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Articles by N Rothman
Total Records ( 8 ) for N Rothman
  P Sun , Y Qiu , Z Zhang , J Wan , T Wang , X Jin , Q Lan , N Rothman and Z. l. Xia
 

DNA damage induced by benzene reactive metabolites is thought of as an important mechanism underlying benzene hematotoxicity and genotoxicity, and genetic variation in cell-cycle control genes may contribute to susceptibility to chronic benzene poisoning (CBP). Using a case-control study that included 307 benzene-poisoned patients and 299 workers occupationally exposed to benzene in south China, we aimed to investigate the association between genetic polymorphisms of p53 and p21 and the odds of CBP. To investigate whether benzene exposure may influence mRNA expression of p53 and p21 in benzene-exposed workers, we also chose 39 CBP workers, 38 occupationally benzene-exposure workers, and 37 nonexposure workers in the same region of China. PCR-restriction fragment length polymorphism technique was applied to detect polymorphisms of p53 (rs17878362, rs1042522, and rs1625895) and p21 (rs1801270 and rs1059234), and real-time PCR was applied to detect the quantity of gene mRNA expression. We found that p21 C98A variant genotypes (CA+AA) or C70T variant genotypes (CT+TT) were associated with decreased odds of CBP [odds ratio (OR), 0.51; 95% confidence interval (95% CI), 0.32-0.83, and OR, 0.53; 95% CI, 0.29-0.95, respectively. Further analysis showed the decreased odds of CBP in the subjects with p21 CC/AT diplotype (OR, 0.51; 95% CI, 0.30-0.85). In addition, p53 mRNA expression of CBP workers or benzene-exposure workers was significantly lower than that of nonexposure workers. Although these results require confirmation and extension, our results show that polymorphisms in p21 may be protective against the risk of CBP in the Chinese occupational population. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1821–8)

  P Bhatti , P. A Stewart , A Hutchinson , N Rothman , M. S Linet , P. D Inskip and P. Rajaraman
 

There is some evidence that oxidative stress plays a role in lead-induced toxicity. Mechanisms for dealing with oxidative stress may be of particular relevance in the brain given the high rate of oxygen metabolism. Using a hospital-based case-control study, we investigated the role of oxidative stress in the potential carcinogenicity of lead through examination of effect modification of the association between occupational lead exposure and brain tumors by single nucleotide polymorphisms in genes with functions related to oxidative stress. The study included 362 patients with glioma (176 of which had glioblastoma multiforme), 134 patients with meningioma, and 494 controls. Lead exposure was estimated by expert review of detailed job history data for each participant. We evaluated effect modification with 142 single nucleotide polymorphisms using likelihood ratio tests that compared nested unconditional logistic regression models that did and did not include a cross-product term for cumulative lead exposure and genotype. When the analyses were restricted to cases with glioblastoma multiforme, RAC2 rs2239774 and two highly correlated GPX1 polymorphisms (rs1050450 and rs18006688) were found to significantly modify the association with lead exposure (P ≤ 0.05) after adjustment for multiple comparisons. Furthermore, the same GPX1 polymorphisms and XDH rs7574920 were found to significantly modify the association between cumulative lead exposure and meningioma. Although the results of this study provide some evidence that lead may cause glioblastoma multiforme and meningioma through mechanisms related to oxidative damage, the results must be confirmed in other populations. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1841–8)

  M Chen , M. A. T Hildebrandt , J Clague , A. M Kamat , A Picornell , J Chang , X Zhang , J Izzo , H Yang , J Lin , J Gu , S Chanock , M Kogevinas , N Rothman , D. T Silverman , M Garcia Closas , H. B Grossman , C. P Dinney , N Malats and X. Wu
 

Sonic hedgehog (Shh) pathway genetic variations may affect bladder cancer risk and clinical outcomes. Therefore, we genotyped 177 single-nucleotide polymorphisms (SNP) in 11 Shh pathway genes in a study including 803 bladder cancer cases and 803 controls. We assessed SNP associations with cancer risk and clinical outcomes in 419 cases of non–muscle-invasive bladder cancer (NMIBC) and 318 cases of muscle-invasive and metastatic bladder cancer (MiMBC). Only three SNPs (GLI3 rs3823720, rs3735361, and rs10951671) reached nominal significance in association with risk (P ≤ 0.05), which became nonsignificant after adjusting for multiple comparisons. Nine SNPs reached a nominally significant individual association with recurrence of NMIBC in patients who received transurethral resection (TUR) only (P ≤ 0.05), of which two (SHH rs1233560 and GLI2 rs11685068) were replicated independently in 356 TUR-only NMIBC patients, with P values of 1.0 x 10–3 (SHH rs1233560) and 1.3 x 10–3 (GLI2 rs11685068). Nine SNPs also reached a nominally significant individual association with clinical outcome of NMIBC patients who received Bacillus Calmette-Guérin (BCG; P ≤ 0.05), of which two, the independent GLI3 variants rs6463089 and rs3801192, remained significant after adjusting for multiple comparisons (P = 2 x 10–4 and 9 x 10–4, respectively). The wild-type genotype of either of these SNPs was associated with a lower recurrence rate and longer recurrence-free survival (versus the variants). Although three SNPs (GLI2 rs735557, GLI2 rs4848632, and SHH rs208684) showed nominal significance in association with overall survival in MiMBC patients (P ≤ 0.05), none remained significant after multiple-comparison adjustments. Germ-line genetic variations in the Shh pathway predicted clinical outcomes of TUR and BCG for NMIBC patients. Cancer Prev Res; 3(10); 1235–45. ©2010 AACR.

  J. Y Lee , A. K Park , K. M Lee , S. K Park , S Han , W Han , D. Y Noh , K. Y Yoo , H Kim , S. J Chanock , N Rothman and D. Kang
 

Objectives: This study was conducted to investigate the role of common variation in innate immunity-related genes as susceptibility factors to breast cancer risk in Korean women. Methods: Total 1536 single-nucleotide polymorphisms (SNPs) in 203 genes were analyzed by Illumina GoldenGate assay in 209 cases and the same numbers of controls. Both SNP and gene-based tests were used to evaluate the association with breast cancer risk. The robustness of results was further evaluated with permutation method, false discovery rate and haplotype analyses. Results: Both SNP and gene-based analyses showed promising associations with breast cancer risk for 17 genes: OR10J3, FCER1A, NCF4, CNTNAP1, CTNNB1, KLKB1, ITGB2, ALOX12B, KLK2, IRAK3, KLK4, STAT6, NCF2, CCL1, C1QR1, MBP and NOS1. The most significant association with breast cancer risk was observed for the OR10J3 SNP (rs2494251, P-value = 1.2 x 10–4) and FCER1A SNP (rs7548864, P-value = 7.7 x 10–4). Gene-based permutation and false discovery rate P-values for OR10J3 SNP (rs2494251) with breast cancer risk were also significant (P = 4 x 10–5 and 0.008, respectively). Haplotype analyses supported these findings that OR10J3 and FCER1A were most significantly associated with risk for breast cancer (P = 2 x 10–4 and 0.004, respectively). Conclusion: This study suggests that common genetic variants in the OR10J3 and FCER1A be strongly associated with breast cancer risk among Korean women.

  G Andreotti , P Boffetta , P. S Rosenberg , S. I Berndt , S Karami , I Menashe , M Yeager , S. J Chanock , D Zaridze , V Matteev , V Janout , H Kollarova , V Bencko , M Navratilova , N Szeszenia Dabrowska , D Mates , N Rothman , P Brennan , W. H Chow and L. E. Moore
 

Hypertension is a known risk factor for renal cell carcinoma (RCC), although the underlying biological mechanisms of its action are unknown. To clarify the role of hypertension in RCC, we examined the risk of RCC in relation to 142 single-nucleotide polymorphisms (SNPs) in eight genes having a role in blood pressure control. We analyzed 777 incident and histologically confirmed RCC cases and 1035 controls who completed an in-person interview as part of a multi-center, hospital-based case–control study in Central Europe. Genotyping was conducted with an Illumina® GoldenGate® Oligo Pool All assay using germ line DNA. Of the eight genes examined, AGT (angiotensinogen) was most strongly associated with RCC (minimum P-value permutation test = 0.02). Of the 17 AGT tagging SNPs considered, associations were strongest for rs1326889 [odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.15–1.58] and rs2493137 (OR = 1.31, 95% CI = 1.12–1.54), which are located in the promoter. Stratified analysis revealed that the effects of the AGT SNPs were statistically significant in participants with hypertension or high body mass index (BMI) (≥25 kg/m2), but not in subjects without hypertension and with a normal BMI (<25 kg/m2). Also, haplotypes with risk-conferring alleles of markers located in the promoter and intron 1 regions of AGT were significantly associated with RCC compared with the common haplotype in subjects with hypertension or high BMI (global P = 0.003). Our findings suggest that common genetic variants of AGT, particularly those in the promoter, increase RCC risk among subjects who are hypertensive or overweight.

  H. D Hosgood , C. S Liu , N Rothman , S. J Weinstein , M. R Bonner , M Shen , U Lim , J Virtamo , W. l Cheng , D Albanes and Q. Lan
 

Mitochondria are eukaryotic organelles responsible for energy production. Mitochondrial DNA (mtDNA) lack introns and protective histones, have limited DNA repair capacity and compensate for damage by increasing the number of mtDNA copies. As a consequence, mitochondria are more susceptible to reactive oxygen species, an important determinant of cancer risk, and it is hypothesized that increased mtDNA copy number may be associated with carcinogenesis. We assessed the association of mtDNA copy number and lung cancer risk in 227 prospectively collected cases and 227 matched controls from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age at randomization, smoking years and number of cigarettes smoked per day. There was suggestion of a dose-dependent relationship between mtDNA copy number and subsequent risk of lung cancer, with a prominent effect observed in the highest mtDNA copy number quartile [ORs (95% CI) by quartile: 1.0 (reference), 1.3 (0.7–2.5), 1.1 (0.6–2.2) and 2.4 (1.1–5.1); Ptrend = 0.008]. This is the first report, to the best of our knowledge, to suggest that mtDNA copy number may be positively associated with subsequent risk of lung cancer in a prospective cohort study; however, replication is needed in other studies and populations.

  D Baris , M. R Karagas , C Verrill , A Johnson , A. S Andrew , C. J Marsit , M Schwenn , J. S Colt , S Cherala , C Samanic , R Waddell , K. P Cantor , A Schned , N Rothman , J Lubin , J. F Fraumeni , R. N Hoover , K. T Kelsey and D. T. Silverman
  Background

Cigarette smoking is a well-established risk factor for bladder cancer. The effects of smoking duration, intensity (cigarettes per day), and total exposure (pack-years); smoking cessation; exposure to environmental tobacco smoke; and changes in the composition of tobacco and cigarette design over time on risk of bladder cancer are unclear.

Methods

We examined bladder cancer risk in relation to smoking practices based on interview data from a large, population-based case–control study conducted in Maine, New Hampshire, and Vermont from 2001 to 2004 (N = 1170 urothelial carcinoma case patients and 1413 control subjects). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression. To examine changes in smoking-induced bladder cancer risk over time, we compared odds ratios from New Hampshire residents in this study (305 case patients and 335 control subjects) with those from two case–control studies conducted in New Hampshire in 1994–1998 and in 1998–2001 (843 case patients and 1183 control subjects).

Results

Regular and current cigarette smokers had higher risks of bladder cancer than never-smokers (for regular smokers, OR = 3.0, 95% CI = 2.4 to 3.6; for current smokers, OR = 5.2, 95% CI = 4.0 to 6.6). In New Hampshire, there was a statistically significant increasing trend in smoking-related bladder cancer risk over three consecutive periods (1994–1998, 1998–2001, and 2002–2004) among former smokers (OR = 1.4, 95% CI = 1.0 to 2.0; OR = 2.0, 95% CI = 1.4 to 2.9; and OR = 2.6, 95% CI = 1.7 to 4.0, respectively) and current smokers (OR = 2.9, 95% CI = 2.0 to 4.2; OR = 4.2, 95% CI = 2.8 to 6.3; OR = 5.5, 95% CI = 3.5 to 8.9, respectively) (P for homogeneity of trends over time periods = .04). We also observed that within categories of intensity, odds ratios increased approximately linearly with increasing pack-years smoked, but the slope of the increasing trend declined with increasing intensity.

Conclusions

Smoking-related risks of bladder cancer appear to have increased in New Hampshire since the mid-1990s. Based on our modeling of pack-years and intensity, smoking fewer cigarettes over a long time appears more harmful than smoking more cigarettes over a shorter time, for equal total pack-years of cigarettes smoked.

  A. N Freedman , L. B Sansbury , W. D Figg , A. L Potosky , S. R Weiss Smith , M. J Khoury , S. A Nelson , R. M Weinshilboum , M. J Ratain , H. L McLeod , R. S Epstein , G. S Ginsburg , R. L Schilsky , G Liu , D. A Flockhart , C. M Ulrich , R. L Davis , L. J Lesko , I Zineh , G Randhawa , C. B Ambrosone , M. V Relling , N Rothman , H Xie , M. R Spitz , R Ballard Barbash , J. H Doroshow and L. M. Minasian
 

Recent advances in genomic research have demonstrated a substantial role for genomic factors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomics and pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, in terms of both adverse effects and treatment efficacy. To identify research priorities as well as the resources and infrastructure needed to advance these fields, the National Cancer Institute (NCI) sponsored a workshop titled "Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation" on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss five science-based recommendations and four infrastructure-based recommendations that were identified as a result of discussions held during this workshop. Key recommendations include 1) supporting the routine collection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observational and population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3) addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomic and pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federal agencies, and with industry. Together, these recommendations will facilitate the discovery and validation of clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response and adverse events, and they will improve both the speed and efficiency by which new pharmacogenomic and pharmacoepidemiologic information is translated into clinical practice.

 
 
 
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