Associations among telomerase activity, p53 protein overexpression, and genetic instability in lung cancer.

Genomic instability is a driving force for tumorigenesis. p53 and telomerase play central roles in maintaining genomic integrity. The purpose of this study was to assess the associations among p53 protein overexpression, telomerase activity and genetic instability in lung cancer. We found that telomerase activity was detectable in 80% of 100 lung tumours, but only 7.7% of 91 paired adjacent normal tissues. p53 protein was overexpressed in 63% of the tumours but only 2% of the normal tissues. p53 was overexpressed in 56 of the 80 (70%) tumour tissues with telomerase activity but only seven of the 20 (35%) without telomerase activity. p53 protein overexpression carried a 6.7-fold (95% confidence interval, 1.7-27.7) increased risk for positive telomerase activity after adjustment by age, sex, ethnicity, smoking status and family history of lung cancer. The mean in vitro bleomycin-induced breaks per cell (a marker of cancer susceptibility) was significantly higher (0.92) for patients who overexpressed p53 in lung tumour tissue than that for patients with no detectable p53 expression in lung tumour tissue (0.65). Our data suggest that p53 protein overexpression may be common in individuals genetically susceptible to carcinogen exposure. p53 status may be related to telomerase expression.

Benzo[a]pyrene diol epoxide-induced 3p21.3 aberrations and genetic predisposition to lung cancer.

3p deletion, a common chromosome defect in lung cancer, occurs more frequently in the lung tumor tissues of smoking patients than it does in those of nonsmoking patients. This pilot study evaluated whether 3p aberrations induced by benzo[a]pyrene diol epoxide (BPDE), the metabolic product of benzo[a]pyrene, a constituent of tobacco smoke, were more common in the peripheral blood lymphocytes of 40 lung cancer patients than they were in those of 54 matched controls. Our hypothesis was that 3p sensitivity to BPDE reflects the susceptibility of a specific locus to damage from carcinogens in tobacco smoke. BPDE-induced chromosome 3p21.3 aberrations were significantly more frequent in cases (34.1 per 1000) than they were in controls (22.1 per 1000; P < 0.0001). However, no such difference was observed for 6q27, a control locus. Using the median value in the controls (20 per 1000) as a cutoff point to classify BPDE-induced sensitivity at 3p21.3 and after adjustment by age, sex, ethnicity, and smoking status, 3p BPDE sensitivity was associated with an elevated risk of 14.1 (95% confidence interval: 3.5, 56.2) for lung cancer. There was also a dose-response relationship between the degree of BPDE sensitivity at 3p21.3 and increased risk for lung cancer. Therefore, 3p may be a molecular target for BPDE damage in lung cancer cases.

Identifying and recruiting healthy control subjects from a managed care organization: a methodology for molecular epidemiological case-control studies of cancer.

Case-control studies with stringent matching criteria require large pools of healthy subjects from which to select matched controls. This paper describes a successful method of identifying a large pool of potential control subjects to participate in two molecular epidemiological case-control studies of lung cancer, each enrolling 400 case subjects and 400 control subjects. These studies are not population based, and the study base is not well-defined. Therefore, potential control subjects are being identified and recruited through 20 area clinic sites of a large multispecialty health maintenance organization. Because the research focus is driven by genetic hypotheses and we are controlling for multiple smoking-related variables, representativeness is of lesser concern. To identify potential control subjects, a one-page questionnaire is distributed to patients in the waiting room to assess contact information as well as data relevant to the case-control matching process. An average of 2,228 questionnaires are returned monthly toward a target pool of 40,000; of these, 59% of the respondents fulfill eligibility criteria as a control subject for one of the studies and are not averse to being contacted in the future for the purpose of research. When compared to former smokers and never smokers, current smokers in the control population were least likely to refuse further contact. A collaborative arrangement with a managed care organization offers a feasible mechanism through which researchers can access a large, ethnically diverse population of potential control subjects.

Case-control assessment of diet and lung cancer risk in African Americans and Mexican Americans.

In this case-control study we determined whether dietary differences underlie some of the ethnic and sex differences in US lung cancer rates. We examined the relationship between diet and lung cancer development in 137 lung cancer cases (93 African Americans and 44 Mexican Americans) and 187 controls (78 African Americans and 109 Mexican Americans). Cases reported a higher daily mean total fat intake (p < 0.001), whereas controls had a higher daily mean intake of dietary fiber (p < 0.001) and fruits (p = 0.02). Ethnic differences in diet were also observed: Mexican Americans consumed less total fat (p < 0.02) and more fiber (p < 0.001) and vegetables (p = 0.08) than African Americans. Additionally, men consumed more total fat (p = 0.08) and less fiber (p = 0.001), fruits (p < 0.001), and vegetables (p = 0.002) than women. Multivariable analysis, after adjustment for the effects of pack-years of smoking, age, total energy intake, sex, and ethnicity, demonstrated a positive association between high total fat consumption and lung cancer risk (p < 0.01) and an inverse association between high fruit consumption and lung cancer risk (p = 0.05). In conclusion, our findings support the hypothesis that diet, particularly high fat consumption and low fruit and vegetable consumption, contributes (independent of cigarette smoking) to the excess lung cancer risk in African-American men, who have the highest lung cancer rates in the United States.

Higher lung cancer risk for younger African-Americans with the Pro/Pro p53 genotype.

A restriction fragment length polymorphism in codon 72 of the p53 gene has been implicated in lung cancer risk, although the functional significance of the polymorphism has not been determined. This association was examined in 109 lung cancer cases (67 African-American and 42 Mexican-American) and 114 controls (74 African-American and 40 Mexican-American) identified from a molecular epidemiological study of lung cancer. The susceptible Pro/Pro genotype was associated with a 1.56-fold higher risk of lung cancer in African-Americans and a 1.95-fold in Mexican-Americans, although neither estimate was statistically significant. In fact, the prevalence of the Pro/Pro genotype was only 2.5% in Mexican-American controls, compared with 20.3% for African-American controls. Patients with the susceptible genotype appeared to have earlier age at diagnosis and lower mean cigarette pack-year exposures than did patients with the Arg/Arg or Arg/Pro genotypes. Risk estimates for the susceptible genotype were 11.29 (1.1, 111.3) for patients < 53 years of age and 14.1 (1.5, 130.6) for patients who reported < 30 pack-years of smoking. The Pro/Pro genotype was not associated with elevated risk in older patients, nor with heavier smokers. If Pro/Pro is a susceptible genotype, the lower prevalence evident in Mexican-Americans may partly explain their lower rates of lung cancer.

A case-control study of wood dust exposure, mutagen sensitivity, and lung cancer risk.

The associations between lung cancer risk, mutagen sensitivity (a marker of cancer susceptibility), and a putative lung carcinogen, wood dust, were assessed in a hospital-based case-control study. There were 113 African -American and 67 Mexican-American cases with newly diagnosed, previously untreated lung cancer and 270 controls, frequency-matched on age, ethnicity, and sex. Mutagen sensitivity ( 1 chromatid break/cell after short-term bleomycin treatment) was associated with statistically significant elevated risk for lung cancer [odds ration (OR) = 4.3; 95% confidence intervals (CI) = 2.3-7.9]. Wood dust exposure was also a significant predictor of risk (overall OR = 3.5; CI = 1.4-8.6) after controlling for smoking and mutagen sensitivity. When stratified by ethnicity, wood dust exposure was s significant risk factor for African-Americans (OR = 5.5; CI = 1.6-18.9) but not for Mexican-Americans (OR = 2.0; CI = 0.5-8.1). The ORs were 3.8 and 4.8 for non-small cell lung cancer in Mexican-Americans (CI = 1.2-18.5). Stratified analysis suggested evidence of strong interactions between wood dust exposure and both mutagen sensitivity and smoking in lung cancer risk.

Nuclear localization of 68 kDa calmodulin-binding protein is associated with the onset of DNA replication.

In Chinese hamster embryo fibroblast cells, an increase in intracellular calmodulin levels coincided with the nuclear localization of a calmodulin-binding protein of about 68 kDa as the cells progressed from G1 to S phase. When cells were limited from entering into S phase, by omitting insulin a defined medium, intracellular CaM levels did not increase and the 68 kDa calmodulin-binding protein was completely absent from the nuclei. Corresponding to the nuclear localization of calmodulin and the 68 kDa calmodulin-binding protein in S phase cells, there was a dramatic increase in DNA polymerase and thymidine kinase activities in the nuclei of S phase cells as compared to G1 phase cells. In addition, the 68 kDa calmodulin-binding protein, along with calmodulin, is observed to be an integral component of replitase complex responsible for nuclear DNA replication in S phase cells. These observations point to the association of calmodulin and calmodulin-binding protein(s) with the replication machinery responsible for nuclear DNA replication during S phase. A possible regulatory role of these proteins in the onset of DNA replication and cell proliferation is discussed.

On the social ecology of dependence and independence in elderly nursing home residents: a replication and extension.

A sample of 40 elderly residents was observed for 14 days on each of three consecutive occasions separated by 3 months. The observations focused on interactions involving the elderly resident and social partners. The results indicated a high level of stability across occasions in resident behaviors. The interactional and behavioral profiles observed were similar across length of institutionalization, sex, and health status of residents for the institutional context studied. Examination of interactional patterns for the different resident behaviors, however, revealed quite discrepant social contingencies. Following dependent self-care behaviors of residents, interactional responses by social partners represented a continuous supportive behavior contingency; following independent self-care behaviors, no social contingencies were observed. Similarly, obstructively engaged and nonengaged resident behaviors were not followed by any social contingencies; following constructively engaged behaviors of residents, an intermittent supportive contingency by social partners was found. The results are discussed in relation to learned helplessness and control.