Burlington, VT, United States
Burlington, VT, United States

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Kohaar I.,U.S. National Cancer Institute | Porter-Gill P.,U.S. National Cancer Institute | Lenz P.,SAIC | Fu Y.-P.,U.S. National Cancer Institute | And 14 more authors.
Journal of the National Cancer Institute | Year: 2013

A monoclonal antibody against prostate stem cell antigen (PSCA) has emerged as a novel cancer therapy currently being tested in clinical trials for prostate and pancreatic cancers, but this treatment is likely to be efficient only in patients with PSCA-expressing tumors. The present study demonstrates that a genetic variant (rs2294008) discovered by bladder cancer genome-wide association studies is a strong predictor of PSCA protein expression in bladder tumors, as measured by two-sided multivariable linear regression (P = 6.46×10-11; n = 278). The association pattern is similar in non-muscle-invasive tumors, stages Ta (P = 3.10×10-5; n = 173) and T1 (P = 2.64×10-5; n = 60), and muscle-invasive tumors, stages T2 (P =.01; n = 23) and T3/4 (P =.03; n = 22). The study suggests that anti-PSCA immunotherapy might be beneficial for bladder cancer patients with high tumor PSCA expression, which is statistically significantly associated with the presence of CT and TT genotypes of a common genetic variant, rs2294008. Future clinical studies will be needed to validate PSCA as a therapeutic target for bladder cancer. © 2012 The Author.


Wu J.W.,U.S. National Institutes of Health | Cross A.J.,U.S. National Institutes of Health | Baris D.,U.S. National Institutes of Health | Ward M.H.,U.S. National Institutes of Health | And 9 more authors.
British Journal of Cancer | Year: 2012

Background: Despite many studies on diet and bladder cancer, there are areas that remain unexplored including meat mutagens, specific vegetable groups, and vitamins from diet.Methods:We conducted a population-based case-control study of bladder cancer in Maine, New Hampshire, and Vermont. A total of 1171 cases were ascertained through hospital pathology records and cancer registries from 2001 to 2004. Overall, 1418 controls were identified from the Department of Motor Vehicles (<65 years) and Center for Medicaid and Medicare Services (65-79 years) and were frequency-matched to cases by state, sex, and age (within 5 years). Diet was assessed with a self-administered Diet History Questionnaire. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Results: Processed meat intake was positively associated with bladder cancer (highest vs lowest quartile OR: 1.28; 95% CI: 1.00-1.65; P trend=0.035), with a stronger association for processed red meat (OR: 1.41; 95% CI: 1.08-1.84; P trend=0.024). There were no associations between intake of fruits or vegetables and bladder cancer. We did, however, observe an inverse association with vitamin B12 intake (OR: 0.77; 95% CI: 0.61-0.99; P=0.019). Conclusion: Vitamin B12 from diet may be protective against bladder cancer, whereas consuming processed meat may increase risk. © 2012 Cancer Research UK.


Koutros S.,U.S. National Cancer Institute | Silverman D.T.,U.S. National Cancer Institute | Baris D.,U.S. National Cancer Institute | Zahm S.H.,U.S. National Cancer Institute | And 9 more authors.
International Journal of Cancer | Year: 2011

Aromatic amine components in hair dyes and polymorphisms in genes that encode enzymes responsible for hair dye metabolism may be related to bladder cancer risk. We evaluated the association between hair dye use and bladder cancer risk and effect modification by N-acetyltransferase-1 (NAT1), NAT2, glutathione S-transferase Mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1) genotypes in a population-based case-control study of 1193 incident cases and 1418 controls from Maine, Vermont and New Hampshire enrolled between 2001 and 2004. Individuals were interviewed in person using a computer-assisted personal interview to assess hair dye use and information on potential confounders and effect modifiers. No overall association between age at first use, year of first use, type of product, color, duration or number of applications of hair dyes and bladder cancer among women or men was apparent, but increased risks were observed in certain subgroups. Women who used permanent dyes and had a college degree, a marker of socioeconomic status, had an increased risk of bladder cancer [odds ratio (OR) = 3.3, 95% confidence interval (CI): 1.2-8.9]. Among these women, we found an increased risk of bladder cancer among exclusive users of permanent hair dyes who had NAT2 slow acetylation phenotype (OR = 7.3, 95% CI: 1.6-32.6) compared to never users of dye with NAT2 rapid/intermediate acetylation phenotype. Although we found no relation between hair dye use and bladder cancer risk in women overall, we detected evidence of associations and gene-environment interaction with permanent hair dye use; however, this was limited to educated women. These results need confirmation with larger numbers, requiring pooling data from multiple studies. Copyright © 2011 UICC.


Moore L.E.,U.S. National Institutes of Health | Baris D.R.,U.S. National Institutes of Health | Figueroa J.D.,U.S. National Institutes of Health | Garcia-Closas M.,U.S. National Institutes of Health | And 13 more authors.
Carcinogenesis | Year: 2011

Associations between bladder cancer risk and NAT2 and GSTM1 polymorphisms have emerged as some of the most consistent findings in the genetic epidemiology of common metabolic polymorphisms and cancer, but their interaction with tobacco use, intensity and duration remain unclear. In a New England population-based case-control study of urothelial carcinoma, we collected mouthwash samples from 1088 of 1171 cases (92.9%) and 1282 of 1418 controls (91.2%) for genotype analysis of GSTM1, GSTT1 and NAT2 polymorphisms. Odds ratios and 95% confidence intervals of bladder cancer among New England Bladder Cancer Study subjects with one or two inactive GSTM1 alleles (i.e. the 'null' genotype) were 1.26 (0.85-1.88) and 1.54 (1.05-2.25), respectively (P-trend = 0.008), compared with those with two active copies. GSTT1 inactive alleles were not associated with risk. NAT2 slow acetylation status was not associated with risk among never (1.04; 0.71-1.51), former (0.95; 0.75-1.20) or current smokers (1.33; 0.91-1.95); however, a relationship emerged when smoking intensity was evaluated. Among slow acetylators who ever smoked at least 40 cigarettes/day, risk was elevated among ever (1.82; 1.14-2.91, P-interaction = 0.07) and current heavy smokers (3.16; 1.22-8.19, P-interaction = 0.03) compared with rapid acetylators in each category; but was not observed at lower intensities. In contrast, the effect of GSTM1-null genotype was not greater among smokers, regardless of intensity. Meta-analysis of the NAT2 associations with bladder cancer showed a highly significant relationship. Findings from this large USA population-based study provided evidence that the NAT2 slow acetylation genotype interacts with tobacco smoking as a function of exposure intensity. Published by Oxford University Press 2010.


Wheeler D.C.,U.S. National Cancer Institute | Wheeler D.C.,Virginia Commonwealth University | Burstyn I.,Philadelphia University | Vermeulen R.,University Utrecht | And 10 more authors.
Occupational and Environmental Medicine | Year: 2013

Objectives Evaluating occupational exposures in population-based case-control studies often requires exposure assessors to review each study participant's reported occupational information job-by-job to derive exposure estimates. Although such assessments likely have underlying decision rules, they usually lack transparency, are time consuming and have uncertain reliability and validity. We aimed to identify the underlying rules to enable documentation, review and future use of these expert-based exposure decisions. Methods Classification and regression trees (CART, predictions from a single tree) and random forests ( predictions from many trees) were used to identify the underlying rules from the questionnaire responses, and an expert's exposure assignments for occupational diesel exhaust exposure for several metrics: binary exposure probability and ordinal exposure probability, intensity and frequency. Data were split into training (n=10 488 jobs), testing (n=2247) and validation (n=2248) datasets. Results The CART and random forest models' predictions agreed with 92-94% of the expert's binary probability assignments. For ordinal probability, intensity and frequency metrics, the two models extracted decision rules more successfully for unexposed and highly exposed jobs (86-90% and 57-85%, respectively) than for low or medium exposed jobs (7-71%). Conclusions CART and random forest models extracted decision rules and accurately predicted an expert's exposure decisions for the majority of jobs, and identified questionnaire response patterns that would require further expert review if the rules were applied to other jobs in the same or different study. This approach makes the exposure assessment process in case-control studies more transparent, and creates a mechanism to efficiently replicate exposure decisions in future studies.


PubMed | University of Houston, Wayne State University, U.S. National Cancer Institute, Maine Cancer Registry and 3 more.
Type: Journal Article | Journal: Occupational and environmental medicine | Year: 2016

Mapping job titles to standardised occupation classification (SOC) codes is an important step in identifying occupational risk factors in epidemiological studies. Because manual coding is time-consuming and has moderate reliability, we developed an algorithm called SOCcer (Standardized Occupation Coding for Computer-assisted Epidemiologic Research) to assign SOC-2010 codes based on free-text job description components.Job title and task-based classifiers were developed by comparing job descriptions to multiple sources linking job and task descriptions to SOC codes. An industry-based classifier was developed based on the SOC prevalence within an industry. These classifiers were used in a logistic model trained using 14983 jobs with expert-assigned SOC codes to obtain empirical weights for an algorithm that scored each SOC/job description. We assigned the highest scoring SOC code to each job. SOCcer was validated in 2 occupational data sources by comparing SOC codes obtained from SOCcer to expert assigned SOC codes and lead exposure estimates obtained by linking SOC codes to a job-exposure matrix.For 11991 case-control study jobs, SOCcer-assigned codes agreed with 44.5% and 76.3% of manually assigned codes at the 6-digit and 2-digit level, respectively. Agreement increased with the score, providing a mechanism to identify assignments needing review. Good agreement was observed between lead estimates based on SOCcer and manual SOC assignments ( 0.6-0.8). Poorer performance was observed for inspection job descriptions, which included abbreviations and worksite-specific terminology.Although some manual coding will remain necessary, using SOCcer may improve the efficiency of incorporating occupation into large-scale epidemiological studies.


PubMed | Maine Cancer Registry, Korea University, Vermont Cancer Registry, U.S. National Institutes of Health and Stewart Exposure Assessments LLC
Type: | Journal: Occupational and environmental medicine | Year: 2014

Metalworking has been associated with bladder cancer risk in many studies. Metalworking fluids (MWFs) are suspected as the putative exposure, but epidemiologic data are limited. Based on state-of-the-art, quantitative exposure assessment, we examined MWF exposure and bladder cancer risk in the New England Bladder Cancer Study.Male cases (n = 895) and population controls (n = 1031) provided occupational histories and information on use of each of three MWF types: (1) straight (mineral oil, additives), (2) soluble (mineral oil, water, additives), and (3) synthetic (water, organics, additives) or semi-synthetic (soluble/synthetic hybrid), in response to exposure-oriented modules administered during personal interviews. We estimated the probability, frequency, and intensity of exposure to each MWF type and, if probability exceeded 50%, cumulative exposure. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for smoking and other risk factors.Risk was increased for men reporting use of straight MWFs (OR=1.7, 95% CI=1.1-2.8), with a significant trend with increasing cumulative exposure (p = 0.024). Use of soluble MWFs conferred a 50% elevated risk (95% CI=0.96-2.5). ORs were nonsignificantly elevated for synthetic MWFs, based on small numbers. Men who were never metalworkers, but held jobs with possible exposure to mineral oil, had a 40% increased risk (95% CI=1.1-1.8).In the most comprehensive assessment of MWF exposure in a bladder cancer case-control study, exposure to straight MWFs significantly increased bladder cancer risk, as did employment in non-metalworking jobs with possible mineral oil exposure. Our results strengthen prior evidence for mineral oil as a bladder carcinogen.


PubMed | Karolinska Institutet, Brown University, International Agency for Research on Cancer IARC WHO, Complex Traits Genetics Team and. and 130 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2014

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 10(-39); Region 3: rs2853677, P = 3.30 10(-36) and PConditional = 2.36 10(-8); Region 4: rs2736098, P = 3.87 10(-12) and PConditional = 5.19 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 10(-6); and Region 6: rs10069690, P = 7.49 10(-15) and PConditional = 5.35 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 10(-18) and PConditional = 7.06 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

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