Biomedical subjects

Margaret R Spitz

Publications and source records attributed to Margaret R Spitz.

At least 19 recordsLinked to original sources

PubMed2007

Dietary zinc, copper and selenium, and risk of lung cancer.

Zinc, copper and selenium are important cofactors for several enzymes that play a role in maintaining DNA integrity. However, limited epidemiologic research on these dietary trace metals and lung cancer risk is available. In an ongoing study of 1,676 incident lung cancer cases and 1,676 matched healthy controls, we studied the associations between dietary zinc, copper and selenium and lung cancer risk. Using multiple logistic regression analysis, the odds ratios (OR) and 95% confidence intervals (CI) of lung cancer for all subjects by increasing quartiles of dietary zinc intake were 1.0, 0.80 (0.65-0.99), 0.64 (0.51-0.81), 0.57 (0.42-0.75), respectively (p trend = 0.0004); similar results were found for men. For dietary copper, the ORs and 95% CI for all subjects were 1.0, 0.59 (0.49-0.73), 0.51 (0.41-0.64), 0.34 (0.26-0.45), respectively (p trend < 0.0001); similar reductions in risk and trend were observed by gender. Dietary selenium intake was not associated with risk, except for a significant inverse trend (p = 0.04) in men. Protective trends (p < 0.05) against lung cancer with increased dietary zinc intake were also found for all ages, BMI > 25, current smokers, pack-years < or =30, light drinkers and participants without emphysema. Increased dietary copper intake was associated with protective trends (p < 0.05) across all ages, BMI, smoking and vitamin/mineral supplement categories, pack-years < or =30 and 30.1-51.75 and participants without emphysema. Our results suggest that dietary zinc and copper intakes are associated with reduced risk of lung cancer. Given the known limitations of case-control studies, these findings must be interpreted with caution and warrant further investigation.

Aged↗

PubMed2006

Aberrant promoter methylation profile and association with survival in patients with non-small cell lung cancer.

PURPOSE: The aim of this study was to investigate the prognostic value of hypermethylation of tumor suppressor genes in patients with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: We examined the methylation status of nine genes in 155 tumors from patients with NSCLC using quantitative methylation-specific PCR. We analyzed the associations between gene methylation status and overall patient survival. RESULTS: The methylation index, defined as the ratio between the number of methylated genes and the number of genes tested, was significantly higher in adenocarcinomas (0.38 +/- 0.20) than in squamous cell carcinomas (0.30 +/- 0.22; P = 0.027), in tumors from older patients (0.37 +/- 0.20) than younger patients (0.30 +/- 0.22; P = 0.040), and in tumors from heavier smokers (0.39 +/- 0.21) than lighter smokers (0.29 +/- 0.20; P = 0.042). In the Cox proportional hazards model, p16 methylation was associated with significantly poorer survival [hazard ratio, 1.95; 95% confidence interval (95% CI), 1.21-3.39]. Kaplan-Meier survival curves showed that patients with hypermethylated p16 had significantly shorter survival (median = 21.7 months) than patients without p16 hypermethylation (median = 62.5 months; P = 0.0001, log-rank test). Hypermethylation of CDH1 or TIMP3 gene was associated with significantly better survival with hazard ratios of 0.51 (95% CI, 0.29-0.90) and 0.59 (95% CI, 0.36-0.97), respectively. Joint analysis of these three genes showed a significant trend for poorer survival as the number of unfavorable events increased (P = 0.0007). CONCLUSION: Hypermethylation of multiple genes exhibited significant differential effect on NSCLC patient survival. Assessment of the effect of each methylated gene on survival is needed to provide optimal prognostic value.

Aged↗

PubMed2006

Joint effect of mutagen sensitivity and insulin-like growth factors in predicting the risk of developing secondary primary tumors and tumor recurrence in patients with head and neck cancer.

PURPOSE: Early-stage head and neck cancer patients are at high risks for tumor recurrence and secondary primary tumor (SPT) development. We hypothesized that latent genetic instability and proliferation potential may be associated with elevated risks of SPT and recurrence. EXPERIMENTAL DESIGN: We conducted a nested case-control study within a randomized, placebo-controlled chemoprevention trial in patients with early-stage head and neck cancer. We compared prediagnostic bleomycin-induced chromatid breaks in peripheral blood lymphocyte cultures (as an indicator of latent genetic instability) between 298 cases (patients with SPT/recurrence) and 693 controls (patients without SPT/recurrence). We also determined the joint effects of latent genetic instability and elevated proliferation potential [indicated by serum insulin-like growth factor (IGF) level] in modulating the risk of SPT and recurrence. RESULTS: In the Cox proportional hazards model, patients with higher mutagen sensitivity (using a cutoff of > or =0.50 breaks per cell) exhibited a significantly increased risk of developing SPT/recurrence [hazard ratio, 1.38; 95% confidence interval (95% CI), 1.02-1.86]. Cases also exhibited significantly higher levels of IGF-I and IGF-binding protein-3 than controls (P = 0.022 and 0.042, respectively). Moreover, there were joint effects between mutagen sensitivity and IGFs in modulating SPT/recurrence risk. Using patients with low IGF-I level and low mutagen sensitivity profile as the reference group, the odds ratios of developing SPT/recurrence for patients with high IGF-I level alone, high mutagen sensitivity alone, and both high IGF-I level and high mutagen sensitivity were 2.85 (95% CI, 0.92-8.82), 3.92 (95% CI, 1.28-11.97), and 6.16 (95% CI, 2.03-18.71), respectively. A similar joint effect was observed for mutagen sensitivity and IGF-binding protein-3 level. CONCLUSIONS: This is the largest prospective study to evaluate mutagen sensitivity as a prognosis marker in head and neck cancer because mutagen sensitivity data were derived from baseline samples drawn before the development of SPT or tumor recurrence. The results also show for the first time that latent genetic instability and elevated proliferation potential jointly elevate the risk of second tumors in early-stage head and neck cancers.

Bleomycin↗

PubMed2006

172G>T variant in the 5' untranslated region of DNA repair gene RAD51 reduces risk of squamous cell carcinoma of the head and neck and interacts with a P53 codon 72 variant.

RAD51 participates in homologous recombination (HR) repair of double-stranded DNA breaks (DSBs) that may cause genomic instability and cancer. Two single-nucleotide polymorphisms (SNPs) and three P53 binding sites have been found in the RAD51 promoter and 5' untranslated region. We hypothesized that RAD51 and P53 SNPs may interact and alter risk of squamous cell carcinoma of the head and neck (SCCHN) and we genotyped for RAD51 135G>C and 172G>T and P53 Arg72Pro SNPs in 716 SCCHN patients and 719 matched controls (all non-Hispanic whites) and evaluated their effects on gamma radiation-induced mutagen sensitivity. We found that RAD51 172TT homozygotes had a significantly decreased risk [adjusted odds ratio (OR) = 0.66, 95% confidence interval (CI) = 0.50-0.87] of SCCHN, compared with carriers of other genotypes, particularly in P53 Arg72Arg homozygotes (adjusted OR = 0.60, 95% CI = 0.41-0.89) (homogeneity test P = 0.047), although no alterations in the risk were associated with the RAD51 135G>C and P53 Arg72Pro SNPs. Consistent with a protective effect of the 172TT genotype, significantly fewer gamma radiation-induced chromatid breaks per cell were present in 172TT homozygotes (mean +/- SD = 0.36 +/- 0.13) than in subjects with other genotypes (mean +/- SD = 0.46 +/- 0.13, P < 0.001) among 148 control subjects we tested. The finding that the functional RAD51 172G>T SNP, particularly in the presence of the P53 Arg72Arg genotype, may be a marker of susceptibility to SCCHN needs to be validated by larger studies of different ethnic populations.

5' Untranslated Regions↗

PubMed2006

Expression of telomere-associated genes as prognostic markers for overall survival in patients with non-small cell lung cancer.

PURPOSE: Human telomeres, which are composed of long, repetitive sequences of TTAGGG and a variety of proteins, function as a protective structure capping the ends of chromosomes. Telomere dysfunction plays important roles in cancer initiation and progression. TRF1, TRF2, POT1, and RAP1 are four major telomere proteins that regulate telomere stability and telomere length. We hypothesized that the expression of these genes would have significant predictive value for cancer development and prognosis. EXPERIMENTAL DESIGN: We compared the mRNA expression level of TRF1, TRF2, POT1, and RAP1 between tumor and adjacent normal tissues from 148 patients with non-small cell lung cancer using real-time quantitative PCR. We then estimated the prognostic value of the mRNA expression of these genes in tumors. RESULTS: The expression level of TRF1 was significantly lower in tumor tissues than in adjacent normal tissues (P < 0.0001); no significant difference was found for TRF2, POT1, and RAP1. The expression of RAP1 gene in tumors was highly predictive of overall survival. In the Cox proportional hazards model, patients with higher RAP1 expression were associated with a significantly better survival [hazard ratio (HR), 0.47; 95% confidence interval (95% CI), 0.24-0.91]. This improved survival was more prominent in men (HR, 0.45; 95% CI, 0.22-0.996) and in ever smokers (HR, 0.50; 95% CI, 0.24-1.02). Kaplan-Meier survival curves showed that patients with higher RAP1 expression had significantly longer median survival than patients with lower expression (median = 51.21 versus 15.34 months, P < 0.0009). The expressions of TRF2 in tumor tissues were significantly correlated with tumor grades (P = 0.0114). CONCLUSIONS: RAP1 expression may be a useful biomarker of tumor progression and survival.

Aged↗

PubMed2006

Polymorphisms of FAS and FAS ligand genes involved in the death pathway and risk and progression of squamous cell carcinoma of the head and neck.

PURPOSE: Alteration of the FAS/FAS ligand (FASLG) pathway regulating cell death may lead to cancer development, but the effects of functional promoter polymorphisms of the FAS and FASLG genes on risk of squamous cell carcinoma of the head and neck (SCCHN) are unknown. DESIGN: We genotyped the FAS -1377 G>A, FAS -670 A>G, FASLG -844 C>T, and FASLG IVS2nt -124 A>G polymorphisms in 721 case patients with SCCHN and 1,234 cancer-free non-Hispanic White control subjects frequency-matched by age and sex. Multivariate logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Compared with the FAS -1377 GG and -670 AA genotypes, the FAS -1377 AA and -670 (GG+AG) genotypes were associated with an increased risk of SCCHN (OR, 2.23; 95% CI, 1.07-4.64 and OR, 1.24; 95% CI, 1.01-1.52, respectively), whereas no risk of SCCHN was associated with any of the FASLG genotypes. When we used the combined FAS -1377 (GG+AG)/-670 AA genotypes as the reference, we found that the individuals carrying the FAS -1377 AA/-670 (GG+AG) had the highest risk (OR, 2.69; 95% CI, 1.24-5.83), whereas individuals carrying genotypes other than FAS -1377 (GG+AG)/-670 AA had a higher risk of SCCHN (OR, 1.24; 95% CI, 1.01-1.52). Furthermore, the elevated risk was particularly evident for pharyngeal cancer with the larger tumors without regional lymph metastasis (OR, 1.77; 95% CI, 1.07-2.94). CONCLUSIONS: The FAS (but not FASLG) polymorphisms seem to contribute to risk of developing SCCHN, particularly the pharyngeal cancer in non-Hispanic Whites. However, potential selection bias warrants future population-based studies to verify the findings.

Adolescent↗

PubMed2006

Polymorphisms of STK15 (Aurora-A) gene and lung cancer risk in Caucasians.

STK15/Aurora-A is a centrosome-localized serine/threonine kinase that functions primarily in centrosome maturation and mitotic spindle assembly. In a large lung cancer case-control study of 1401 cases and 1397 controls including three ethnic groups, we examined the associations between two non-synonymous SNPs (Phe31Ile and Val57Ile) of the STK15 gene and lung cancer risk. There were statistically significant differences in the distribution of the genotypes (P<0.0001) and haplotypes (P<0.0001) by ethnicity for the Phe31Ile, but not the Val57Ile variant. Caucasians with the homozygous variant Phe31Ile genotype (Ile/Ile) were at a significantly reduced risk for lung cancer [odds ratio (OR)=0.63, 95% confidence interval (CI)=0.41-0.96]. The variant allele of Val57Ile was not associated with lung cancer risk overall. However, men with the homozygous variant genotype (Ile/Ile) had a reduced lung cancer risk as compared with men with the wild-type genotype (Val/Val) (OR=0.42, 95% CI=0.19-0.94). When we performed joint analysis of these two polymorphisms, compared with the reference group (TT+GG, 40.99% of controls), homozygous Ile31 allele/wild-type Val57 allele (AA+GG) carriers (5.45% of controls) exhibited a reduced lung cancer risk (OR=0.78, 95% CI=0.63-0.97). This is the first epidemiological study to report significant associations between STK15 polymorphisms and lung cancer risk.

Aurora Kinase A↗

PubMed2006

Bladder cancer risk as modified by family history and smoking.

BACKGROUND: The familial risk of bladder cancer (BC) is not well understood and, to date, little attention has been paid to the joint effect of smoking and family history in modifying the risk of BC. The authors investigated the role of family history in association with the risk of BC. METHODS: Case and control probands were identified as part of an on-going BC case-control study. The relative risk associated with a family history of BC was estimated. RESULTS: In total, 713 cases and 658 controls were included. In a case-control analysis, compared with individuals who never smoked and who had no family history of BC, probands who had smoked and who also had a positive family history were at 5.31-fold increased risk of BC (P for interaction = .04). The 713 case probands and the 658 controls reported 5160 and 4816 first-degree relatives, respectively. Compared with never-smoking relatives who had probands diagnosed with BC at an older age (age >65 years), ever-smoking relatives who had probands diagnosed at a younger age (ages 40-65 years) showed a 6.89-fold (95% confidence interval, from 2.25-fold to 21.12-fold) increased risk. Similar results were obtained for the joint effects of family history of BC and smoking. CONCLUSIONS. The current results indicated that a positive family history of BC may have interacted with smoking habits to increase the risk of BC in the study population.

Aged↗

PubMed2006

Human sensitivity to PhIP: a novel marker for prostate cancer risk.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) has been implicated in the development of colon, prostate and mammary gland tumors in rats. In this study, we developed a modified in vitro mutagen sensitivity assay, with activated PhIP (N-OH-PhIP) as the challenge mutagen and chromosome aberrations as the endpoint, and applied it in a pilot prostate cancer case-control study of 81 cases and 84 age and ethnicity-matched controls. Our results showed significantly higher baseline breaks among the cases, mean+/-S.E.=1.86+/-0.23 versus 0.96+/-0.14 in controls; P=0.006. Individuals with high baseline breaks (dichotomized at the control median) had a 36% increased risk for PC (OR=1.36; 95% CI=1.08-1.72). In stratified analysis, high baseline breaks was associated in younger participants (< or = 60 years) with an OR of 1.71 (1.14-2.57) and in those with a positive family history of PC, an OR of 1.43 (0.97-2.11). PhIP treatment induced significantly higher breaks in cases, mean+/-S.E.=5.07+/-0.39 versus 3.83+/-0.24 in controls; P=0.05. Higher PhIP-induced breaks was associated with an overall 17% increased risk for PC (OR=1.17; 95% CI=1.03-1.33), a significantly increased risks (OR=1.19; 95% CI=1.00-1.41) among younger participants, non-smokers (OR=1.39, 1.03-1.88) and 1.20 (1.00-1.45) among those with no family history of PC. Results from this pilot study demonstrate differential sensitivity to PhIP among subgroups and therefore, this assay have potential as a susceptibility marker for prostate cancer risk.

Adult↗

PubMed2006

Evaluation of glutathione S-transferase polymorphisms and mutagen sensitivity as risk factors for the development of second primary tumors in patients previously diagnosed with early-stage head and neck cancer.

BACKGROUND: The objective of this study was to evaluate the effects of polymorphisms in 2 genes in the glutathione S-transferase (GST) family and the mutagen-sensitivity phenotype on the risk of second primary tumors (SPTs) in patients with previously diagnosed early-stage head and neck squamous cell carcinoma. Data were available for 303 patients who were enrolled in a placebo-controlled chemoprevention trial of low-dose 13-cis-retinoic acid to reduce the occurrence of SPTs. METHODS: A Cox proportional hazards model and survival tree analysis were used to evaluate the association between specified genetic variations and the development of SPTs. The average number of bleomycin-induced chromatid breaks per cell was used to quantify mutagen sensitivity as an individual patient's degree of sensitivity to genotoxicity. RESULTS: The GST-M1 null genotype was associated with an increased risk for any SPTs (hazard ratio [HR], 1.99; 95% confidence interval [95% CI], 1.11-3.56) and for tobacco-related SPTs (HR, 2.16; 95% CI, 1.01-4.62) after adjusting for covariates. The GST-T1 null genotype and bleomycin-induced chromatid breaks were not associated with a statistically significant increased risk for SPTs or tobacco-related SPTs after similar adjustment. Simultaneous nonnull status for both GST genotypes was associated with a decreased risk for any SPTs (HR, 0.52; 95% CI, 0.28-0.96) and tobacco-related SPTs (HR, 0.50; 95% CI, 0.22-1.11) compared with null status for GST-M1 accompanied by nonnull status for GST-T1. CONCLUSIONS: An association was observed between the development of SPTs and the GST-M1 null genotype after successful treatment for early-stage head and neck squamous cell carcinoma. The GST-T1 null genotype and bleomycin-induced chromatid breaks were not associated with an increased risk, and no significant interactions were identified.

Aged↗

PubMed2006

Cytokinesis-blocked micronucleus assay as a novel biomarker for lung cancer risk.

In this case-control study, we modified the cytokinesis-block micronucleus (CBMN) assay, an established biomarker for genomic instability, to evaluate susceptibility to the nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by measuring the frequency of NNK-induced chromosomal damage endpoints (micronuclei, nucleoplasmic bridges, and nuclear buds) per 1,000 binucleated lymphocytes. Spontaneous and NNK-induced chromosomal damage were significantly higher in lung cancer patients compared with controls. Forty-seven percent of cases (versus 12% of controls) had >or=4 spontaneous micronuclei, 66% of cases (and no controls) had >or=4 spontaneous nucleoplasmic bridges, and 25% of cases (versus 5% of controls) had >or=1 spontaneous nuclear bud (P < 0.001). Similarly, 40% of cases (versus 6% of the controls) had >or=5 NNK-induced micronuclei, 89% of cases (and no controls) had >or=6 induced nucleoplasmic bridges, and 23% of cases (versus 2% of controls) had >or=2 induced nuclear buds (P < 0.001). When analyzed on a continuous scale, spontaneous micronuclei, nucleoplasmic bridges, and nuclear buds were associated with 2-, 29-, and 6-fold increases in cancer risk, respectively. Similarly, NNK-induced risks were 2.3-, 45.5-, and 10-fold, respectively. We evaluated the use of CBMN assay to predict cancer risk based on the numbers of micronuclei, nucleoplasmic bridges, and nuclear buds defined by percentile cut points in controls. Probabilities of being a cancer patient were 96%, 98%, and 100% when using the 95th percentiles of spontaneous and NNK-induced micronuclei, nucleoplasmic bridges, and nuclear buds, respectively. Our study indicates that the CBMN assay is extremely sensitive to NNK-induced genetic damage and may serve as a strong predictor of lung cancer risk.

Carcinogens↗

PubMed2006

Mutagen sensitivity has high heritability: evidence from a twin study.

Despite numerous studies showing that mutagen sensitivity is a cancer predisposition factor, the heritability of mutagen sensitivity has not been clearly established. In this report, we used a classic twin study design to examine the role of genetic and environmental factors on the mutagen sensitivity phenotype. Mutagen sensitivity was measured in peripheral blood lymphocytes from 460 individuals [148 pairs of monozygotic (MZ) twins, 57 pairs of dizygotic (DZ) twins, and 50 siblings]. The intraclass correlation coefficients were all significantly higher in MZ twins than in dizygotes (DZ pairs and MZ-sibling pairs combined) for sensitivity to four different mutagen challenges. Applying biometric genetic modeling, we calculated a genetic heritability of 40.7%, 48.0%, 62.5%, and 58.8% for bleomycin, benzo[a]pyrene diol epoxide, gamma-radiation, and 4-nitroquinoline-1-oxide sensitivity, respectively. This study provides the strongest and most direct evidence that mutagen sensitivity is highly heritable, thereby validating the use of mutagen sensitivity as a cancer susceptibility factor.

Genetic Predisposition to Disease↗

PubMed2006

Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer--a plan to move forward.

This article reviews progress in chemopreventive drug development, especially data and concepts that are new since the 2002 AACR report on treatment and prevention of intraepithelial neoplasia. Molecular biomarker expressions involved in mechanisms of carcinogenesis and genetic progression models of intraepithelial neoplasia are discussed and analyzed for how they can inform mechanism-based, molecularly targeted drug development as well as risk stratification, cohort selection, and end-point selection for clinical trials. We outline the concept of augmenting the risk, mechanistic, and disease data from histopathologic intraepithelial neoplasia assessments with molecular biomarker data. Updates of work in 10 clinical target organ sites include new data on molecular progression, significant completed trials, new agents of interest, and promising directions for future clinical studies. This overview concludes with strategies for accelerating chemopreventive drug development, such as integrating the best science into chemopreventive strategies and regulatory policy, providing incentives for industry to accelerate preventive drugs, fostering multisector cooperation in sharing clinical samples and data, and creating public-private partnerships to foster new regulatory policies and public education.

Biomarkers, Tumor↗

PubMed2006

MDM2 gene promoter polymorphisms and risk of lung cancer: a case-control analysis.

The MDM2 protein negatively regulates p53 expression level in modulating DNA repair, cell-cycle control, cell growth and apoptosis. Polymorphisms in the promoter region of the MDM2 gene have been shown to alter protein expression and may, thus, play a role in carcinogenesis. To test our hypothesis that the MDM2 promoter polymorphisms are associated with risk of lung cancer, we conducted a hospital-based, case-control study of 1026 non-Hispanic white patients newly diagnosed with lung cancer and 1145 cancer-free controls who were frequency-matched by age (+/-5 years), sex, ethnicity and smoking status. We genotyped for the MDM2 promoter G2580T (also called SNP309) and G2164A polymorphisms that have a minor allele frequency >0.05. The distributions of the MDM2-2580G variant allele and genotypes were significantly less common among the cases than among the controls (P = 0.038 and 0.045, respectively), but this was not evident for MDM2-2164G (P = 0.865 and 0.614, respectively). Compared with the MDM2-2580TT genotype, the MDM2-2580G variant genotypes were associated with a decreased risk of lung cancer [odds ratio = 0.81 and 95% confidence interval = 0.67-0.98 for GT, 0.83 (0.63-1.08) for GG, and 0.81 (0.68-0.97) for the combined GT/GG genotype]. However, no significant association was observed between the MDM2-2164G variant genotypes and lung cancer risk. Our results suggest that the MDM2-2580G allele may be a marker of reduced genetic susceptibility to lung cancer in the non-Hispanic white population, a finding that seems to contradict previous reports.

Adult↗

PubMed2006

Cyclin D1 gene polymorphism as a risk factor for oral premalignant lesions.

BACKGROUND: Deregulation of cell cycle plays an important role in tumorigenesis. Cyclin D1 gene (CCND1) is a key regulator of the G(1) phase of the cell cycle. METHODS: In this case-control study of 115 oral premalignant lesion (OPL) patients and 230 controls, we genotyped the CCND1 single nucleotide polymorphism (SNP) at the exon 4 splice site (G870A) and determined the association of this SNP with the risk of developing OPLs. RESULTS: We found significant associations between the heterozygous variant allele (GA), the homozygous variant allele (AA) and OPL risk, with adjusted odds ratios (ORs) of 1.91 [95% confidence interval (CI), 1.05-3.48] and 2.38 (95% CI, 1.16-4.87), respectively. The OR for individuals with at least one variant allele was 2.04 (95% CI, 1.15-3.60). When further stratified analyses were performed, the increased risk was more evident in younger individuals (OR = 2.82; 95% CI, 1.32-6.02), in men (OR = 2.97; 95%CI, 1.31-6.71) and in never smokers (OR = 2.92; 95% CI, 1.09-7.82). Finally, we found joint effects between the variant alleles and the smoking status. Using never smokers with the wild-type (GG) genotypes as the reference group, the ORs for never smokers with the variant genotypes (G/A + A/A), smokers with the G/G genotype and smokers with the G/A + A/A genotypes were 2.92 (1.09-7.82), 3.95 (1.36-11.5) and 7.01 (2.68-18.4), respectively. CONCLUSION: Our results suggest that the CCND1 G870A SNP may contribute to genetic susceptibility to OPLs and involve in oral cancer development.

Adult↗

PubMed2006

Never smokers and lung cancer risk: a case-control study of epidemiological factors.

We performed an analysis of potential epidemiological risk factors for lung cancer using data from 280 cases and 242 hospital-based controls, all lifetime never smokers (those who had smoked <100 cigarettes in their lifetimes) and frequency matched on age, gender and ethnicity. The data on demographic characteristics, medical history of respiratory diseases (asthma, emphysema, pneumonia and hay fever), weight and height, family history, female characteristics and environmental tobacco smoke (ETS) and dust exposure were derived from personal interviews. We performed a logistic regression analysis of these variables adjusting for age, gender, ethnicity, income and years of education. Exposure to ETS (OR = 2.08, 95% CI [1.25-3.43]) and dusts (OR = 2.43, 95% CI [1.53-3.88]) were associated with significantly increased risk. In the analysis for joint effects, exposure to both ETS and dusts conferred a higher risk (OR = 3.25, 95% CI [1.58-6.70]) than exposure to either alone. Family history of any cancer with onset before age 50 in at least 1 first degree relative was a significant risk predictor (OR = 1.70, 95% CI [1.10-2.64]). Individuals with a self-reported physician-diagnosed history of hay fever, but not asthma, had a decreased lung cancer risk (OR = 0.57, 95% CI [0.35-0.92]). In the multivariate analysis, exposure to ETS and dusts, and family history of cancer with onset before age 50 were significant risk factors, while a history of hay fever (occurring without asthma) was significantly protective.

Adult↗

PubMed2006

An epidemiologic study of early onset lung cancer.

Using cases from an ongoing case-control study, we completed a case series analysis by comparing epidemiologic, clinical and survival characteristics among lung cancer patients characterized by age at diagnosis. Our sample included 230 early onset lung cancer (EOLC) (all Caucasian and no older than 50 years of age at diagnosis) and 426 later-onset cases (LOLC) (all Caucasian and no younger than 70 years of age at diagnosis) who were referred to The University of Texas M.D. Anderson Cancer Center, Houston between 1995 and 2004. Detailed lifestyle, exposure, clinical, survival and self-reported cancer family history data were available from personal interviews. We observed a higher proportion of never smokers (23.9%) for the EOLC cases as compared to the LOLC cases (17.6%) and a higher proportion of former smokers (59.4%) among the LOLC cases compared to EOLC cases (17.8%). Adenocarcinoma was the most common histology (55.2%) among the EOLC cases. More (83.4%) of the EOLC cases presented with stage 3 or 4 lung cancer compared to the LOLC cases (58.6%). Median (M) survival was 16.7 months among the EOLC cases (M = 19.2 months for the LOLC cases) and the 24-month survival rate was 20.6% for the EOLC cases and 29.5% for the LOLC cases. Female EOLC cases (M = 20.7 months) exhibited better survival than male EOLC cases (M = 13.0 months, P = 0.004). EOLC cases diagnosed with squamous cell carcinoma had poorer survival (M = 8.2 months) compared to cases with other histologies (P < 0.001). For both groups, higher stage at presentation was associated with poorer survival (P < 0.001). These findings support the need for further study in the characterization and identification of genetic factors that influence and modulate early onset lung cancer risk and outcome.

Adult↗

PubMed2006

Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes.

The candidate-gene approach in association studies of polygenic diseases has often yielded conflicting results. In this hospital-based case-control study with 696 white patients newly diagnosed with bladder cancer and 629 unaffected white controls, we applied a multigenic approach to examine the associations with bladder cancer risk of a comprehensive panel of 44 selected polymorphisms in two pathways, DNA repair and cell-cycle control, and to evaluate higher-order gene-gene interactions, using classification and regression tree (CART) analysis. Individually, only XPD Asp312Asn, RAG1 Lys820Arg, and a p53 intronic SNP exhibited statistically significant main effects. However, we found a significant gene-dosage effect for increasing numbers of potential high-risk alleles in DNA-repair and cell-cycle pathways separately and combined. For the nucleotide-excision repair pathway, compared with the referent group (fewer than four adverse alleles), individuals with four (odds ratio [OR] = 1.52, 95% CI 1.05-2.20), five to six (OR = 1.81, 95% CI 1.31-2.50), and seven or more adverse alleles (OR = 2.50, 95% CI 1.69-3.70) had increasingly elevated risks of bladder cancer (P for trend <.001). Each additional adverse allele was associated with a 1.21-fold increase in risk (95% CI 1.12-1.29). For the combined analysis of DNA-repair and cell-cycle SNPs, compared with the referent group (<13 adverse alleles), the ORs for individuals with 13-15, 16-17, and >or=18 adverse alleles were 1.22 (95% CI 0.84-1.76), 1.57 (95% CI 1.05-2.35), and 1.77 (95% CI 1.19-2.63), respectively (P for trend = .002). Each additional high-risk allele was associated with a 1.07-fold significant increase in risk. In addition, we found that smoking had a significant multiplicative interaction with SNPs in the combined DNA-repair and cell-cycle-control pathways (P<.01). All genetic effects were evident only in "ever smokers" (persons who had smoked >or=100 cigarettes) and not in "never smokers." A cross-validation statistical method developed in this study confirmed the above observations. CART analysis revealed potential higher-order gene-gene and gene-smoking interactions and categorized a few higher-risk subgroups for bladder cancer. Moreover, subgroups identified with higher cancer risk also exhibited higher levels of induced genetic damage than did subgroups with lower risk. There was a significant trend of higher numbers of bleomycin- and benzo[a]pyrene diol-epoxide (BPDE)-induced chromatid breaks (by mutagen-sensitivity assay) and DNA damage (by comet assay) for individuals in higher-risk subgroups among cases of bladder cancer in smokers. The P for the trend was .0348 for bleomycin-induced chromosome breaks, .0036 for BPDE-induced chromosome breaks, and .0397 for BPDE-induced DNA damage, indicating that these higher-order gene-gene and gene-smoking interactions included SNPs that modulated repair and resulted in diminished DNA-repair capacity. Thus, genotype/phenotype analyses support findings from CART analyses. This is the first comprehensive study to use a multigenic analysis for bladder cancer, and the data suggest that individuals with a higher number of genetic variations in DNA-repair and cell-cycle-control genes are at an increased risk for bladder cancer, confirming the importance of taking a multigenic pathway-based approach to risk assessment.

Aged↗