals susceptible to OPL is critical to the prevention of oral cancer. In a case-control study consisting of 147 patients with histologically confirmed OPL and 147 matched controls, we evaluated the associations of 10 genetic variants in nine genes of the double-strand break (DSB) DNA repair pathway with OPL risk. The most notable finding was an intronic polymorphism (A17893G) of the XRCC3 gene. Compared with the homozygous wild-type AA genotype, the odds ratios [OR] (95% confidence interval [CI]) for the heterozygous AG and homozygous variant GG genotype were 0.85 (0.49–1.48) and 0.18 (0.07–0.47), respectively (P for trend=0.002). In addition, compared with the most common A-C haplotype of XRCC3 (in the order of A17893G-T241M), the G-C haplotype was associated with a significantly decreased risk of OPL (OR=0.40, 95% CI 0.23–0.68). Moreover, compared with individuals without the G-C haplotype, the ORs were 1.04 (0.56–1.95) and 0.20 (0.08–0.51) for subjects with one copy and two copies of the G-C haplotype, respectively (P for trend=0.005). Classification and regression tree (CART) analysis further revealed potential high-order gene-gene and gene-environmental interactions and categorized subjects into different risk groups according to their specific polymorphic signatures. Overall, our study provides the first epidemiological evidence supporting a connection between DSB gene variants and OPL development. Our data also suggest that the effects of high-order interactions should be taken into consideration when evaluating OPL predisposition.
PMCID: PMC2603619  PMID: 18579371
Double-strand break; Polymorphism; Haplotype; Oral premalignant lesion
22.  Somatic mutations affect key pathways in lung adenocarcinoma 
Ding, Li | Getz, Gad | Wheeler, David A. | Mardis, Elaine R. | McLellan, Michael D. | Cibulskis, Kristian | Sougnez, Carrie | Greulich, Heidi | Muzny, Donna M. | Morgan, Margaret B. | Fulton, Lucinda | Fulton, Robert S. | Zhang, Qunyuan | Wendl, Michael C. | Lawrence, Michael S. | Larson, David E. | Chen, Ken | Dooling, David J. | Sabo, Aniko | Hawes, Alicia C. | Shen, Hua | Jhangiani, Shalini N. | Lewis, Lora R. | Hall, Otis | Zhu, Yiming | Mathew, Tittu | Ren, Yanru | Yao, Jiqiang | Scherer, Steven E. | Clerc, Kerstin | Metcalf, Ginger A. | Ng, Brian | Milosavljevic, Aleksandar | Gonzalez-Garay, Manuel L. | Osborne, John R. | Meyer, Rick | Shi, Xiaoqi | Tang, Yuzhu | Koboldt, Daniel C. | Lin, Ling | Abbott, Rachel | Miner, Tracie L. | Pohl, Craig | Fewell, Ginger | Haipek, Carrie | Schmidt, Heather | Dunford-Shore, Brian H. | Kraja, Aldi | Crosby, Seth D. | Sawyer, Christopher S. | Vickery, Tammi | Sander, Sacha | Robinson, Jody | Winckler, Wendy | Baldwin, Jennifer | Chirieac, Lucian R. | Dutt, Amit | Fennell, Tim | Hanna, Megan | Johnson, Bruce E. | Onofrio, Robert C. | Thomas, Roman K. | Tonon, Giovanni | Weir, Barbara A. | Zhao, Xiaojun | Ziaugra, Liuda | Zody, Michael C. | Giordano, Thomas | Orringer, Mark B. | Roth, Jack A. | Spitz, Margaret R. | Wistuba, Ignacio I. | Ozenberger, Bradley | Good, Peter J. | Chang, Andrew C. | Beer, David G. | Watson, Mark A. | Ladanyi, Marc | Broderick, Stephen | Yoshizawa, Akihiko | Travis, William D. | Pao, William | Province, Michael A. | Weinstock, George M. | Varmus, Harold E. | Gabriel, Stacey B. | Lander, Eric S. | Gibbs, Richard A. | Meyerson, Matthew | Wilson, Richard K.
Nature  2008;455(7216):1069-1075.
Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers—including NF1, APC, RB1 and ATM—and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
PMCID: PMC2694412  PMID: 18948947
23.  Dietary magnesium and DNA repair capacity as risk factors for lung cancer 
Carcinogenesis  2008;29(5):949-956.
Magnesium (Mg) is required for maintenance of genomic stability; however, data on the relationship between dietary Mg intake and lung cancer are lacking. In an ongoing lung cancer case–control study, we identified 1139 cases and 1210 matched healthy controls with data on both diet and DNA repair capacity (DRC). Dietary intake was assessed using a modified Block-NCI food frequency questionnaire and DRC was measured using the host-cell reactivation assay to assess repair in lymphocyte cultures. After adjustment for potential confounding factors including DRC, the odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer with increasing quartiles of dietary Mg intake were 1.0, 0.83 (0.66–1.05), 0.64 (0.50–0.83) and 0.47 (0.36–0.61), respectively, for all subjects (P-trend < 0.0001). Similar results were observed by histology and clinical stage of lung cancer. Low dietary Mg intake was associated with poorer DRC and increased risk of lung cancer. In joint effects analyses, compared with those with high dietary Mg intake and proficient DRC, the OR (95% CI) for lung cancer in the presence of both low dietary Mg and suboptimal DRC was 2.36 (1.83–3.04). Similar results were observed for men and women. The effects were more pronounced among older subjects (>60 years), current or heavier smokers, drinkers, those with a family history of cancer in first-degree relatives, small cell lung cancer and late-stage disease. These intriguing results need to be confirmed in prospective studies.
PMCID: PMC2902380  PMID: 18448487
24.  Effect of different types of smoking and synergism with Hepatitis C virus on risk of hepatocellular carcinoma in American men and women: Case-control study 
The International Agency for Research on Cancer has declared smoking to be a risk factor for hepatocellular carcinoma (HCC). However, passive exposure to cigarette smoke and use of noncigarette tobacco products on the risk of HCC has not been examined. Therefore, we evaluated the independent effects of different types of smoking exposure along with multiple risk factors for HCC and determined whether the magnitude of smoking was modified by other risk factors in men and women. We conducted a case-control study at The University of Texas M. D. Anderson Cancer Center where 319 HCC patients and 1,061 healthy control subjects were personally interviewed for several HCC risk factors. Multivariate logistic regression analysis was performed to estimate the adjusted odds ratio (AOR) and 95% confidence interval (CI) for each potential risk factor. Use of smokeless tobacco (chewing tobacco and snuff), cigars, pipes and passive smoking exposure were not related to HCC among noncigarette smokers. However, regular cigarette smoking was associated with HCC in men: AOR, 1.9 (95% CI, 1.1–3.1). Heavy alcohol consumption was associated with HCC in women: AOR, 7.7 (95% CI, 2.3–25.1). Cigarette smoking interacted synergistically with chronic infection of hepatitis C virus in men: AOR, 136.3 (95% CI, 43.2–429.6) and with heavy alcohol consumption in women: AOR, 13.7 (95% CI, 3.2–57.9). We conclude that sex differences were observed in HCC relationship with cigarette smoking and alcohol consumption. Controlling for smoking exposure might be a prudent approach to the prevention of HCC, especially in patients with chronic viral hepatitis infections.
PMCID: PMC2673571  PMID: 18688864
passive smoking; HCC; cigarette smoking; gender; pipes; cigars; tobacco
25.  Single Nucleotide Polymorphisms in Selected Apoptotic Genes and BPDE-Induced Apoptotic Capacity in Apparently Normal Primary Lymphocytes: A Genotype-Phenotype Correlation Analysis 
Journal of Cancer Epidemiology  2008;2008:147905.
Apoptotic capacity (AC) in primary lymphocytes may be a marker for cancer susceptibility, and functional single nucleotide polymorphisms (SNPs) in genes involved in apoptotic pathways may modulate cellular AC in response to DNA damage. To further examine the correlation between apoptotic genotypes and phenotype, we genotyped 14 published SNPs in 11 apoptosis-related genes (i.e., p53, Bcl-2, BAX, CASP9, DR4, Fas, FasL, CASP8, CASP10, CASP3, and CASP7) and assessed the AC in response to benzo[a]pyrene-7,8-9,10-diol epoxide (BPDE) in cultured primary lymphocytes from 172 cancer-free subjects. We found that among these 14 SNPs, R72P, intron 3 16-bp del/ins, and intron 6 G>A in p53, −938C>A in Bcl-2, and I522L in CASP10 were significant predictors of the BPDE-induced lymphocytic AC in single-locus analysis. In the combined analysis of the three p53 variants, we found that the individuals with the diplotypes carrying 0-1 copy of the common p53 R-del-G haplotype had higher AC values compared to other genotypes. Although the study size may not have the statistical power to detect the role of other SNPs in AC, our findings suggest that some SNPs in genes involved in the intrinsic apoptotic pathway may modulate lymphocytic AC in response to BPDE exposure in the general population. Larger studies are needed to validate these findings for further studying individual susceptibility to cancer and other apoptosis-related diseases.
PMCID: PMC2859018  PMID: 20445773

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