The prognosis of MBM is variable with prolonged survival in a subset. It is unclear whether MBMs differ from extracranial metastases (EcM) and primary melanomas (PrM).
To study the biology of MBM we performed histopathologic analysis of tumor blocks from patients' craniotomy samples and whole genome expression profiling (WGEP) with confirmatory immunohistochemistry (IHC).
Mononuclear infiltrate and low intratumoral hemorrhage were associated with prolonged overall survival (OS). Pathway analysis of WGEP data from 29 such craniotomy tumor blocks demonstrated that several immune-related BioCarta gene sets were associated with prolonged OS. WGEP analysis of MBM in comparison with same-patient EcM and PrM showed that MBM and EcM were similar—but both differ significantly from PrM. IHC analysis revealed that peritumoral CD3+ and CD8+ cells were associated with prolonged OS.
MBMs are more similar to EcM compared to PrM. Immune infiltrate is a favorable prognostic factor for MBM.
Melanoma; Brain Metastases; Craniotomy Immune Infiltrate; Gene Expression Profiling
Functional polymorphisms in drug metabolizing enzymes (DMEs) may be determinants of survival in oral and oropharyngeal squamous cell carcinoma (OOSCC).
OOSCC cases (N=159) with a history of either tobacco or alcohol use were genotyped for polymorphisms in eight DMEs. Overall and disease-specific survival were analyzed using Kaplan-Meier plots and the log-rank test. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) in exploratory analyses of patient subgroups.
Kaplan-Meier analyses showed N-acteyltransferase-2 (NAT2) fast acetylators experienced a 19.7% higher 5-year survival rate than slow acetylators (P=0.03) and this association was similar in oropharyngeal and oral cancer. After multiple adjustment, including tumor site and stage, the NAT2 fast acetylator phenotype was associated with improved overall survival (vs. slow acetylators) provided chemotherapy or radiation were not used (HR, 0.26; 95% CI, 0.10–0.66). However, NAT2 phenotype was unrelated to survival in patients treated with chemoradiotherapy (HR, 1.21; 95% CI, 0. 54–2.73) or radiotherapy (HR, 0.67; 95% CI, 0.31–1.59) (P-for-NAT2/treatment-interaction=0.04). Normal activity GSTP1 was associated with a 19.2% reduction in 5-year disease-specific survival relative to reduced activity GSTP1 (P=0.04) but this association was not modified by treatment.
Our results suggest that functional polymorphisms in NAT2 and GSTP1 are associated with OOSCC survival. Confirmation of these results in larger studies is required.
head and neck neoplasms; NAT2; GSTP1; polymorphism single nucelotide; SNP
To investigate the association between inherited variation in the estrogen receptor beta (ERβ) gene (ESR2) and ERβ lung tumor expression, a phenotype that possibly affects survival differently in men and women.
We genotyped 135 lung cancer patients for 22 ESR2 single nucleotide polymorphisms (SNPs) and measured nuclear and cytoplasmic ERβ expression by immunohistochemistry (IHC) in their primary lung tumor. Distributing Allred ERβ IHC scores according to ESR2 genotype classified under a dominant genetic model, we used rank sum tests to identify ESR2 SNPs significantly associated (p<0.05) with ERβ expression.
35%, 35%, and 29% of lung tumors showed no/low (Allred <6), intermediate (Allred 6 to 7), and maximal (Allred 8) cytoplasmic ERβ expression, whereas 13%, 27%, and 60% showed no/low, intermediate, and maximal nuclear ERβ expression. For SNPs rs8021944, rs1256061 and rs10146204, ERβ expression was higher according to the rank sum test in lung tumors from patients with at least one minor allele. For each of these three SNPs, the odds of maximal (Allred 8) relative to no/low (Allred <6) ERβ expression was 3-fold higher in tumors from patients with at least one minor allele than in tumors from patients homozygous for the common allele.
Inherited variability in ESR2 may determine ERβ lung tumor expression.
lung cancer; genetic polymorphism; estrogen receptor
Passive smoke is carcinogenic but its association with head and neck squamous cell carcinoma (HNSCC) is uncertain.
We conducted a case-control study of childhood passive smoke exposure (CPSE) and HNSCC in 858 cases and 806 frequency-matched controls using an interviewer-administered questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated with logistic regression controlling for adult smoking in the total study population, and in never-smokers only (184 cases and 415 controls). CPSE was also studied in oropharyngeal separately from other HNSCC using polytomous logistic regression.
CPSE was associated with HNSCC (OR, 1.28; 95% CI, 1.01-1.63) after controlling for adult smoking and other factors. This association was similar in magnitude, although not statistically significant, among subjects who never smoked as adults (OR, 1.19, 95% CI, 0.80-1.76). CPSE was associated more strongly with oropharyngeal cancer (a HNSCC subtype commonly associated with human papillomavirus (HPV) infection) than with HNSCC at non-oropharyngeal sites (OR, 2.02; 95% CI, 1.01-4.06, N=52 cases vs. OR, 1.04; 95% CI, 0.68-1.60, N=132 cases; P-for-heterogeneity=0.08).
Data from this large US-based case control study suggest a role for CPSE in HNSCC etiology.
adolescent; child; head and neck neoplasms; infant; oropharyngeal neoplasms; tobacco smoke pollution
Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC)(1, 2). Identification of mutations that predict therapeutic response would be a major advance. We determined the mutationally altered, targetable mitogenic pathways in a large HNSCC cohort. Analysis of whole-exome sequencing data from 151 tumors revealed the PI3K pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway-mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of HPV-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and non-canonical PIK3CA mutations were sensitive to an m-TOR/PI3K inhibitor (BEZ-235) in contrast to PIK3CA wildtype tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.
PI3K; mutation; BEZ-235; head and neck cancer
Functional CYP2A6 genetic variation partially determines nicotine metabolism. In 2005, we examined functional CYP2A6 variants associated with reduced metabolism (CYP2A6*2, CYP2A6*9, CYP2A6*4), smoking history, and change in smoking in 878 adult smokers undergoing lung cancer screening in an urban setting. At one year, 216 quit smoking for more than 30 days while 662 continued smoking. Compared to subjects who smoked 30 cigarettes per day at baseline, the odds of a reduced metabolism genotype was 52% higher in subjects smoking 20–29 cigarettes per day and 86% higher in subjects smoking less than 20 cigarettes per day (p-trend = 0.016). Reduced metabolism genotypes appeared unrelated to quitting. Though related to smoking dose, CYP2A6 may not influence cessation.
smoking cessation; smoking initiation; cigarette smoking; genetics; cytochrome P450; nicotine metabolism
DNA repair and cell cycle control play an important role in the repair of DNA damage caused by cigarette smoking. Given this role, functionally relevant single nucleotide polymorphisms (SNPs) in genes in these pathways may well affect the risk of smoking-related lung cancer. We examined the relationship between 240 SNPs in DNA repair and cell cycle control pathway genes and lung cancer risk in a case-control study of white current and ex-cigarette smokers (722 cases and 929 controls). Additive, dominant and recessive genetic models were evaluated for each SNP. A genetic risk summary score was also constructed. Odds ratios (OR) for lung cancer risk and 95% confidence intervals (95% CI) were estimated using logistic regression models. Thirty-eight SNPs were associated with lung cancer risk in our study population at P<0.05. The strongest associations were observed for rs2074508 in GTF2H4 (Padditive=0.003), rs10500298 in LIG1 (Precessive=2.7×10−4), rs747658 and rs3219073 in PARP1 (rs747658: Padditive=5.8×10−5; rs3219073: Padditive=4.6×10−5), and rs1799782 and rs3213255 in XRCC1 (rs1799782: Pdominant=0.006; rs3213255: Precessive=0.004). Compared to individuals with first quartile (lowest) risk summary scores, individuals with third and fourth quartile summary score results were at increased risk for lung cancer (OR: 2.21, 95% CI: 1.66–2.95 and OR: 3.44, 95% CI: 2.58–4.59, respectively; Ptrend<0.0001). Our data suggests that variation in DNA repair and cell cycle control pathway genes is associated with smoking-related lung cancer risk. Additionally, combining genotype information for SNPs in these pathways may assist in classifying current and ex-cigarette smokers according to lung cancer risk.
SNP; case-control; lung cancer
Classical drug exposure: response studies in clinical pharmacology represent the quintessential prototype for Bench to Bedside-Clinical Translational Research. A fundamental premise of this approach is for a multidisciplinary team of researchers to design and execute complex, in-depth mechanistic studies conducted in relatively small groups of subjects. The infrastructure support for this genre of clinical research is not well-handled by scaling down of infrastructure used for large Phase III clinical trials. We describe a novel, integrated strategy, whose focus is to support and manage a study using an Information Hub, Communication Hub, and Data Hub design. This design is illustrated by an application to a series of varied projects sponsored by Special Clinical Centers of Research in chronic obstructive pulmonary disease at the University of Pittsburgh. In contrast to classical informatics support, it is readily scalable to large studies. Our experience suggests the culture consequences of research group self-empowerment is not only economically efficient but transformative to the research process.
institutional management teams; organization and administration; information services; information storage and retrieval
Genetic variation in xenobiotic metabolizing enzymes may explain differing susceptibilities to the cancer causing effects of tobacco and alcohol.
We compared 203 oral squamous cell carcinoma cases and 416 controls for single nucleotide polymorphisms (SNPs) in 8 genes (CYP1A1, CYP2E1, MPO, mEH, GSTM1, GSTT1, GSTP1, and NAT2). Except for NAT2, genotype frequencies were similar in the 2 groups. We classified subjects as fast or slow NAT2 acetylators genotyping 13 NAT2 SNPs.
Fast acetylators were overrepresented in cases (53.7%) compared with controls (43.9%; odds ratio (OR) 1.55, 95% confidence interval (CI) 1.08–2.20; p value = .03). Gene–gene interaction testing suggested several cancer-NAT2 associations, with association strongest among persons without a CYP1A1 variant (*2C or *4) allele (OR 1.77, 95% CI 1.20–2.60, p value = .03) or with a variant MPO (463A) allele (OR 2.38, 95% CI 1.34–4.21, p value = .05).
These results implicate fast NAT2 acetylation as a risk factor for oral cancer.
tobacco; oral cancer; polymorphism; metabolizing enzymes; susceptibility
Technology is constantly evolving, necessitating the development of workflows for efficient use of high-dimensional data. We develop and test an empirical workflow for predictive modeling based on single nucleotide polymorphisms (SNP) from genome-wide association study (GWAS) datasets. To this aim, we use as a case study SNP-based prediction of survival for non-small cell lung cancer (NSCLC) with a Bayesian rule learner system (BRL+). Lung cancer is a leading cause of mortality. Standard treatment for early stages of NSCLC is surgery. Adjuvant chemotherapy would be beneficial for patients with early recurrence; consequently, we need models capable of such prediction. This workflow outlines the challenges involved in processing GWAS datasets from one popular platform (Affymetrix®), from the results files of the hybridization experiment to the model construction. Our results show that our workflow is feasible and efficient for processing such data while also yielding SNP based models with high predictive accuracy over cross validation.
Germline variation in DNA damage response may explain variable treatment outcomes from squamous cell carcinoma of the head and neck (SCCHN). Grouping patients according to stage and radiation treatment, we compared SCCHN survival according to ERCC2 A35931C (Lys751Gln, rs13181) and CCND1 G870A (Pro241Pro, rs9344) genotypes.
Recruiting a hospital-based SCCHN case series (all white, 24.7% female, mean age 58.4 years), this treatment outcome cohort study genotyped n=275 stage III-IV cases initially treated with radiation (with or without chemotherapy) and n=80 stage III-IV and n=130 stage I-II cases initially treated without radiation or chemotherapy and used Kaplan-Meier and Cox regression analysis to compare genotype groups according to overall, disease-specific, progression-free, and recurrence-free survival.
ERCC2-35931 AA predicted worse survival in stage III-IV treated with radiation (multiply adjusted hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.15-2.40; HR over the first three follow-up years 1.92, 95% CI 1.28-2.88) and better survival in stage III-IV not treated with radiation (HR 0.26, 95% CI 0.11-0.62). Unassociated with survival in stage III-IV treated with radiation (HR 1.00, 95% CI 0.67-1.51), CCND1-870 GG predicted better survival in stage III-IV not treated with radiation (HR 0.14, 95% CI 0.04-0.50). Survival in stage I-II did not depend on ERCC2 A35931C or CCND1 G870A genotype.
Promoting tumor progression in untreated patients, germline differences in DNA repair or cell cycle control may improve treatment outcome in patients treated with DNA damaging agents.
ERCC2 A35931C may help distinguish advanced stage SCCHN with better outcomes from radiation treatment.
Tumor-specific biomarkers that predict resistance to DNA damaging agents may improve therapeutic outcomes by guiding the selection of effective therapies and limiting morbidity related to ineffective approaches. XPF (ERCC4) is an essential component of several DNA repair pathways and XPF-deficient cells are exquisitely sensitive to DNA damaging agents. The purpose of this study was to determine whether XPF expression levels predict clinical response to DNA damaging agents in head and neck squamous cell carcinoma (HNSCC).
Quantitative immunohistochemistry was used to measure XPF expression in tumors from a cohort of 80 patients with newly diagnosed HNSCC treated with radiation therapy with or without platinum-based chemotherapy; samples were collected prospectively. Genomic DNA isolated from blood samples was analyzed for nine single nucleotide polymorphisms in the XPF gene using a custom array. The primary endpoint was progression-free survival (PFS).
XPF expression was higher in tumors from the oral cavity than from the other sites (p<0.01). High XPF expression correlated with early time to progression both by univariate (HR =1.87, p=0.03) and multivariate analysis (HR =1.83, p=0.05). The one year PFS for high expressers was 47% (95% CI = 31% – 62%) compared to 72% (95% CI = 55% – 83%) for low expressers. In addition, we identified four XPF single nucleotide polymorphisms (SNPs) that demonstrated marginal association with treatment failure.
Expression level of XPF in HNSCC tumors correlates with clinical response to DNA damaging agents. XPF has potential to guide next-generation personalized cancer therapy.
XPF-ERCC1; DNA repair; SNP; platinum; biomarker
Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papilloma virus was detectable by sequencing of DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), the analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (e.g., NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.
Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non–small cell lung cancer (NSCLC).
To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307 260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided.
SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10−6), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10−7). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10−6) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35).
These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.
Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx and esophagus) in women (odds ratio (OR) =1.24, P=0.003) with little effect in men (OR=1.04, P=0.35).
In a coordinated genotyping study within the International Head and Neck Cancer Epidemiology (INHANCE) consortium, we have sought to replicate these findings in an additional 4,604 cases and 6,239 controls from 10 independent UADT cancer case-control studies.
rs16969968 was again associated with UADT cancers in women (OR=1.21, 95% confidence interval(CI)=1.08–1.36, P=0.001) and a similar lack of observed effect in men (OR=1.02, 95%CI=0.95–1.09, P=0.66) (P-heterogeneity=0.01). In a pooled analysis of the original and current studies, totaling 8,572 UADT cancer cases and 11,558 controls, the association was observed among females (OR=1.22, 95%CI=1.12–1.34, P=7×10−6) but not males (OR=1.02, 95%CI=0.97–1.08, P=0.35) (P-heterogeneity=6×10−4). There was little evidence for a sex difference in the association between this variant and cigarettes smoked per day, with male and female rs16969968 variant carriers smoking approximately the same amount more in the 11,991 ever smokers in the pooled analysis of the 14 studies (P-heterogeneity=0.86).
This study has confirmed a sex difference in the association between the 15q25 variant rs16969968 and UADT cancers.
Further research is warranted to elucidate the mechanisms underlying these observations.
genetic variants; 15q25; nicotinic acetylcholine receptor; upper aerodigestive tract cancers; cigarettes per day
We hypothesized that bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), will potentiate the activity of pemetrexed, a multitargeted antifolate, in squamous cell carcinoma of the head and neck (SCCHN).
Patients and Methods
Patients with previously untreated, recurrent, or metastatic SCCHN were treated with pemetrexed 500 mg/m2 and bevacizumab 15 mg/kg given intravenously every 21 days with folic acid and B12 supplementation until disease progression. Primary end point was time-to-progression (TTP). DNA was isolated from whole blood samples for the detection of polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase (MTHFR), and VEGF.
Forty patients were enrolled. The median TTP was 5 months, and the median overall survival (OS) was 11.3 months. In 37 evaluable patients, the overall response rate was 30%, including a complete response rate of 5%, and the disease control rate was 86%. Grade 3 to 5 bleeding events occurred in six patients (15%): four were grade 3, and two were fatal. Other serious toxicities in 10% or more of patients included neutropenia (10%) and infection (12.5%). One patient died of sepsis after receiving eight cycles of therapy. For the MTHFR A1298C (rs1801131) single nucleotide polymorphisms, homozygote patients with AA had worse OS (P = .034).
The addition of bevacizumab to pemetrexed resulted in promising efficacy outcomes in SCCHN. Bleeding events were frequent but some may have been due to natural history of disease. Polymorphisms in MTHFR may offer potential for treatment individualization.
Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
We have used a two-phased study approach to identify common genetic variation involved in susceptibility to upper aero-digestive tract cancer. Using Illumina HumanHap300 beadchips, 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls, were genotyped for a panel 317,000 genetic variants that represent the majority of common genetic in the human genome. The 19 top-ranked variants were then studied in an additional series of 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies. Five variants were significantly associated with UADT cancer risk after the completion of both stages, including three residing within the alcohol dehydrogenase genes (ADH1B, ADH1C, ADH7) that have been previously described. Two additional variants were found, one near the ALDH2 gene and a second variant located in HEL308, a DNA repair gene. These results implicate two variants 4q21 and 12q24 and further highlight three ADH variants UADT cancer susceptibility.
Computed tomography (CT) lung cancer screening offers a unique clinical setting in which to promote smoking cessation. Focusing on outcomes related to the reporting of CT abnormality, we examined the natural history of smoking in the Pittsburgh Lung Screening Study (PLuSS).
PLuSS recruited 50 to 79 year-old current and former cigarette smokers living in the Pittsburgh area. We examined self-reported smoking outcomes one year after study entry in a subgroup that contained n=2094 active cigarette smokers without interval lung cancer diagnosis (50.7% women, median age 57 years, 40 year median duration of cigarette smoking, and 65.2% ≥ 20 cigarettes per day). Analyses compared efforts to quit in relation to physician referral for abnormal CT.
Since study entry, 58.5% (95% confidence interval (CI) 56.3%, 60.6%) reported any quit attempt and 27.2% (95% CI 25.3%, 29.1%) any quit interval longer than 30 days. One year after study entry, 15.5% (95% CI 14.0%, 17.1%) reported not smoking for more than 30 days. Comparing persons referred because of CT abnormalities creating moderate or high lung cancer suspicion (n=156; 7.4%) to persons not referred for any reason (n=1145; 54.7%), propensity score-adjusted fractions with any quit attempt and with any quit interval longer than 30 days increased 18.8% (95% CI 11.1%, 26.5%) and 17.7% (95% CI 9.4%, 26.0%), respectively. The fraction quit more than 30 days at one year increased 12.2% (95% CI 4.9%, 19.5%).
Persons who experienced referral because of abnormal CT reported more smoking cessation.
Smoking cessation strategies continue to have disappointing results. By determining the interindividual genetic differences that influence smoking behaviors, we may be able to develop tailored strategies that increase the likelihood of successful cessation. This study attempts to determine genetic influences on the relationship between the dopamine pathway and smoking cessation by examining associations with a variable number tandem repeat variation in SLC6A3 and the DRD2 variants TaqIA (A2 vs. A1), TaqIB (B2 vs. B1), C957T (C vs. T), and -141C Ins/Del (C vs. Del). Baseline smokers in the Pittsburgh Lung Screening Study who provided information on smoking status one year later were evaluated. We frequency-matched those who were not abstinent at one year to those who were abstinent at one year by gender, decade of age, and time of enrollment (three month intervals) in a three to one ratio (N=881). Logistic regression was used to identify the effect of genotype on abstinence at one year. In a model containing the matching variables and other genotypes, DRD2 TaqIA was significantly associated with being abstinent at one year (p=0.01). Compared to participants who were homozygous TaqIA major allele (A2A2), participants who carried at least one minor allele (A1) were less likely to quit (Odds Ratio: 0.47, 95% CI: 0.24–0.94). The other dopamine receptor genotypes and the SLC6A3 genotype were not associated with smoking status at one-year. The association between DRD2 TaqIA and smoking cessation supports the hypothesis that genetic variation in the dopamine pathway influences smoking cessation.
tobacco use cessation; genotype; case-control study; dopamine
We previously conducted a study to assess whether household exposures to tap water increased an individual’s internal dose of trihalomethanes (THMs). Increases in blood THM levels among subjects who showered or bathed were variable, with increased levels tending to cluster in two groups.
Our goal was to assess the importance of personal characteristics, previous exposures, genetic polymorphisms, and environmental exposures in determining THM concentrations in blood after showering.
One hundred study participants completed a health symptom questionnaire, a 48-hr food and water consumption diary, and took a 10-min shower in a controlled setting. We examined THM levels in blood samples collected at baseline and 10 and 30 min after the shower. We assessed the significance of personal characteristics, previous exposures to THMs, and specific gene polymorphisms in predicting postshower blood THM concentrations.
We did not observe the clustering of blood THM concentrations observed in our earlier study. We found that environmental THM concentrations were important predictors of blood THM concentrations immediately after showering. For example, the chloroform concentration in the shower stall air was the most important predictor of blood chloroform levels 10 min after the shower (p < 0.001). Personal characteristics, previous exposures to THMs, and specific polymorphisms in CYP2D6 and GSTT1 genes were significant predictors of both baseline and postshowering blood THM concentrations as well as of changes in THM concentrations associated with showering.
The inclusion of information about individual physiologic characteristics and environmental measurements would be valuable in future studies to assess human health effects from exposures to THMs in tap water.
CYP2D6; CYP2E1; disinfection by-products; drinking water disinfection; GSTT1; showering exposures; trihalomethanes