Robert M. Chamberlain

Usefulness of cardiovascular family history data for population-based preventive medicine and medical research (The Health Family Tree Study and the NHLBI Family Heart Study) ☆

Detailed medical family history data have been proposed to be effective in identifying high-risk families for targeted intervention. With use of a validated and standardized quantitative family risk score (FRS), the degree of familial aggregation of coronary heart disease (CHD), stroke, hypertension, and diabetes was obtained from 122,155 Utah families and 6,578 Texas families in the large, population-based Health Family Tree Study, and 1,442 families in the NHLBI Family Heart Study in Massachusetts, Minnesota, North Carolina, and Utah. Utah families with a positive family history of CHD (FRS > or =0.5) represented only 14% of the general population but accounted for 72% of persons with early CHD (men before age 55 years, women before age 65 years) and 48% of CHD at all ages. For strokes, 11% of families with FRS > or =0.5 accounted for 86% of early strokes (<75 years) and 68% of all strokes. Analyses of >5,000 families sampled each year in Utah for 14 years demonstrated a gradual decrease in the frequency of a strong positive family history of CHD (-26%/decade) and stroke (-15%/decade) that paralleled a decrease in incidence rates (r = 0.86, p <0.001 for CHD; r = 0.66, p <0.01 for stroke). Because of the collaboration of schools, health departments, and medical schools, the Health Family Tree Study proved to be a highly cost-efficient method for identifying 17,064 CHD-prone families and 13,106 stroke-prone families (at a cost of about

Genetic variations in PI3K-AKT-mTOR pathway and bladder cancer risk

27 per high-risk family) in whom well-established preventive measures can be encouraged. We conclude that most early cardiovascular events in a population occur in families with a positive family history of cardiovascular disease. Family history collection is a validated and relatively inexpensive tool for family-based preventive medicine and medical research.

Racial Disparity in Survival of Patients with Squamous Cell Carcinoma of the Oral Cavity and Pharynx

Genetic variations in phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway may affect critical cellular functions and increase an individuals cancer risk. We systematically evaluate 231 single-nucleotide polymorphisms (SNPs) in 19 genes in the PI3K-AKT-mTOR signaling pathway as predictors of bladder cancer risk. In individual SNP analysis, four SNPs in regulatory associated protein of mTOR (RAPTOR) remained significant after correcting for multiple testing: rs11653499 [odds ratio (OR): 1.79, 95% confidence interval (CI): 1.24-2.60, P = 0.002], rs7211818 (OR: 2.13, 95% CI: 1.35-3.36, P = 0.001), rs7212142 (OR: 1.57, 95% CI: 1.19-2.07, P = 0.002) and rs9674559 (OR: 2.05, 95% CI: 1.31-3.21, P = 0.002), among which rs7211818 and rs9674559 are within the same haplotype block. In haplotype analysis, compared with the most common haplotypes, haplotype containing the rs7212142 wild-type allele showed a protective effect of bladder cancer (OR: 0.83, 95% CI: 0.70-0.97). In contrast, the haplotype containing the rs7211818 variant allele showed a 1.32-fold elevated bladder cancer risk (95% CI: 1.09-1.60). In combined analysis of three independent significant RAPTOR SNPs (rs11653499, rs7211818 and rs7212142), a significant trend was observed for increased risk with an increase in the number of unfavorable genotypes (P for trend <0.001). Compared with the subjects without any of the unfavorable genotypes, those carrying all three unfavorable genotypes showed a 2.22-fold (95% CI: 1.33-3.71) increased bladder cancer risk. This is the first study to evaluate the role of germ line genetic variations in PI3K-AKT-mTOR pathway as cancer susceptibility factors that will help us identify high-risk individuals for bladder cancer.

p73 G4C14-to-A4T14 Polymorphism and Risk of Lung Cancer

Background This study was designed to determine if race and age are independent prognostic factors for survival in patients treated for squamous cell carcinoma of the oral cavity and pharynx. Methods Retrospective study. Results Out of 909 patients registered, 815 (90%) were white and 94 (10%) were African-American. The median age was 60 years (range 1993). The African-American patients had a significantly lower 5 year survival rate of 27.6% (95% CI 19.938.3) compared with white patients with a survival rate of 52.0% (95% CI 48.755.6) (P < 0.001). The greatest racial disparities in survival were observed in patients under 60 years of age [29.2% (95% CI 19.543.6) vs 60.9% (95% CI 56.366.0) for AfricanAmerican and white patients, respectively, P < 0.001], and in African-American men compared with white men [20.2% (95% CI 12.630.2) vs 51.0% (95% CI 46.753.0), P < 0.001]. A multivariate Cox model, stratified according to stage of disease, indicated that race, age, and type of treatment were statistically significant predictors of survival. After adjusting for race and treatment received, African-American patients had a relative risk of dying of 1.61 (95% CI 1.232.10) compared with white patients. All patients 60 years of age and older had a higher risk of dying 1.59 (95% CI 1.311.92). Compared with surgical treatment alone, radiotherapy and other treatments were both associated with increased risk of dying with respective relative risks of 1.34 (95% CI 1.011.76) and 1.94 (95% CI 1.521.48). Conclusions African-American patients had poorer survival outcomes, with race and age emerging as significant independent predictors of survival after treatment for oral and pharyngeal cancer, compared with their white counterparts. Primary and secondary prevention programs that target younger patients at high risk might reduce environmental risk factors such as smoking and alcohol consumption, which may play a greater role in the acquired susceptibility for oral and pharyngeal cancer in African-American males.

Cigarette smoking patterns in patients after treatment of upper aerodigestive tract cancers.

Genetic variants in genes controlling cellular processes such as cell cycle, DNA repair, and apoptosis may modulate lung cancer risk. p73 has some p53-like activity and plays an important role in modulating these processes. The noncoding region of exon 2 of the p73 gene has two polymorphisms that are in complete linkage disequilibrium with one another, which may alter translation efficiency of the p73 protein. To test the hypothesis that this p73 polymorphism plays a role in the etiology of lung cancer, we conducted a hospital-based case-control study of 1054 patients newly diagnosed with lung cancer and 1139 cancer-free controls and evaluated the association between the p73 variant AT allele and risk of lung cancer. Cancer-free controls were frequency matched to the cases by age (±5 years), sex, and smoking status, and all subjects were non-Hispanic whites. The variant AT allele and genotypes were more common among the cases than among the controls (P = 0.0007 and P < 0.001, respectively). Compared with the GC/GC genotype, the variant GC/AT and AT/AT genotypes were associated with a statistically significantly increased risk for lung cancer [adjusted odds ratio (OR) = 1.32, 95% confidence interval (CI), 1.10–1.59 and OR = 1.54, 95% CI, 1.05–2.26, respectively] in an allele dose-effect relationship (trend test: P < 0.001). The risk associated with the AT allele (GC/AT+AT/AT) was more pronounced in younger (≤50 years) individuals (OR = 1.53, 95% CI, 1.00–2.37), men (OR = 1.61, 95% CI, 1.26–2.06), light smokers (OR = 1.58, 95% CI, 1.17–2.14), and squamous cell lung carcinoma (OR = 1.79, 95% CI, 1.32–2.42). These results suggest that this p73 polymorphism may be a marker for susceptibility to lung cancer.

Sex differences in survival in non-small cell lung cancer patients 1974–1998

There is a paucity of data on variables predictive of successful smoking cessation in cancer patients. In this questionnaire-based study, we report the smoking status of 75 patients (46 men, 29 women) with head and neck cancer followed for a minimum of 30 months after definitive therapy. Seventy-one percent of the men and 61% of the women who were current smokers at diagnosis stopped smoking subsequent to diagnosis and treatment. Only 29% and 39%, respectively, continued to smoke, most at decreased intensity. Patients with laryngeal cancer were most likely to have stopped (83%). Conversely, patients with oral cavity cancer were most likely to be continuing smokers (66%). In addition, older age, college education, and lighter smoking habits were somewhat predictive of successful cessation. Fear of recurrent disease and physician advice were the questionnaire-listed incentives most often chosen as contributing to success in cessation. The role health professionals can play in counseling cancer patients to stop smoking is stressed.

Genetic variations of the PI3K-AKT-mTOR pathway and clinical outcome in muscle invasive and metastatic bladder cancer patients

This study comprised a total of 7,553 patients with non-small cell lung cancer (2,660 women and 4,893 men) treated at a comprehensive cancer centre between 1974 and 1998. Significant differences in tumour histology were associated with gender (p < 0.001); adenocarcinoma was the most common diagnosis in both men (50.0%) and women (41.7%); squamous cell carcinoma was the second most prevalent diagnosis (21% and 31% in women and men, respectively); and bronchioalveolar tumours were more prevalent in men (3% compared with 7% in women). Frequency distributions with local, regional or distant disease at registration were similar between men and women (p = 0.906). In a multivariable Cox regression analysis the indications were that gender is an important risk factor for survival. Adjusting for age, stage, treatment received and ability to pay for care, a statistically significant interaction between gender and tumour histology (p = 0.043) was found, where, in relation to female sex and histologies other than squamous carcinoma, women who presented with squamous carcinoma had an increased risk of death (HR = 1.09, 95% CI 1.02-1.18) while men had an increased risk of death for all histologies (HR = 1.29, 95% CI 1.21-1.40, and HR = 1.15, 95% CI 1.07-1.24 for squamous and other histologies, respectively). This study confirms previous reports of strong gender-dependent differences in survival in patients with non-small cell lung cancer, including a histology-specific effect in women.

Association between the V109G Polymorphism of the p27 Gene and the Risk and Progression of Oral Squamous Cell Carcinoma

The phosphoinositide-3 kinase (PI3K)-AKT- mammalian target of rapamycin (mTOR) pathway is an important cellular pathway controlling cell growth, tumorigenesis, cell invasion and drug response. We hypothesized that genetic variations in the PI3K-AKT-mTOR pathway may affect the survival in muscle invasive and metastatic bladder cancer (MiM-BC) patients. We conducted a follow-up study of 319 MiM-BC patients to systematically evaluate 289 single-nucleotide polymorphisms (SNPs) of 20 genes in the PI3K-AKT-mTOR pathway as predicators of survival. In multivariate Cox regression, AKT2 rs3730050, PIK3R1 rs10515074 and RAPTOR rs9906827 were significantly associated with survival. In combined analysis, we found a cumulative effect of these three SNPs on survival. With the increasing number of unfavorable genotypes, there was a significant trend of higher risk of death in multivariate Cox regression (P for trend <0.001) and shorter median survival time in Kaplan-Meier estimates (P log rank <0.001). This is the first study to evaluate the role of germ line genetic variations in the PI3K-AKT-mTOR pathway genes as predictors of MiM-BC clinical outcomes. These findings warrant further replication in independent populations and may provide information on disease management and development of target therapies.

Polymorphisms in XPD exons 10 and 23 and bladder cancer risk

Purpose: Abnormalities in p27 may alter cell cycle delay required for DNA repair after exposure to carcinogens. A coding exon 1 polymorphism at codon 109 (T→G) in p27 was identified and thought to have an effect on the functions of its protein. We hypothesized that this p27 T109G polymorphism is associated with squamous cell carcinoma of the head and neck (SCCHN) risk. Experimental Design: We tested this hypothesis in a hospital-based case-control study of 713 patients newly diagnosed with SCCHN and 1224 cancer-free controls frequency matched to the cases by age (±5 years), sex, and smoking status. All subjects were non-Hispanic whites. We genotyped for this p27 variant using genomic DNA from each subject. Results: Compared with the p27 109VV variant, the p27 109GG variant was associated with a nonsignificantly increased risk of SCCHN [crude odds ratio (OR) = 1.29; 95% confidence interval (CI) = 0.88–1.90; adjusted OR = 1.20; 95% CI = 0.81–1.77], but the risk was statistically significant among men (adjusted OR = 1.55, 95% CI = 1.00–2.42), current alcohol users (adjusted OR = 1.68, 95% CI = 1.01–2.82), and patients with oral cavity cancer (adjusted OR = 1.77, 95% CI = 1.03–3.04). The p27 109GG variant was also associated with oral tumor overall stage, suggesting that it may play a role in tumor progression. Conclusions: Our findings suggest that the p27 109GG variant genotype may not play a major role in the etiology of SCCHN but may be associated with an increased risk in at-risk subgroups or subsets of SCCHN, particularly oral cavity cancer and possibly tumor progression. Larger studies with oral squamous cell carcinoma are needed to verify these findings.

Genotypes and haplotypes of ERCC1 and ERCC2/XPD genes predict levels of benzo[a]pyrene diol epoxide-induced DNA adducts in cultured primary lymphocytes from healthy individuals: a genotype-phenotype correlation analysis

Introduction: The nucleotide excision repair gene, xeroderma pigmentosum complementation group D (XPD), has been hypothesized to have a role in cancer risk, but results from prior molecular epidemiologic studies and genotype-phenotype analyses are conflicting. Materials and Methods: We examined the frequency of the XPD Asp312Asn polymorphism in exon 10 and the XPD Lys751Gln polymorphism in exon 23 in 505 incident bladder cancer cases and 486 healthy controls. Results: Overall, the XPD exon 10 and 23 genotypes were not associated with bladder cancer risk, after adjusting for age, sex, ethnicity, and smoking status. A gender-specific role was evident that showed an increased risk for women, but not for men, associated with the variant genotypes for both exons. For example, when the exon 23 variant allele genotypes were combined (Lys/Gln + Gln/Gln), there was an increased bladder cancer risk in women [odds ratio (OR), 1.69; 95% confidence interval (95% CI), 1.12-2.58] but not in men (OR, 0.99; 95% CI, 0.79-1.24; Pinteraction = 0.041; OR, 1.62; 95% CI, 1.02-2.58). There was also a gene-smoking interaction that showed the variant alleles for either exon or the combination of both increase the risk of bladder cancer for light and heavy smokers. For exon 23 (Pinteraction = 0.057; OR, 1.21; 95% CI, 0.99-1.47), heavy smokers (≥20 pack-years) who carried the exon 23 variant allele genotypes had an OR of 4.13 (95% CI, 2.53-6.73), whereas heavy smokers with the wild-type genotypes were at lower risk (OR, 3.55; 95% CI, 2.19-5.75). Moderate smokers (1-19 pack-years) with the variant allele genotypes had an OR of 1.54 (95% CI, 0.94-2.53), whereas moderate smokers with the wild-type genotypes had an OR of 1.12 (95% CI, 0.63-1.98). Conclusions: Although we did not observe main effects associated with the XPD genotypes, these results do suggest the variant allele genotypes were associated with increased bladder cancer risk in women and smokers with statistically significant interactions in the exon 23 polymorphism. Although there is biological plausibility, these novel findings for gender and smoking should be interpreted with caution upon confirmation in larger studies.