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26.  Genetic Variation in the PNPLA3 Gene and Hepatocellular Carcinoma in USA: Risk and Prognosis Prediction 
Molecular carcinogenesis  2013;52(0):10.1002/mc.22057.
Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic with high prevalence in Western countries. Genome-wide association studies had reported that a variation in the patatin-like phospholipase domain containing 3 (PNPLA3) gene is associated with high susceptibility to NAFLD. However, the relationship between this variation and hepatocellular carcinoma (HCC) has not been well established. We investigated the impact of PNPLA3 genetic variation (rs738409: C>G) on HCC risk and prognosis in the United States by conducting a case–control study that included 257 newly diagnosed and pathologically confirmed Caucasian patients with HCC (cases) and 494 healthy controls. Multivariate logistics and Cox regression models were used to control for the confounding effects of HCC risk and prognostic factors. We observed higher risk of HCC for subjects with a homozygous GG genotype than for those with CC or CG genotypes, the adjusted odds ratio (OR) was 3.21 (95% confidence interval [CI], 1.68–6.41). We observed risk modification among individuals with diabetes mellitus (OR = 19.11; 95% CI, 5.13–71.20). The PNPLA3 GG genotype was significantly associated with underlying cirrhosis in HCC patients (OR = 2.48; 95% CI, 1.05–5.87). Moreover, GG allele represents an independent risk factor for death. The adjusted hazard ratio of the GG genotype was 2.11 (95% CI, 1.26–3.52) compared with CC and CG genotypes. PNPLA3 genetic variation (rs738409: C>G) may determine individual susceptibility to HCC development and poor prognosis. Further experimental investigations are necessary for thorough assessment of the hepatocarcinogenic role of PNPLA3.
PMCID: PMC3808509  PMID: 23776098
molecular epidemiology; genetic susceptibility; case–control; single nucleotide polymorphism
27.  Increased risk of lung cancer in individuals with a family history of the disease: A pooled analysis from the International Lung Cancer Consortium 
Background and Methods
Familial aggregation of lung cancer exists after accounting for cigarette smoking. However, the extent to which family history affects risk by smoking status, histology, relative type and ethnicity is not well described. This pooled analysis included 24 case-control studies in the International Lung Cancer Consortium. Each study collected age of onset/interview, gender, race/ethnicity, cigarette smoking, histology and first-degree family history of lung cancer. Data from 24,380 lung cancer cases and 23,305 healthy controls were analyzed. Unconditional logistic regression models and generalized estimating equations were used to estimate odds ratios and 95% confidence intervals.
Individuals with a first-degree relative with lung cancer had a 1.51-fold increase in risk of lung cancer, after adjustment for smoking and other potential confounders(95% CI: 1.39, 1.63). The association was strongest for those with a family history in a sibling, after adjustment (OR=1.82, 95% CI: 1.62, 2.05). No modifying effect by histologic type was found. Never smokers showed a lower association with positive familial history of lung cancer (OR=1.25, 95% CI: 1.03, 1.52), slightly stronger for those with an affected sibling (OR=1.44, 95% CI: 1.07, 1.93), after adjustment.
The increased risk among never smokers and similar magnitudes of the effect of family history on lung cancer risk across histological types suggests familial aggregation of lung cancer is independent of those associated with cigarette smoking. While the role of genetic variation in the etiology of lung cancer remains to be fully characterized, family history assessment is immediately available and those with a positive history represent a higher risk group.
PMCID: PMC3445438  PMID: 22436981
28.  Genome-wide gene–environment interaction analysis for asbestos exposure in lung cancer susceptibility 
Carcinogenesis  2012;33(8):1531-1537.
Asbestos exposure is a known risk factor for lung cancer. Although recent genome-wide association studies (GWASs) have identified some novel loci for lung cancer risk, few addressed genome-wide gene–environment interactions. To determine gene–asbestos interactions in lung cancer risk, we conducted genome-wide gene–environment interaction analyses at levels of single nucleotide polymorphisms (SNPs), genes and pathways, using our published Texas lung cancer GWAS dataset. This dataset included 317 498 SNPs from 1154 lung cancer cases and 1137 cancer-free controls. The initial SNP-level P-values for interactions between genetic variants and self-reported asbestos exposure were estimated by unconditional logistic regression models with adjustment for age, sex, smoking status and pack-years. The P-value for the most significant SNP rs13383928 was 2.17×10–6, which did not reach the genome-wide statistical significance. Using a versatile gene-based test approach, we found that the top significant gene was C7orf54, located on 7q32.1 (P = 8.90×10–5). Interestingly, most of the other significant genes were located on 11q13. When we used an improved gene-set-enrichment analysis approach, we found that the Fas signaling pathway and the antigen processing and presentation pathway were most significant (nominal P < 0.001; false discovery rate < 0.05) among 250 pathways containing 17 572 genes. We believe that our analysis is a pilot study that first describes the gene–asbestos interaction in lung cancer risk at levels of SNPs, genes and pathways. Our findings suggest that immune function regulation-related pathways may be mechanistically involved in asbestos-associated lung cancer risk.
Abbreviations:CIconfidence intervalEenvironmentFDRfalse discovery rateGgeneGSEAgene-set-enrichment analysisGWASgenome-wide association studiesi-GSEAimproved gene-set-enrichment analysis approachORodds ratioSNPsingle nucleotide polymorphism
PMCID: PMC3499061  PMID: 22637743
29.  Association Between Hypothyroidism and Hepatocellular Carcinoma: A Case-Control Study in the United States 
Hepatology (Baltimore, Md.)  2009;49(5):1563-1570.
Thyroid hormones play an essential role in lipid mobilization, lipid degradation, and fatty acid oxidation. Hypothyroidism has been associated with nonalcoholic steatohepatitis; however, the association between thyroid diseases and hepatocellular carcinoma (HCC) in men and women has not been well established. We investigated the association between hypothyroidism and HCC risk in men and women in a case-control study, which included 420 eligible patients with HCC and 1104 healthy controls. We used multivariate unconditional logistic regression models to control for the confounding effects of established HCC risk factors. A long-term history of hypothyroidism (> 10 years) was associated with a statistically significant high risk of HCC in women; after adjusting for demographic factors, diabetes, hepatitis, alcohol consumption, cigarette smoking, and family history of cancer, the odds ratio (OR) was 2.9 (95% confidence interval [CI], 1.3–6.3). Restricted analyses among hepatitis virus—negative subjects, nondrinkers, nondiabetics, nonsmokers, and nonobese individuals indicated a significant association between hypothyroidism and HCC, with an approximate two-fold to three-fold increased risk of HCC development. We observed risk modification among women with diabetes mellitus (OR = 9.4; 95% CI = 2.7–32.7) and chronic hepatitis virus infection (OR = 31.2; 95% CI = 6.3–153.2). A history of hyperthyroidism was not significantly related to HCC (OR = 1.7; CI = 0.6–5.1). We noted significant elevated risk association between hypothyroidism and HCC in women that was independent of established HCC risk factors. Experimental investigations are necessary for thorough assessment of the relationship between thyroid disorders and HCC.
PMCID: PMC3715879  PMID: 19399911
30.  Bridging the clinical gaps: genetic, epigenetic and transcriptomic biomarkers for the early detection of lung cancer in the post-National Lung Screening Trial era 
BMC Medicine  2013;11:168.
Lung cancer is the leading cause of cancer death worldwide in part due to our inability to identify which smokers are at highest risk and the lack of effective tools to detect the disease at its earliest and potentially curable stage. Recent results from the National Lung Screening Trial have shown that annual screening of high-risk smokers with low-dose helical computed tomography of the chest can reduce lung cancer mortality. However, molecular biomarkers are needed to identify which current and former smokers would benefit most from annual computed tomography scan screening in order to reduce the costs and morbidity associated with this procedure. Additionally, there is an urgent clinical need to develop biomarkers that can distinguish benign from malignant lesions found on computed tomography of the chest given its very high false positive rate. This review highlights recent genetic, transcriptomic and epigenomic biomarkers that are emerging as tools for the early detection of lung cancer both in the diagnostic and screening setting.
PMCID: PMC3717087  PMID: 23870182
Biomarker; Diagnostics; Early detection; Epigenetics; Genetics; Lung cancer; Screening; Transcriptomics
31.  Genetic variants in the PI3K/PTEN/AKT/MTOR pathway predict head and neck cancer patient second primary tumor/recurrence risk and response to retinoid chemoprevention 
Clinical Cancer Research  2012;18(13):3705-3713.
The development of second primary tumors (SPT) or recurrence alters prognosis for curatively-treated head and neck squamous cell carcinoma (HNSCC) patients. 13-cis-retnoic acid (13-cRA) has been tested as a chemoprevention agent in clinical trials with mixed results. Therefore, we investigated if genetic variants in the PI3K/PTEN/AKT/MTOR pathway could serve as biomarkers to identify which patients are at high risk of an SPT/recurrence while also predicting response to 13-cRA chemoprevention.
Experimental Design
A total of 137 pathway SNPs were genotyped in 440 patients from the Retinoid Head and Neck Second Primary Trial and assessed for SPT/recurrence risk and response to 13-cRA. Risk models were created based on epidemiology, clinical, and genetic data.
Twenty-two genetic loci were associated with increased SPT/recurrence risk with six also being associated with a significant benefit following chemoprevention. Combined analysis of these high-risk/high-benefit loci identified a significant (P = 1.54×10−4) dose-response relationship for SPT/recurrence risk, with patients carrying 4–5 high-risk genotypes having a 3.76-fold (95%CI:1.87–7.57) increase in risk in the placebo group (n=215). Patients carrying 4–5 high-risk loci showed the most benefit from 13-cRA chemoprevention with a 73% reduction in SPT/recurrence (95%CI:0.13–0.58) compared to those with the same number of high-risk genotypes who were randomized to receive placebo. Incorporation of these loci into a risk model significantly improved the discriminatory ability over models with epidemiology, clinical, and previously identified genetic variables.
These results demonstrate that loci within this important pathway could identify individuals with a high-risk/high-benefit profile and are a step towards personalized chemoprevention for HNSCC patients.
PMCID: PMC3404728  PMID: 22577058
32.  Body Mass Index and Risk of Lung Cancer Among Never, Former, and Current Smokers 
Although obesity has been directly linked to the development of many cancers, many epidemiological studies have found that body mass index (BMI)—a surrogate marker of obesity—is inversely associated with the risk of lung cancer. These studies are difficult to interpret because of potential confounding by cigarette smoking, a major risk factor for lung cancer that is associated with lower BMI.
We prospectively examined the association between BMI and the risk of lung cancer among 448 732 men and women aged 50–71 years who were recruited during 1995–1996 for the National Institutes of Health–AARP Diet and Health Study. BMI was calculated based on the participant’s self-reported height and weight on the baseline questionnaire. We identified 9437 incident lung carcinomas (including 415 in never smokers) during a mean follow-up of 9.7 years through 2006. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for lung cancer risk factors, including smoking status. To address potential bias due to preexisting undiagnosed disease, we excluded potentially unhealthy participants in sensitivity analyses. All statistical tests were two-sided.
The crude incidence rate of lung cancer over the study follow-up period was 233 per 100 000 person-years among men and 192 per 100 000 person-years among women. BMI was inversely associated with the risk of lung cancer among both men and women (BMI ≥35 vs 22.5–24.99 kg/m2: HR = 0.81, 95% CI = 0.70 to 0.94 and HR = 0.73, 95% CI = 0.61 to 0.87, respectively). The inverse association was restricted to current and former smokers and was stronger after adjustment for smoking. Among smokers, the inverse association persisted even after finely stratifying on smoking status, time since quitting smoking, and number of cigarettes smoked per day. Sensitivity analyses did not support the possibility that the inverse association was due to prevalent undiagnosed disease.
Our results suggest that a higher BMI is associated with a reduced risk of lung cancer in current and former smokers. Our inability to attribute the inverse association between BMI and the risk of lung cancer to residual confounding by smoking or to bias suggests the need for considering other explanations.
PMCID: PMC3352831  PMID: 22457475
Evolutionary aspects of the genetic architecture of common human diseases remain enigmatic. The results of more than 200 genome-wide association studies published to date were compiled in a catalog ( We used cataloged data to determine whether derived (mutant) alleles are associated with higher risk of human disease more frequently than ancestral alleles. We placed all allelic variants into ten categories of population frequency (0%–100%) in 10% increments. We then analyzed the relationship between allelic frequency, evolutionary status of the polymorphic site (ancestral versus derived), and disease risk status (risk versus protection). Given the same population frequency, derived alleles are more likely to be risk associated than ancestral alleles, as are rarer alleles. The common interpretation of this association is that negative selection prevents fixation of the risk variants. However, disease stratification as early or late onset suggests that weak selection against risk-associated alleles is unlikely a major factor shaping genetic architecture of common diseases. Our results clearly suggest that the duration of existence of an allele in a population is more important. Alleles existing longer tend to show weaker linkage disequilibrium with neighboring alleles, including the causal alleles, and are less likely to tag a SNP-disease association.
PMCID: PMC3655427  PMID: 22809343
Genome-wide association studies; ancestral allele; derived allele; minor allele frequency
34.  Genetic Variants on 15q25.1, Smoking, and Lung Cancer: An Assessment of Mediation and Interaction 
American Journal of Epidemiology  2012;175(10):1013-1020.
Genome-wide association studies have identified variants on chromosome 15q25.1 that increase the risks of both lung cancer and nicotine dependence and associated smoking behavior. However, there remains debate as to whether the association with lung cancer is direct or is mediated by pathways related to smoking behavior. Here, the authors apply a novel method for mediation analysis, allowing for gene-environment interaction, to a lung cancer case-control study (1992–2004) conducted at Massachusetts General Hospital using 2 single nucleotide polymorphisms, rs8034191 and rs1051730, on 15q25.1. The results are validated using data from 3 other lung cancer studies. Tests for additive interaction (P = 2 × 10−10 and P = 1 × 10−9) and multiplicative interaction (P = 0.01 and P = 0.01) were significant. Pooled analyses yielded a direct-effect odds ratio of 1.26 (95% confidence interval (CI): 1.19, 1.33; P = 2 × 10−15) for rs8034191 and an indirect-effect odds ratio of 1.01 (95% CI: 1.00, 1.01; P = 0.09); the proportion of increased risk mediated by smoking was 3.2%. For rs1051730, direct- and indirect-effect odds ratios were 1.26 (95% CI: 1.19, 1.33; P = 1 × 10−15) and 1.00 (95% CI: 0.99, 1.01; P = 0.22), respectively, with a proportion mediated of 2.3%. Adjustment for measurement error in smoking behavior allowing up to 75% measurement error increased the proportions mediated to 12.5% and 9.2%, respectively. These analyses indicate that the association of the variants with lung cancer operates primarily through other pathways.
PMCID: PMC3353137  PMID: 22306564
gene-environment interaction; lung neoplasms; mediation; pathway analysis; smoking
35.  Evolutionary evidence of the effect of rare variants on disease etiology 
Clinical genetics  2010;79(3):199-206.
The common disease/common variant hypothesis has been popular for describing the genetic architecture of common human diseases for several years. According to the originally stated hypothesis, one or a few common genetic variants with a relatively large effect size control the risk of common diseases. A growing body of evidence, however, suggests that rare single-nucleotide polymorphisms (SNPs), i.e., those with a minor allele frequency of less than 5%, are also an important component of the genetic architecture of common human diseases. In this study, we analyzed the relevance of rare SNPs to the risk of common disease from an evolutionary perspective and found that rare SNPs are more likely than common SNPs to be functional and tend to have a stronger effect size than do common SNPs. This observation, plus the fact that most of the SNPs in the human genome are rare, suggests that rare SNPs are a crucial element of the genetic architecture of common human diseases. We propose that the next generation of genomic studies should focus on analyzing rare SNPs. Further, targeting patients with a family history of the disease, an extreme phenotype, or early disease onset may facilitate the detection of risk-associated rare SNPs.
PMCID: PMC3652532  PMID: 20831747
Single Nucleotide Polymorphisms (SNPs); Genome Wide Association Studies (GWAS); Minor Allele Frequency (MAF); negative selection
36.  Pilot Study of CYP2B6 Genetic Variation to Explore the Contribution of Nitrosamine Activation to Lung Carcinogenesis 
We explored the contribution of nitrosamine metabolism to lung cancer in a pilot investigation of genetic variation in CYP2B6, a high-affinity enzymatic activator of tobacco-specific nitrosamines with a negligible role in nicotine metabolism. Previously we found that variation in CYP2A6 and CHRNA5-CHRNA3-CHRNB4 combined to increase lung cancer risk in a case-control study in European American ever-smokers (n = 860). However, these genes are involved in the pharmacology of both nicotine, through which they alter smoking behaviours, and carcinogenic nitrosamines. Herein, we separated participants by CYP2B6 genotype into a high- vs. low-risk group (*1/*1 + *1/*6 vs. *6/*6). Odds ratios estimated through logistic regression modeling were 1.25 (95% CI 0.68–2.30), 1.27 (95% CI 0.89–1.79) and 1.56 (95% CI 1.04–2.31) for CYP2B6, CYP2A6 and CHRNA5-CHRNA3-CHRNB4, respectively, with negligible differences when all genes were evaluated concurrently. Modeling the combined impact of high-risk genotypes yielded odds ratios that rose from 2.05 (95% CI 0.39–10.9) to 2.43 (95% CI 0.47–12.7) to 3.94 (95% CI 0.72–21.5) for those with 1, 2 and 3 vs. 0 high-risk genotypes, respectively. Findings from this pilot point to genetic variation in CYP2B6 as a lung cancer risk factor supporting a role for nitrosamine metabolic activation in the molecular mechanism of lung carcinogenesis.
PMCID: PMC3645749  PMID: 23591849
CYP2B6; CYP2A6; CHRNA5-CHRNA3-CHRNB4; tobacco specific nitrosamines; lung cancer risk; genetic variation
37.  Unopposed Estrogen and Estrogen Plus Progestin Menopausal Hormone Therapy and Lung Cancer Risk in the NIH-AARP Diet and Health Study Cohort 
Cancer causes & control : CCC  2012;23(3):487-496.
Previous studies have reported that lung cancer risk may either be decreased, increased or unaffected by prior use of menopausal hormone therapy (MHT).
To examine this issue further, we examined relationships among 118,008 women, ages 50–71 years who were recruited during 1995–1996 for the NIH-AARP Diet and Health Study and in whom 2,097 incident lung carcinomas were identified during follow-up through 2006. Multivariable Cox proportional hazards models estimated relative risks (RR) and 95% confidence intervals (CIs) associated with various measures of self-reported MHT use.
We found no evidence that either estrogen therapy (ET)-only or estrogen plus progestin therapy (EPT) use was substantially related to subsequent lung cancer risk (respective RRs and 95% CIs for ever use = 0.97, 0.86–1.09 and 1.03, 0.90–1.17). There were no significant variations according to currency or duration of use of either formulation, nor was there evidence that risks varied within subgroups defined by cigarette smoking or body size. The absence of effect was seen for nearly all lung cancer subtypes, with the exception of an increased risk of undifferentiated/large cell cancers associated with long-term ET-only use (Ptrend=0.02), a relationship not observed among EPT users.
Our results failed to support any substantial alterations in lung cancer risk associated with use of either unopposed estrogen or estrogen plus progestin MHT, even when detailed exposure measures and other risk predictors were considered.
PMCID: PMC3328187  PMID: 22367699
lung cancer; menopausal hormone therapy; risk; histology
38.  Investigating Multiple Candidate Genes and Nutrients in the Folate Metabolism Pathway to Detect Genetic and Nutritional Risk Factors for Lung Cancer 
PLoS ONE  2013;8(1):e53475.
Folate metabolism, with its importance to DNA repair, provides a promising region for genetic investigation of lung cancer risk. This project investigates genes (MTHFR, MTR, MTRR, CBS, SHMT1, TYMS), folate metabolism related nutrients (B vitamins, methionine, choline, and betaine) and their gene-nutrient interactions.
We analyzed 115 tag single nucleotide polymorphisms (SNPs) and 15 nutrients from 1239 and 1692 non-Hispanic white, histologically-confirmed lung cancer cases and controls, respectively, using stochastic search variable selection (a Bayesian model averaging approach). Analyses were stratified by current, former, and never smoking status.
Rs6893114 in MTRR (odds ratio [OR] = 2.10; 95% credible interval [CI]: 1.20–3.48) and alcohol (drinkers vs. non-drinkers, OR = 0.48; 95% CI: 0.26–0.84) were associated with lung cancer risk in current smokers. Rs13170530 in MTRR (OR = 1.70; 95% CI: 1.10–2.87) and two SNP*nutrient interactions [betaine*rs2658161 (OR = 0.42; 95% CI: 0.19–0.88) and betaine*rs16948305 (OR = 0.54; 95% CI: 0.30–0.91)] were associated with lung cancer risk in former smokers. SNPs in MTRR (rs13162612; OR = 0.25; 95% CI: 0.11–0.58; rs10512948; OR = 0.61; 95% CI: 0.41–0.90; rs2924471; OR = 3.31; 95% CI: 1.66–6.59), and MTHFR (rs9651118; OR = 0.63; 95% CI: 0.43–0.95) and three SNP*nutrient interactions (choline*rs10475407; OR = 1.62; 95% CI: 1.11–2.42; choline*rs11134290; OR = 0.51; 95% CI: 0.27–0.92; and riboflavin*rs8767412; OR = 0.40; 95% CI: 0.15–0.95) were associated with lung cancer risk in never smokers.
This study identified possible nutrient and genetic factors related to folate metabolism associated with lung cancer risk, which could potentially lead to nutritional interventions tailored by smoking status to reduce lung cancer risk.
PMCID: PMC3553105  PMID: 23372658
39.  Cigarette Experimentation and the Population Attributable Fraction for Associated Genetic and Non-Genetic Risk Factors 
PLoS ONE  2013;8(1):e53868.
We, and others, have shown that experimenting with cigarettes is a function of both non-genetic and genetic factors. In this analysis we ask: how much of the total risk of experimenting with cigarettes, among those who had not experimented with cigarettes when they enrolled in a prospective cohort, is attributable to genetic factors and to non-genetic factors?
Participants (N = 1,118 Mexican origin youth), recruited from a large population-based cohort study in Houston, Texas, provided prospective data on cigarette experimentation over three years. Non-genetic data were elicited twice – baseline and follow-up. Participants were genotyped for 672 functional and tagging variants in the dopamine, serotonin and opioid pathways.
In the overall model, the adjusted combined non-genetic PAF was 71.2% and the adjusted combined genetic PAF was 58.5%. Among committed never smokers the adjusted combined non-genetic PAF was 67.0% and the adjusted combined genetic PAF was 53.5%. However, among cognitively susceptible youth, the adjusted combined non-genetic PAF was 52.0% and the adjusted combined genetic PAF was 68.4%.
Our results suggest there may be differences in genotypes between youth who think they will try cigarettes in the future compared to their peers who think they will not and underscore the possibility that the relative influence of genetic vs. non-genetic factors on the uptake of smoking may vary between these two groups of youth.
A clearer understanding of the relative role of genetic vs. non-genetic factors in the uptake of smoking may have implications for the design of prevention programs.
PMCID: PMC3547034  PMID: 23342024
40.  Cigarette Experimentation in Mexican Origin Youth: Psychosocial and Genetic Determinants 
Established psychosocial risk factors increase the risk for experimentation among Mexican-origin youth. Now we comprehensively investigate the added contribution of select polymorphisms in candidate genetic pathways associated with sensation seeking, risk taking, and smoking phenotypes to predict experimentation.
Participants, (N=1,118 Mexican origin youth) recruited from a large population-based cohort study in Houston, Texas, provided prospective data on cigarette experimentation over three years. Psychosocial data were elicited twice—baseline and final follow-up. Participants were genotyped for 672 functional and tagging variants in the dopamine, serotonin and opioid pathways.
After adjusting for gender and age, with a Bayesian False Discovery Probability set at 0.8 and prior probability of 0.05, six gene variants were significantly associated with risk of experimentation. After controlling for established risk factors, multivariable analyses revealed that participants with six or more risk alleles were 2.25 (95%CI: 1.62–3.13) times more likely to have experimented since baseline compared to participants with five or fewer. Among committed never smokers (N=872), three genes (OPRM1, SNAP25, HTR1B) were associated with experimentation as were all psychosocial factors. Among susceptible youth (N=246) older age at baseline, living with a smoker, and three different genes (HTR2A, DRD2, SLC6A3) predicted experimentation.
Our findings, which have implications for development of culturally-specific interventions, need to be validated in other ethnic groups.
These results suggest that variations in select genes interact with a cognitive predisposition toward smoking. In susceptible adolescents, the impact of the genetic variants appears to be larger compared to committed never smokers.
PMCID: PMC3382046  PMID: 22028400
41.  Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes 
The phosphatidylinositol 3-kinase (PI3K)/PTEN/AKT/mTOR and Ras/Raf/MEK/ERK pathways have been implicated in endometrial tumorigenesis. In this candidate pathway analysis, we investigated associations between genetic variations in these two pathways and both risk and clinical outcomes of endometrial cancer.
We genotyped a total of 48 potentially functional SNPs in 11 key genes (AKT1, AKT2, AKT3, BRAF, FRAP1, KRAS, PDPK1, PIK3CA, PIK3CB, PIK3R1, and PTEN) with the Sequenom genotyping platform in 115 endometrial cancer patients and 230 cancer-free women to evaluate their associations with risk, survival, and recurrence of endometrial cancer.
We found the following: (1) PIK3CA rs6443624 and rs9838411 variants either borderline or significantly decreased risk of endometrial cancer in a dominant model (adjusted odds ratio [OR], 0.62; 95% CI, 0.39–1.00 and 0.59; 95% CI, 0.36–0.95, respectively). Furthermore, there was a statistically significant multiplicative interaction (Pint = 0.036) between these two loci in risk of endometrial cancer. In contrast, the AKT1 rs2498801 genotype significantly increased risk of endometrial cancer (adjusted OR, 1.94; 95% CI, 1.02–3.67 in a recessive model). (2) In Cox regression analyses, three SNPs (PIK3R1 rs1862162, AKT2 rs892119, and PIK3CA rs2699887) showed significant associations with survival of endometrial cancer patients. (3) KRAS rs7312175 and PIK3CA rs6443624 had significant effects on recurrence of endometrial cancer individually and combined in a locus–dosage manner (adjusted Ptrend = 0.003).
These results suggest that common genetic variations in these pathways may modulate risk and clinical outcomes of endometrial cancer. Further replication and functional studies are needed to confirm these findings.
PMCID: PMC3526101  PMID: 22146979
PI3K/PTEN/AKT/mTOR and RAS/RAF/MEK/ERK pathways; Polymorphisms; Endometrial cancer risk; Survival; Recurrence
42.  Association of smoking with tumor size at diagnosis in non-small cell lung cancer 
Tumor size at diagnosis (TSD) indirectly reflects tumor growth rate. The relationship between TSD and smoking is poorly understood. The aim of the study was to determine the relationship between smoking and TSD. We reviewed 1712 newly diagnosed and previously untreated non-small cell lung cancer (NSCLC) patients’ electronic medical records and collected tumor characteristics. Demographic and epidemiologic characteristics were derived from questionnaires administered during personal interviews. Univariate and multivariate linear regression models were used to evaluate the relationship between TSD and smoking controlling for demographic and clinical factors. We also investigated the relationship between the rs1051730 SNP in an intron of the CHRNA3 gene (the polymorphism most significantly associated with lung cancer risk and smoking behavior) and TSD. We found a strong dose dependent relationship between TSD and smoking. Current smokers had largest and never smokers smallest TSD with former smokers having intermediate TSD. In the multivariate linear regression model, smoking status (never, former, and current), histological type (adenocarcinoma vs SqCC), and gender were significant predictors of TSD. Smoking duration and intensity may explain the gender effect in predicting TSD. We found that the variant allele of rs1051730 in CHRNA3 gene was associated with larger TSD of squamous cell carcinoma. In the multivariate linear regression model, both rs1051730 and smoking were significant predictors for the size of squamous carcinomas. We conclude that smoking is positively associated with lung tumor size at the moment of diagnosis.
PMCID: PMC3197014  PMID: 21645942
Lung cancer; tumor size; epidemiologic characteristics; risk factors; CHRNA3
43.  Common genetic variants in cell cycle pathway are associated with survival in stage III–IV non-small-cell lung cancer 
Carcinogenesis  2011;32(12):1867-1871.
Cell cycle progression contributes to the cellular response to DNA-damaging factors, such as chemotherapy and radiation. We hypothesized that the genetic variations in cell cycle pathway genes may modulate treatment responses and affect survival in patients with advanced non-small-cell lung cancer (NSCLC). We genotyped 374 single-nucleotide polymorphisms (SNPs) from 49 cell cycle-related genes in 598 patients with stages III–IV NSCLC treated with first-line platinum-based chemotherapy with/without radiation. We analyzed the individual and combined associations of these SNPs with survival and evaluated their gene–gene interactions using survival tree analysis. In the analysis of survival in all the patients, 39 SNPs reached nominal significance (P < 0.05) and 4 SNPs were significant at P <0.01. However, none of these SNPs remained significant after correction for multiple comparisons at a false discovery rate of 10%. In stratified analysis by treatment modality, after adjusting for multiple comparisons, nine SNPs in chemotherapy alone and one SNP in chemoradiation remained significant. The most significant SNP in chemotherapy group was CCNB2:rs1486878 [hazard ratio (HR) = 1.69, 95% confidence interval (CI), 1.25–2.30, P = 0.001]. TP73: rs3765701 was the only significant SNP in chemoradiation group (HR = 1.87; 95% CI = 1.35–2.59, P = 1.8 × 10−4). In cumulative analysis, we found a significant gene-dosage effect in patients receiving chemotherapy alone. Survival tree analysis demonstrated potential higher order gene–gene and gene–treatment interactions, which could be used to predict survival status based on distinct genetic signatures. These results suggest that genetic variations in cell cycle pathway genes may affect the survival of patients with stages III–IV NSCLC individually and jointly.
PMCID: PMC3220611  PMID: 21965272
44.  A case-control study of a sex-specific association between a 15q25 variant and lung cancer risk 
Genetic variants located at 15q25, including those in the cholinergic receptor nicotinic cluster (CHRNA5) have been implicated in both lung cancer risk and nicotine dependence in recent genome-wide association studies. Among these variants, a 22 base pair insertion/deletion, rs3841324 showed the strongest association with CHRNA5 mRNA expression levels. However the influence of rs3841324 on lung cancer risk has not been studied in depth.
We have therefore evaluated the association of rs3841324 genotypes with lung cancer risk in a case-control study of 624 Caucasian subjects with lung cancer and 766 age- and sex-matched cancer-free Caucasian controls. We also evaluated the joint effects of rs3841324 with single-nucleotide polymorphisms (SNPs) rs16969968 and rs8034191 in the 15q25 region that have been consistently implicated in lung cancer risk.
We found that the homozygous genotype with both short alleles (SS) of rs3841324 was associated with a decreased lung cancer risk in female ever smokers relative to the homozygous wild-type (LL) and heterozygous (LS) genotypes combined in a recessive model (OR adjusted = 0.55, 95% CI = 0.31–0.89, P = 0.0168). There was no evidence for a sex difference in the association between this variant and cigarettes smoked per day (CPD). Diplotype analysis of rs3841324 with either rs16969968 or rs8034191 showed that these polymorphisms influenced the lung cancer risk independently.
Conclusions and impact
This study has shown a sex difference in the association between the 15q25 variant rs3841324 and lung cancers. Further research is warranted to elucidate the mechanisms underlying these observations.
PMCID: PMC3277830  PMID: 22028403
lung cancer; CHRNA5; Chromosome 15q25; rs3841324; sex-specific association
45.  Detectable clonal mosaicism and its relationship to aging and cancer 
Jacobs, Kevin B | Yeager, Meredith | Zhou, Weiyin | Wacholder, Sholom | Wang, Zhaoming | Rodriguez-Santiago, Benjamin | Hutchinson, Amy | Deng, Xiang | Liu, Chenwei | Horner, Marie-Josephe | Cullen, Michael | Epstein, Caroline G | Burdett, Laurie | Dean, Michael C | Chatterjee, Nilanjan | Sampson, Joshua | Chung, Charles C | Kovaks, Joseph | Gapstur, Susan M | Stevens, Victoria L | Teras, Lauren T | Gaudet, Mia M | Albanes, Demetrius | Weinstein, Stephanie J | Virtamo, Jarmo | Taylor, Philip R | Freedman, Neal D | Abnet, Christian C | Goldstein, Alisa M | Hu, Nan | Yu, Kai | Yuan, Jian-Min | Liao, Linda | Ding, Ti | Qiao, You-Lin | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Aldrich, Melinda C | Amos, Christopher | Blot, William J | Bock, Cathryn H | Gillanders, Elizabeth M | Harris, Curtis C | Haiman, Christopher A | Henderson, Brian E | Kolonel, Laurence N | Le Marchand, Loic | McNeill, Lorna H | Rybicki, Benjamin A | Schwartz, Ann G | Signorello, Lisa B | Spitz, Margaret R | Wiencke, John K | Wrensch, Margaret | Wu, Xifeng | Zanetti, Krista A | Ziegler, Regina G | Figueroa, Jonine D | Garcia-Closas, Montserrat | Malats, Nuria | Marenne, Gaelle | Prokunina-Olsson, Ludmila | Baris, Dalsu | Schwenn, Molly | Johnson, Alison | Landi, Maria Teresa | Goldin, Lynn | Consonni, Dario | Bertazzi, Pier Alberto | Rotunno, Melissa | Rajaraman, Preetha | Andersson, Ulrika | Freeman, Laura E Beane | Berg, Christine D | Buring, Julie E | Butler, Mary A | Carreon, Tania | Feychting, Maria | Ahlbom, Anders | Gaziano, J Michael | Giles, Graham G | Hallmans, Goran | Hankinson, Susan E | Hartge, Patricia | Henriksson, Roger | Inskip, Peter D | Johansen, Christoffer | Landgren, Annelie | McKean-Cowdin, Roberta | Michaud, Dominique S | Melin, Beatrice S | Peters, Ulrike | Ruder, Avima M | Sesso, Howard D | Severi, Gianluca | Shu, Xiao-Ou | Visvanathan, Kala | White, Emily | Wolk, Alicja | Zeleniuch-Jacquotte, Anne | Zheng, Wei | Silverman, Debra T | Kogevinas, Manolis | Gonzalez, Juan R | Villa, Olaya | Li, Donghui | Duell, Eric J | Risch, Harvey A | Olson, Sara H | Kooperberg, Charles | Wolpin, Brian M | Jiao, Li | Hassan, Manal | Wheeler, William | Arslan, Alan A | Bas Bueno-de-Mesquita, H | Fuchs, Charles S | Gallinger, Steven | Gross, Myron D | Holly, Elizabeth A | Klein, Alison P | LaCroix, Andrea | Mandelson, Margaret T | Petersen, Gloria | Boutron-Ruault, Marie-Christine | Bracci, Paige M | Canzian, Federico | Chang, Kenneth | Cotterchio, Michelle | Giovannucci, Edward L | Goggins, Michael | Bolton, Judith A Hoffman | Jenab, Mazda | Khaw, Kay-Tee | Krogh, Vittorio | Kurtz, Robert C | McWilliams, Robert R | Mendelsohn, Julie B | Rabe, Kari G | Riboli, Elio | Tjønneland, Anne | Tobias, Geoffrey S | Trichopoulos, Dimitrios | Elena, Joanne W | Yu, Herbert | Amundadottir, Laufey | Stolzenberg-Solomon, Rachael Z | Kraft, Peter | Schumacher, Fredrick | Stram, Daniel | Savage, Sharon A | Mirabello, Lisa | Andrulis, Irene L | Wunder, Jay S | García, Ana Patiño | Sierrasesúmaga, Luis | Barkauskas, Donald A | Gorlick, Richard G | Purdue, Mark | Chow, Wong-Ho | Moore, Lee E | Schwartz, Kendra L | Davis, Faith G | Hsing, Ann W | Berndt, Sonja I | Black, Amanda | Wentzensen, Nicolas | Brinton, Louise A | Lissowska, Jolanta | Peplonska, Beata | McGlynn, Katherine A | Cook, Michael B | Graubard, Barry I | Kratz, Christian P | Greene, Mark H | Erickson, Ralph L | Hunter, David J | Thomas, Gilles | Hoover, Robert N | Real, Francisco X | Fraumeni, Joseph F | Caporaso, Neil E | Tucker, Margaret | Rothman, Nathaniel | Pérez-Jurado, Luis A | Chanock, Stephen J
Nature genetics  2012;44(6):651-658.
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.
PMCID: PMC3372921  PMID: 22561519
46.  Reproductive and Hormonal Factors and Lung Cancer Risk in the NIH-AARP Diet and Health Study Cohort 
Lung cancer exhibits unique patterns among women, including high adenocarcinoma rates among non-smokers. Inconsistent findings regarding hormonal factors on risk may reflect incomplete control for confounding, misclassification of exposures, or insufficient attention to variation by histology.
Among 185,017 women, ages 50–71 years, recruited during 1995–1996 for the NIH-AARP Diet and Health Study, we identified 3,512 incident lung cancers (including 276 in never smokers) in follow-up through December 2006. Multivariable Cox proportional hazards models estimated relative risks (RRs) and 95% confidence intervals (CIs) for self-reported hormonally-related risk factors.
After adjustment for smoking and other confounders, subjects with late menarche were at reduced risk, with the association specific for adenocarcinomas (RR=0.72 for menarche 15+ vs. <11, p for trend<0.01). Subjects with early ages at ovarian cessation (either from natural menopause or bilateral oophorectomy) were at an increased risk for adenocarcinomas and squamous cell tumors, but the associations were strongest for smokers, suggesting either residual confounding or an enhanced effect of menopausally-related factors among subjects with decreased endogenous estrogens. In contrast, we saw no relationships of risk with either parity, age at first birth, or exogenous hormone use.
Elevated levels of hormones may adversely affect lung function early in life, while assisting with cellular and immunologic responses later in life. Additional attention towards the role of hormonal factors may further our understanding of lung carcinogenesis.
Our findings provide some support for a role of hormonal factors in the etiology of lung cancer, although the mechanisms appear complicated.
PMCID: PMC3507989  PMID: 21467241
lung cancer; hormonal factors; menopause; risk; histology
47.  DNA Repair Capacity in Peripheral Lymphocytes Predicts Survival of Patients With Non–Small-Cell Lung Cancer Treated With First-Line Platinum-Based Chemotherapy  
Journal of Clinical Oncology  2011;29(31):4121-4128.
Platinum-based regimens are the standard chemotherapy for patients with advanced non–small-cell lung cancer (NSCLC). DNA repair capacity (DRC) in tumor cells plays an important role in resistance to platinum-based drugs. We have previously reported that efficient DRC, as assessed by an in vitro lymphocyte-based assay, was a determinant of poor survival in patients with NSCLC in a relatively small data set. In this larger independent study of 591 patients with NSCLC, we further evaluated whether DRC in peripheral lymphocytes predicts survival of patients with NSCLC who receive platinum-based chemotherapy.
Patients and Methods
All patients were recruited at The University of Texas MD Anderson Cancer Center and donated blood samples before the start of any chemotherapy. We measured DRC in cultured T lymphocytes by using the host-cell reactivation assay, and we assessed associations between DRC in peripheral lymphocytes and survival of patients with NSCLC who were treated with first-line platinum-based chemotherapy.
We found an inverse association between DRC in peripheral lymphocytes and patient survival. Compared with patients in the low tertile of DRC, patients with NSCLC in the high tertile of DRC had significantly worse overall and 3-year survival (adjusted hazard ratio [HR], 1.33; 95% CI, 1.04 to 1.71; P = .023; and HR, 1.35; 95% CI, 1.04 to 1.76; P = .025, respectively). This trend was more pronounced in patients with early-stage tumors, adenocarcinoma, or squamous cell carcinoma.
We confirmed that DRC in peripheral lymphocytes is an independent predictor of survival for patients with NSCLC treated with platinum-based chemotherapy.
PMCID: PMC3675702  PMID: 21947825
48.  ATM sequence variants associate with susceptibility to non-small cell lung cancer 
ATM gene mutations have been implicated in many human cancers. However, the role of ATM polymorphisms in lung carcinogenesis is largely unexplored. We conducted a case-control analysis of 556 Caucasian non-small-cell lung cancer (NSCLC) patients and 556 controls frequency-matched on age, gender and smoking status. We genotyped 11 single nucleotide polymorphisms of the ATM gene and found that compared with the wild-type allele-containing genotypes, the homozygous variant genotypes of ATM08 (rs227060) and ATM10 (rs170548) were associated with elevated NSCLC risk with ORs of 1.55 (95% CI: 1.02–2.35) and 1.51 (0.99–2.31), respectively. ATM haplotypes and diplotypes were inferred using the Expectation-Maximization algorithm. Haplotype H5 was significantly associated with reduced NSCLC risk in former smokers with an OR of 0.47 (0.25–0.96) compared with the common H1 haplotype. Compared with the H1–H2 diplotype, H2–H2 and H3–H4 diplotypes were associated with increased NSCLC risk with ORs of 1.58 (0.99–2.54) and 2.29 (1.05–5.00), respectively. We then evaluated genotype–phenotype correlation in the control group using the comet assay to determine DNA damage and DNA repair capacity. Compared with individuals with at least 1 wild-type allele, the homozygous variant carriers of either ATM08 or ATM10 exhibited significantly increased DNA damage as evidenced by a higher mean value of the radiation-induced olive tail moment (ATM08: 4.86 ± 2.43 vs. 3.79 ± 1.51, p = 0.04; ATM10: 5.14 ± 2.37 vs. 3.79 ± 1.54, p = 0.01). Our study presents the first epidemiologic evidence that ATM genetic variants may affect NSCLC predisposition, and that the risk-conferring variants might act through down-regulating the functions of ATM in DNA repair activity upon genetic insults such as ionizing radiation.
PMCID: PMC3477817  PMID: 17582598
ATM; polymorphism; haplotype; diplotype; NSCLC
49.  A Smoking-based Carcinogenesis Model for Lung Cancer Risk Prediction 
Lung cancer is the leading cancer killer for both men and women worldwide. Over 80% of lung cancers are attributed to smoking. In this analysis, the authors propose to use a two-stage clonal expansion (TSCE) model to predict an individual’s lung cancer risk based on gender and smoking history. The TSCE model is traditionally fitted to prospective cohort data. Here, the authors describe a new method that allows for the reconstruction of cohort data from the combination of risk factor data obtained from a case-control study, and tabled incidence/mortality rate data, and discuss alternative approaches. The method is applied to fit a TSCE model based on smoking. The fitted model is validated against independent data from the control arm of a lung cancer chemoprevention trial, CARET, where it accurately predicted the number of lung cancer deaths observed.
PMCID: PMC3116088  PMID: 21140453
TSCE model; lung cancer; risk prediction; smoking
50.  Method for Evaluating Multiple Mediators: Mediating Effects of Smoking and COPD on the Association between the CHRNA5-A3 Variant and Lung Cancer Risk 
PLoS ONE  2012;7(10):e47705.
A mediation model explores the direct and indirect effects between an independent variable and a dependent variable by including other variables (or mediators). Mediation analysis has recently been used to dissect the direct and indirect effects of genetic variants on complex diseases using case-control studies. However, bias could arise in the estimations of the genetic variant-mediator association because the presence or absence of the mediator in the study samples is not sampled following the principles of case-control study design. In this case, the mediation analysis using data from case-control studies might lead to biased estimates of coefficients and indirect effects. In this article, we investigated a multiple-mediation model involving a three-path mediating effect through two mediators using case-control study data. We propose an approach to correct bias in coefficients and provide accurate estimates of the specific indirect effects. Our approach can also be used when the original case-control study is frequency matched on one of the mediators. We employed bootstrapping to assess the significance of indirect effects. We conducted simulation studies to investigate the performance of the proposed approach, and showed that it provides more accurate estimates of the indirect effects as well as the percent mediated than standard regressions. We then applied this approach to study the mediating effects of both smoking and chronic obstructive pulmonary disease (COPD) on the association between the CHRNA5-A3 gene locus and lung cancer risk using data from a lung cancer case-control study. The results showed that the genetic variant influences lung cancer risk indirectly through all three different pathways. The percent of genetic association mediated was 18.3% through smoking alone, 30.2% through COPD alone, and 20.6% through the path including both smoking and COPD, and the total genetic variant-lung cancer association explained by the two mediators was 69.1%.
PMCID: PMC3471886  PMID: 23077662

Results 26-50 (117)