Evolutionary evidence of the effect of rare variants on disease etiology.

The common disease/common variant hypothesis has been popular for describing the genetic architecture of common human diseases for several years. According to the originally stated hypothesis, one or a few common genetic variants with a large effect size control the risk of common diseases. A growing body of evidence, however, suggests that rare single-nucleotide polymorphisms (SNPs), i.e. those with a minor allele frequency of less than 5%, are also an important component of the genetic architecture of common human diseases. In this study, we analyzed the relevance of rare SNPs to the risk of common diseases from an evolutionary perspective and found that rare SNPs are more likely than common SNPs to be functional and tend to have a stronger effect size than do common SNPs. This observation, and the fact that most of the SNPs in the human genome are rare, suggests that rare SNPs are a crucial element of the genetic architecture of common human diseases. We propose that the next generation of genomic studies should focus on analyzing rare SNPs. Further, targeting patients with a family history of the disease, an extreme phenotype, or early disease onset may facilitate the detection of risk-associated rare SNPs.

Comparison of discriminatory power and accuracy of three lung cancer risk models.

BACKGROUND: Three lung cancer (LC) models have recently been constructed to predict an individual's absolute risk of LC within a defined period. Given their potential application in prevention strategies, a comparison of their accuracy in an independent population is important. METHODS: We used data for 3197 patients with LC and 1703 cancer-free controls recruited to an ongoing case-control study at the Harvard School of Public Health and Massachusetts General Hospital. We estimated the 5-year LC risk for each risk model and compared the discriminatory power, accuracy, and clinical utility of these models. RESULTS: Overall, the Liverpool Lung Project (LLP) and Spitz models had comparable discriminatory power (0.69), whereas the Bach model had significantly lower power (0.66; P=0.02). Positive predictive values were highest with the Spitz models, whereas negative predictive values were highest with the LLP model. The Spitz and Bach models had lower sensitivity but better specificity than did the LLP model. CONCLUSION: We observed modest differences in discriminatory power among the three LC risk models, but discriminatory powers were moderate at best, highlighting the difficulty in developing effective risk models.

Dietary boron and hormone replacement therapy as risk factors for lung cancer in women.

Hormone replacement therapy (HRT) may reduce lung cancer risk. Dietary boron may have actions similar to those of HRT; however, no previous study has reported the associations between dietary boron intake and lung cancer risk or the joint effects of boron intake and HRT use on lung cancer risk. The authors examined the associations between boron intake and the joint effects of boron intake and HRT on lung cancer risk in women. In an ongoing case-control study in Houston, Texas (July 1995 through April 2005, end date for this analysis), 763 women were diagnosed with lung cancer, and 838 were matched healthy controls with data on both diet and HRT. Multiple logistic regression analyses were conducted to assess the associations between dietary boron and HRT with lung cancer risk. After adjustment for potential confounders, the odds ratios for lung cancer with decreasing quartiles of dietary boron intake were 1.0, 1.39 (95% confidence interval (CI): 1.02, 1.90), 1.64 (95% CI: 1.20, 2.24), and 1.95 (95% CI: 1.42, 2.68) mg/day, respectively, for all women (p(trend) < 0.0001). In joint-effects analyses, compared with women with high dietary boron intake who used HRT, the odds ratio for lung cancer for low dietary boron intake and no HRT use was 2.07 (95% CI: 1.53, 2.81). Boron intake was inversely associated with lung cancer in women, whereas women who consumed low boron and did not use HRT were at substantial increased odds.

Expression of methylation-related genes is associated with overall survival in patients with non-small cell lung cancer.

The abnormality of DNA methylation is involved in tumour progression, and thus has a modulating effect on clinical outcome of cancer patients. In this study, we measured the mRNA expression levels of three methylation-regulating genes (DNMT1, DNMT3b, and MBD2) in 148 tumour samples from patients with non-small cell lung cancer (NSCLC) using quantitative real-time polymerase chain reaction and then determined their prognostic values. Our data showed that the high level of DNMT1 expression was significantly associated with an increased risk of death in all NSCLC patients (hazard ratio (HR), 1.74; 95% confidence interval (95% CI), 1.04-2.90). However, the high level of DNMT3b expression was significantly associated with poor prognosis only in young patients (<65 years). The high level of MBD2 expression had a significantly reduced risk for death only in male patients and in squamous cell lung carcinoma (SQLC) patients. All three combination groups with DNMT1 and DNMT3b, DNMT1 and MBD2 or DNMT3b and MBD2 revealed significant combined effects in male patients and SQLC patients. Our results suggest that DNMT1, DNMT3b, and MBD2 may play important roles in modulating NSCLC patient survival and thus be useful for identifying NSCLC patients who would benefit most from aggressive therapy.

Neuroblastoma: case-control analysis of birth characteristics.

The peak incidence of neuroblastoma during early infancy indicates that prenatal factors may play a role in the pathogenesis of this disease. A population-based case-control study was conducted comparing birth certificate data of 157 children who later died from neuroblastoma in Texas with 314 controls randomly selected from all Texas live births. Analysis of birth certificate data revealed a protective relative risk estimate for preterm births (less than 37-wk gestation), with an overall odds ratio of 0.29 (95% confidence limits of 0.10-0.86). This effect was independent of birth weight and ethnic group. A statistically significant odds ratio of 3.22 was detected for term babies whose birth weight was low. The findings suggest that the fetus is susceptible to an in utero oncogenic initiator or promoter during the last 4 weeks of gestation.

Mutagen sensitivity in patients with head and neck cancers: a biologic marker for risk of multiple primary malignancies.

Eighty-four patients with head and neck cancers were evaluated for in vitro sensitivity to mutagens and then followed longitudinally for development of multiple primary malignancies. We assessed mutagen sensitivity by exposing lymphocytes to bleomycin in vitro and quantitating the bleomycin-induced chromosomal breaks per cell. The mutagen-hypersensitive patients, ie, those who expressed greater than 1.0 break per cell, were significantly more likely to develop multiple primary cancers than were patients who were less sensitive (less than or equal to 1.0 break per cell) (relative risk = 4.4; 95% confidence limits = 1.2, 15.8). This relationship was independent of age, sex, site, and treatment of first primary cancer and tobacco or alcohol exposures. Sensitivity to bleomycin-induced chromosomal damage serves as an indicator of genetic susceptibility to multiple primary malignancies in patients with head and neck cancers.

Seasonal diagnosis of Hodgkin's disease among young adults.

Among 3,707 incident cases of Hodgkin's disease analyzed by month of initially confirmed diagnosis, there was no evidence of seasonal variation for boys or girls (less than 15 yr old) or for older persons (greater than or equal to 40 yr old). However, for young adults (15-39 yr old) there was significant fluctuation of month of diagnosis. February was the month of peak diagnosis both among young men (P = .002) and among young women, although not significant at conventional levels (P = .30). This seasonal variation is consistent with the hypothesis that Hodgkin's disease in young adults is the rare manifestation of a prevalent infection with low pathogenicity.

Incidence of testicular cancer in the United States related to marital status, histology, and ethnicity.

Analyses were made of the marital status of 3,346 patients with the diagnosis of testicular cancer. Among whites, blacks, and Puerto Rico Hispanics, the risk was greater among single than married men. Among whites and both Puerto Rico and New Mexico Hispanic groups, the elevated risk was apparent for histologic types other than seminoma. Among single white men, this excess risk began after 25-29 years of age. During the 10 years 1973 through 1982, incidence increased among single men under age 45, but little increase in incidence was found for married men. There was a striking increase among single men ages 30-44. These data confirm that single men are more susceptible to non-seminoma testicular cancer than are married men after the age of 30. Testicular cancer is increasing fastest among single men of ages 30-44.

Joint effect of insulin-like growth factors and mutagen sensitivity in lung cancer risk.

BACKGROUND: We hypothesize that accumulation of genetic damage is dependent on an individual's intrinsic carcinogen sensitivity and on various humoral factors (e.g., insulin-like growth factors [IGFs]) that enhance proliferation, resistance to apoptotic cell death, and clonal outgrowth of genetically damaged cells. We tested this hypothesis by determining whether proliferation potential and genetic instability are associated with the risk of lung cancer. METHODS: In a study of 183 lung cancer patients and 227 matched control subjects, we examined the joint effects of latent genetic instability (measured as mutagen sensitivity) and elevated proliferation potential (assessed by measuring IGFs) in lung cancer risk. Levels of IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in plasma were measured by use of immunoassay kits. Mutagen sensitivity was assessed by quantitating bleomycin- and benzo[a]pyrene diol epoxide (BPDE)-induced chromatid breaks in peripheral blood lymphocyte cultures. RESULTS: Although not statistically significant, the mean levels of IGF-I and the molar ratio of IGF-I/IGFBP-3 were higher in patients with advanced or poorly differentiated disease than in patients with early or well-differentiated disease. Variation in IGFs was not associated with any specific histologic type or tumor stage. High levels of IGF-I and enhanced mutagen sensitivity were individually associated with increased risk of lung cancer: odds ratio (OR) of 2.13 (95% confidence interval [CI] = 1.20-3.78) for IGF-I, 2.50 (95% CI = 1. 49-4.20) for bleomycin sensitivity, and 2.95 (95% CI = 1.72-5.06) for BPDE sensitivity. The OR was statistically significantly elevated to 8.88 for both higher IGF-I and bleomycin sensitivity (95% CI = 3.67-21.50) and to 13.53 for higher IGF-I and BPDE sensitivity combined (95% CI = 4.48-40.89). With all three risk factors considered together, the OR was 17.09 (95% CI = 4.16-70.27). High levels of IGFBP-3 alone were associated with reduced lung cancer risk: OR = 0.59 (95% CI = 0.33-1.05). CONCLUSIONS: Our data suggest that individuals with genetic instability and higher proliferation potential are at enhanced risk for lung cancer.

Molecular epidemiology and retinoid chemoprevention of head and neck cancer.

Head and neck cancer is a major worldwide health problem; it has been estimated that approximately 900,000 people were diagnosed with this disease in 1995. Patients are generally treated with surgery and/or radiation therapy. Treatment, especially of patients with early stage (I or II) head and neck squamous cell carcinoma, is often successful. A serious concern, however, is the fact that these patients subsequently develop second primary tumors at an annual rate of 4%-7%. Molecular analyses of premalignant and malignant tissues have produced strong evidence that clonal genetic alterations occur during the early stage of aerodigestive tract carcinogenesis. Although the roles of tobacco and diet in head and neck carcinogenesis have been the subjects of epidemiologic investigations for many years, it has only recently become possible to integrate information regarding genetic susceptibility factors into the development of comprehensive risk models for these cancers. The molecular and epidemiologic studies provide the foundation on which clinical trials can be designed to evaluate the role of retinoids and other compounds in the reversal of premalignancy and the prevention of second primary tumors (i.e., in chemoprevention). This translational approach has led to studies of the utility of intermediate end point markers, such as the nuclear retinoic acid receptors, in chemoprevention strategies. Given the rapid advances occurring in this area of research, it may soon be possible to use these biomarkers to identify patients who are most at risk for developing head and neck cancer and who are most likely to benefit from chemopreventive interventions.

Incidence of prostate cancer and marital status.

Analyses were made of the marital status of 48,106 men with adenocarcinoma of the prostate, who were reported to the Surveillance, Epidemiology, and End Results program of the National Cancer Institute during the 9 years ending in 1981. The hypothesis tested was that widowers and possibly divorced men were at higher risk for developing this cancer than were married men. Age- and marital-specific incidence rates were calculated for 4 age groups (45-54, 55-64, 65-74, and greater than or equal to 75 yr) for U.S. white, black, and Puerto Rico Hispanic men. Risks for other marital status groups were calculated relative to "married." Among the 45-54 age group, all ethnic groups had an excess risk for widowed as compared to the risk for married men [whites, relative risk (RR) = 1.7; blacks, RR = 1.5; Hispanics, RR = 2.5]. These excesses were not significantly different from unity. In the other 3 age groups and among each ethnic group, among whom 97.3% of all prostate cancers occurred, there was no suggestion of an excess risk for the development of prostate cancer among widowed men relative to married men. Unexpected findings were significant deficits in risk for single, separated, and divorced white men as compared to the risk for married men. Thus this study does not support an association between widowerhood and an increased risk for the development of prostate cancer. Additional studies are required to investigate a suggestion of decreased risk for older, separated, and divorced men.

Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis.

BACKGROUND: Insulin-like growth factors (IGFs), in particular IGF-I and IGF-II, strongly stimulate the proliferation of a variety of cancer cells, including those from lung cancer. To examine the possible causal role of IGFs in lung cancer development, we compared plasma levels of IGF-I, IGF-II, and an IGF-binding protein (IGFBP-3) in patients with newly diagnosed lung cancer and in control subjects. METHODS: From an ongoing hospital-based, case-control study, we selected 204 consecutive patients with histologically confirmed, primary lung cancer and 218 control subjects who were matched to the case patients by age, sex, race, and smoking status. IGF-I, IGF-II, and IGFBP-3 plasma levels were measured by enzyme-linked immunosorbent assay and then divided into quartiles, based on their distribution in the control subjects. Associations between the IGF variables and lung cancer risk were estimated by use of odds ratios (ORs). Reported P values are two-sided. RESULTS: IGF and IGFBP-3 levels were positively correlated (all r>.27; all P<.001). High plasma levels of IGF-I were associated with an increased risk of lung cancer (OR = 2.06; 95% confidence interval [CI] = 1.19-3.56; P = .01), and this association was dose dependent in both univariate and multivariate analyses. Plasma IGFBP-3 showed no association with lung cancer risk unless adjusted for IGF-I level; when both of these variables were analyzed together, high plasma levels of IGFBP-3 were associated with reduced risk of lung cancer (OR = 0.48; 95% CI = 0.25-0.92; P = .03). IGF-II was not associated with lung cancer risk. CONCLUSIONS: Plasma levels of IGF-I are higher and plasma levels of IGFBP-3 are lower in patients with lung cancer than in control subjects. If these findings can be confirmed in prospective studies, measuring levels of IGF-I and IGFBP-3 in blood may prove useful in assessing lung cancer risk.

Ethnic patterns of Hodgkin's disease incidence among children and adolescents in the United States, 1973-82.

The descriptive epidemiologic findings were summarized on 1,109 patients (white, black, and Hispanic) under 20 years of age who were diagnosed with Hodgkin's disease as reported to the Surveillance, Epidemiology, and End Results ("SEER") Program of the National Cancer Institute from 1973 to 1982. Across all ethnic strata, incidence rates increased with advancing age at diagnosis, with white adolescents 15-19 years old exhibiting the highest rates (male, 3.67; female, 4.18). Gender difference among children 0-14 years of age was most evident in blacks (male:female ratio: 4.0 for blacks, 1.0 for whites). Highest adolescent:childhood ratios of incidence rates were noted for females (5.81 for whites and 8.29 for New Mexico Hispanics) and lowest, for Hispanic males (1.25, New Mexico; 2.15, Puerto Rico). Whites exhibited the highest percentage of the nodular sclerosis histologic subtype (65%) and Hispanics, the lowest (45%). Conversely, Hispanics had higher rates of histologic types associated with a poorer prognosis (mixed cellularity and lymphocyte depletion). These differing age and histologic patterns were consistent with previously described international patterns of disease occurrence. Analysis of secular trends for whites from 1969 to 1982 revealed relatively stable rates for youngest ages and male adolescents. Rates increased over time for white female adolescents, but the trend was not statistically significant.

Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study.

BACKGROUND: Only a fraction of cigarette smokers develop lung cancer, suggesting that people differ in their susceptibility to this disease. We investigated whether differences in DNA repair capacity (DRC) for repairing tobacco carcinogen-induced DNA damage are associated with differential susceptibility to lung cancer. METHODS: From August 1, 1995, through April 30, 1999, we conducted a hospital-based, case-control study of 316 newly diagnosed lung cancer patients and 316 cancer-free control subjects matched on age, sex, and smoking status. DRC was measured in cultured lymphocytes with the use of the host-cell reactivation assay with a reporter gene damaged by a known activated tobacco carcinogen, benzo[a]pyrene diol epoxide. Statistical tests were two-sided. RESULTS: Overall, lower DRC was observed in case patients than in control subjects (P:<.001) and was associated with a greater than twofold increased risk of lung cancer. Compared with the highest DRC quartile in the control subjects and after adjustment for age, sex, pack-years of smoking, family history of cancer, and other covariates, reduced DRC was associated with increased risk of lung cancer in a dose-dependent fashion (odds ratio [OR] = 1.8 with 95% confidence interval [CI] = 1.1-3.1, OR = 2.0 with 95% CI = 1.2-3.4, and OR = 4. 3 with 95% CI = 2.6-7.2 for the second, third, and fourth quartiles, respectively; P:(trend)<.001). Case patients who were younger at diagnosis (<60 years old), female, or lighter smokers or who reported a family history of cancer exhibited the lowest DRC and the highest lung cancer risk among their subgroups, suggesting that these subgroups may be especially susceptible to lung cancer. CONCLUSION: The results provide evidence that low DRC is associated with increased risk of lung cancer. The findings from this hospital-based, case-control study should be validated in prospective studies.

Benzo[a]pyrene diol epoxide and bleomycin sensitivity and susceptibility to cancer of upper aerodigestive tract.

BACKGROUND: Tobacco smoking is an established risk factor for cancers of the upper aerodigestive tract, and measurement of chromosomal aberrations, i.e., chromatid breaks, induced in lymphocytes in vitro by bleomycin has been shown to be a predictor of risk for these cancers. In a case-control study, we recruited case subjects who were previously treated with surgery and/or radiotherapy for stage I or stage II squamous cell carcinoma of the head and neck to test the hypothesis that lymphocytic chromatid breaks induced by benzo[a]pyrene diol epoxide (BPDE), a tobacco mutagen, may also be associated with risk of developing cancers of the upper aerodigestive tract. METHODS: Case subjects were matched to control subjects on the basis of age, sex, ethnicity, and smoking status. Primary lymphocytes from 67 case subjects and 81 control subjects were treated with 2 microM BPDE for 24 hours, and the frequency of induced chromatid breaks was determined. All statistical tests were two-sided. RESULTS: Lymphocytes from case subjects compared with lymphocytes from control subjects showed significantly more breaks per cell induced by BPDE (mean+/-standard deviation, 0.77+/-0.38 versus 0.49+/-0.25; P<.001). Lymphocytes from 64.2% of case subjects were sensitive to BPDE (using a cutoff value of > or =0.60 break per cell). Subjects in the highest quartile of chromatid breaks had an approximately 20-fold increased risk of cancer compared with those in the lowest quartile after adjustment for age, sex, ethnicity, and smoking status. The association between BPDE sensitivity and cancer risk was higher in former smokers than in current smokers and higher in younger patients than in older patients. Subjects with sensitivity to both BPDE and bleomycin were at a 19.2-fold increased risk of cancer compared with those who were not sensitive to either agent. CONCLUSIONS: Mutagen sensitivity assays may aid in identifying individuals at risk of cancer, and use of parallel assays with two mutagens may improve risk predictability.

Mutagen sensitivity as a risk factor for second malignant tumors following malignancies of the upper aerodigestive tract.

BACKGROUND: Second malignant tumors in patients successfully treated for an initial cancer of the upper aerodigestive tract are an important cause of morbidity and mortality. Biologic markers capable of identifying high-risk subgroups of patients who could be targeted for intensive clinical surveillance, therefore, have immense therapeutic and prognostic relevance. We previously demonstrated in a pilot study of 84 patients with cancers of the upper aerodigestive tract that mutagen sensitivity was a significant predictor of risk of developing second malignant tumors. PURPOSE: We extended the study to include 278 patients diagnosed with previously untreated cancers of the upper aerodigestive tract from 1987 to August 1993. METHODS: For each patient, base-line (pretreatment) mutagen sensitivity was measured in vitro in 50 metaphases established from peripheral lymphocyte cultures. Patients with an average of more than 1 chromosomal break/cell were deemed mutagen hypersensitive. Cox proportional hazards analysis was used to predict the risk of developing second malignant tumors associated with mutagen sensitivity. RESULTS: Overall, 44% of the case group exhibited mutagen hypersensitivity. There were no differences in the distribution of mutagen hypersensitivity by site, sex, stage of disease, or smoking status. There were 17 synchronous and 11 metachronous cancers, of which 15 (54%) were smoking-related malignancies. Sixteen (13.1%) of the mutagen-sensitive patients developed second malignant tumors, compared with 12 (7.7%) of the nonsensitive patients. The mean break/cell value (+/- SD) for patients developing second malignant tumors was 1.17 (+/- 0.54), compared with 0.98 (+/- 0.44) for patients with only one cancer (P = .04). Mutagen hypersensitivity conferred a relative risk of 2.67 (95% confidence interval = 1.22-5.79) of developing second malignant tumors. CONCLUSIONS: Mutagen hypersensitivity increases the risk of developing second malignant tumors. IMPLICATIONS: Future research should focus on the molecular mechanisms underlying mutagen sensitivity.

Case-control study of the D2 dopamine receptor gene and smoking status in lung cancer patients.

BACKGROUND: Interindividual differences in the structure and expression of the dopamine receptor genes affect dopamine availability and may be the genetic basis for variation in vulnerability to tobacco smoking. In this study, prevalences of polymorphisms in the TaqIA allele (A1 and A2) and the TaqIB allele (B1 and B2) of the D2 dopamine receptor gene in 157 lung cancer case patients and 126 control subjects were determined to assess whether individuals homozygous or heterozygous for the less common A1 and B1 alleles are more vulnerable to nicotine addiction. METHODS: Case and control subjects were accrued from an ongoing epidemiologic study. Blood samples were collected from them and subjected to molecular genetic analyses. Subjects were interviewed to obtain relevant information. Current and former smokers were administered a questionnaire to quantify their addiction to nicotine. RESULTS: The combined B1B2 genotypes appeared to be more prevalent in ever smokers than in never smokers among case patients (30.3% versus 13.3%; two-sided P = .233) and among control subjects (30.9% and 0%; two-sided P = .02); statistically significant differences were not observed among those with A1 genotypes. Statistically significant correlations between the presence of the A1 and B1 alleles were observed (r = .73 for case subjects and r = .76 for control subjects; two-sided P<.001). Individuals with rarer genotypes reported having been substantially younger at the time of smoking initiation (statistically significant for both A1 and B1) and having attempted to quit smoking fewer times (statistically significant for only A1). CONCLUSION: Variant alleles of the D2 dopamine receptor gene may play a role in determining nicotine addiction, although the associations between the at-risk genotypes and measures of nicotine addiction were not entirely consistent.

Genetic susceptibility to head and neck squamous cell carcinoma.

BACKGROUND: In addition to influences of exposure to carcinogenic compounds, the development of cancer may depend on an individual intrinsic cancer susceptibility. Biomarkers for cancer susceptibility can be powerful additions to epidemiologic analyses. PURPOSE: This multicenter, case-control analysis combines previously published data and new data to substantiate the value of mutagen sensitivity as a biomarker of susceptibility to head and neck squamous cell carcinoma and, more importantly, to gain insight into the interaction between susceptibility and exposure to carcinogens. METHODS: Mutagen sensitivity (mean number of chromatid breaks per cell of cultured lymphocytes treated with bleomycin in the late S-G2 phase of the cell cycle) was determined in 313 patients with head and neck cancer and in 334 control subjects at two major U.S. medical institutions and one European institution, yielding a unique study population. The ages of the case and control subjects, as well as their history of use of tobacco and alcohol, were also recorded. The relationships between variables were analyzed by use of Student's t tests, Spearman's rank correlations, and multiple linear regression. For estimation of cancer risk, crude odds rations (ORs) were measured and multiple logistic regression was performed. All P values were based on two-sided tests. RESULTS: There were no differences across institutions in the distribution of mutagen sensitivity (Kruskal-Wallis test) for both case subjects and control subjects. Values for case subjects were consistently and significantly (P<.0001) higher than values for control subjects in the overall analyses. Age and tobacco or alcohol use did not influence the outcome in terms of mutagen-sensitivity values for either the case or the control subjects. A mean number of breaks per cell dichotomized at 1.0 was found to be the best predictor of a hypersensitive phenotype. For nonsensitive, heavy smokers, the OR was 11.5 (95% confidence interval [CI] = 5.0-26.6). This risk increased dramatically in mutagen-hypersensitive, heavy smokers to 44.5 (95% CI = 17.4-114.0). Multiple logistic regression analysis confirmed these results, and a significant trend was found (P<.01) for the dose-dependent increase in cancer risk by smoking. The consumption of alcohol potentiated the effects of smoking, resulting in an OR of 57.5 (95% CI = 17.5-188.0) in hypersensitive persons. CONCLUSIONS: Mutagen sensitivity was found to be a biomarker of cancer susceptibility. This study underscores the importance of utilizing both susceptibility markers and the exposure data for the identification of persons at high risk of developing cancer. IMPLICATIONS: More accurate risk estimation can define susceptible subgroups who might be targeted for intensive behavioral interventions, surveillance through screening, and enrollment in chemoprevention programs.

A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter enhances lung cancer susceptibility.

Extracellular matrix-degrading matrix metalloproteinase-1 (MMP-1) is one of the interstitial collagenases likely to be involved in tumor invasion and metastasis. MMP-1 may also contribute to tumor initiation and development by altering the cellular microenvironment that facilitates tumor formation. Recent studies have found that overexpression of MMP-1 is associated with the initial stages of cancer development in addition to promoting cellular invasion; however, preexisting oncogenic mutations or chemical carcinogens are required to initiate tumorigenesis as well. There is a single nucleotide polymorphism located in the promoter region of MMP-1 that partially regulates gene expression. The 2G/2G genotype enhances transcriptional activity and may be associated with an increased lung cancer risk. Using a case-control study, we tested the hypotheses that (a) individuals with the 2G/2G genotype may be at an increased risk for lung cancer; and (b) the risk should be greatly elevated in smoking individuals. PCR-RFLP was used to determine the MMP-1 genotypes in 456 lung-cancer cases and 451 frequency-matched controls of Caucasian ethnicity. Overall, there was a significant association between the 2G/2G genotype and lung cancer risk [odds ratio (OR), 1.76; 95% confidence interval (CI), 1.29-2.39]. In current smokers, the lung cancer risk associated with the 2G/2G genotype was significantly elevated (OR, 3.16; 95% CI, 1.87-5.35). However, this association was less evident in former smokers (OR, 1.23; 95% CI, 0.81-1.87) and absent in never smokers (OR, 1.09; 95% CI, 0.31-3.91). Similarly, this risk was more evident in heavy smokers (OR, 2.55; 95% CI, 1.61-4.03) than in light smokers (OR, 1.40; 95% CI, 0.84-2.32). Interestingly, men were observed to have a 2.15-fold increased lung cancer risk (OR, 2.15; 95% CI, 1.42-3.26) compared with women (OR, 1.34; 95% CI, 0.84-2.15). Furthermore, subjects with 2G/2G genotype developed lung cancer earlier (60.94 +/- 0.64 years old) than patients with 1G/1G and 1G/2G genotypes (62.91 +/- 0.59 years old; P = 0.024). Our data demonstrate that the 2G/2G genotype enhances lung cancer susceptibility especially in current smokers. To our knowledge, these results report the first molecular epidemiological evidence of the MMP-1 promoter polymorphism associated with the development of lung cancer in the presence of continuing carcinogenic exposure.

Reduced DNA repair capacity in lung cancer patients.

Although lung cancer is the paradigm of a tobacco-induced malignancy, host-specific factors modulate susceptibility to tobacco carcinogenesis. Variations in DNA repair may influence the rate of removal of DNA damage and of fixation of mutations. To test the hypothesis that genetically determined DNA repair capacity (DRC) modulates lung cancer susceptibility, we conducted a pilot case-control study of 51 patients with newly diagnosed, previously untreated lung cancer and 56 controls identified from local community centers and frequency matched to the cases on age, sex, and ethnicity. The subjects were ascertained and interviewed for an ongoing molecular epidemiological investigation of lung cancer susceptibility. We measured DRC in the subjects' peripheral blood lymphocytes by using the host-cell reactivation assay, which measures cellular reactivation of a reporter gene damaged by exposure to 75 microM benzo(a)pyrene diol epoxide. The mean level of DRC in cases (3.3%) was significantly lower than that in controls (5.1%) (P < 0.01). Only nine cases (18%) had DNA repair levels greater than the median value of repair in the controls. This median level of DRC in controls was used as the cutoff value for calculating the odds ratios. After adjustment for age, sex, ethnicity, and smoking status, the cases were five times more likely than the controls to have reduced DRC (odds ratio, 5.7; 95% confidence interval, 2.1-15.7). Younger cases (< 65 years) and smokers were more likely than controls to have reduced DRC. These findings suggest that individuals with reduced DRC are at an increased risk of developing lung cancer.