Baldness, acne and testicular germ cell tumours.

Androgen levels during critical periods of testicular development may be involved in the aetiology of testicular germ cell tumours (TGCT). We evaluated the roles of adolescent and early adult life correlates of androgen exposure and TGCT in a hospital-based case-control study. TGCT cases (n=187) and controls (n=148), matched on age, race and state of residence, participated in the study. Unconditional logistic regression was used to estimate associations between TGCT and male pattern baldness, severe acne, markers of puberty onset and body size. Cases were significantly less likely to report hair loss than controls [odds ratio (OR): 0.6; 95% confidence interval (CI): 0.4, 1.0]. Amount of hair loss, increasing age at onset and increasing rate of loss were all inversely associated with TGCT (rate of hair loss: p-trend=0.03; age at onset: p-trend=0.03; amount of hair loss: p-trend=0.01). History of severe acne was inversely associated with TGCT (OR: 0.5; 95% CI: 0.3, 0.9) and height was positively associated with TGCT (p-trend=0.02). Increased endogenous androgen levels during puberty and early adulthood may be associated with a decreased risk of TGCT. Additional studies of endogenous hormone levels during puberty and early adult life are warranted, especially studies evaluating the role of androgen synthesis, metabolism and uptake.

Survival of patients with multiple primary malignancies: a study of 783 patients with gastrointestinal stromal tumor.

BACKGROUND: We sought to investigate the characteristics and survival rate of patients with gastrointestinal stromal tumor (GIST) associated with other primary malignancies. PATIENTS AND METHODS: A total of 783 patients with GIST were identified from 1995 to 2007. Additional primaries included tumors not considered metastasis, invasion, or recurrence of GIST, nor non-melanoma skin cancer. Data on gender, age at diagnosis, follow-up time after diagnosis, and death were collected. RESULTS: Of the 783 patients with GIST, 153(20%) were identified with at least one additional primary. Patients with additional primaries were more often men (M : F 1.5 versus 1.3) and older (66 versus 53 years). More patients had another cancer diagnosed before (134) than after (52) GIST. Primaries observed before GIST were cancers of the prostate (25), breast (12), esophagus (9), and kidney (7) and melanoma (6). Lung (5) and kidney (5) primaries were the most frequent after GIST. The 5-year survival was 68% for patients with primaries before GIST, 61% for patients with primaries after GIST, 58% for patients with GIST only, and 49% for patients with two or more primaries in addition to GIST (P = 0.002). CONCLUSIONS: Approximately 20% of patients with GIST develop other cancers. Inferior median 5-year survival was observed in patients with GIST with two or more other cancers. The etiology and clinical implications of other malignancies in patients with GIST should be investigated.

Risk factors of myelodysplastic syndromes: a case-control study.

Little is known about the etiology of myelodysplastic syndromes (MDS). A hospital-based case-control study of 354 adult de novo MDS cases and 452 controls was conducted to investigate associations between lifestyle characteristics and MDS risk. The distribution by French-American-British (FAB) type was 67 (19%) refractory anemia (RA), 38 (11%) refractory anemia with ringed sideroblasts (RARS), 43 (12%) chronic myelomonocytic leukemia (CMML), 136 (38%) RA with excess blasts (RAEB), and 70 (20%) RAEB in transformation (RAEBT). Multivariate logistic regression analyses were performed among all MDS cases and among each FAB type and gender. For all MDS combined, family history of hematopoietic cancer (odds ratio (OR) = 1.92), smoking (OR = 1.65), and exposure to agricultural chemicals (OR = 4.55) or solvents (OR = 2.05) were associated with MDS risk. Among RA/RARS cases, smoking (OR = 2.23) and agricultural chemical exposure (OR = 5.68) were the only risk factors identified. For RAEB/RAEBT cases, family history of hematopoietic cancer (OR = 2.10), smoking (OR = 1.52), and exposure to agricultural chemicals (OR = 3.79) or solvents (OR = 2.71) were independent risk factors. Drinking wine reduced risk for all FAB types by almost 50% (OR = 0.54). We found a joint effect between smoking and chemical exposure with the highest risk among smokers exposed to solvents/agricultural chemicals (OR = 3.22). Results from this large study suggest that several factors play a role in MDS predisposition with possible joint effects. Risk profiles seem to differ by FAB type and gender.

An intronic poly (AT) polymorphism of the DNA repair gene XPC and risk of squamous cell carcinoma of the head and neck: a case-control study.

Inherited polymorphisms of DNA repair genes may contribute to variations in DNA repair capacity and genetic susceptibility to cancer. In a hospital-based case-control study of 287 non-Hispanic white patients with newly diagnosed SCCHN and 311 control subjects matched on age, sex, ethnicity, and smoking status, we investigated the role of a newly identified variant allele of XPC, XPC-PAT+. We found that the frequency of the XPC-PAT+ allele was higher in the cases (0.409) than in the controls (0.333; P = 0.007). Fifty cases (17.4%) and 37 controls (11.9%) were XPC-PAT+/+, and 135 (47.0%) cases and 133 controls (42.8%) were XPC-PAT+/-. XPC-PAT+/- and XPC-PAT+/+ subjects were at significantly increased risk for SCCHN [adjusted odds ratios = 1.44 and 1.85, respectively (95% confidence intervals, 1.01-2.05 and 1.12-3.05, respectively; trend test, P = 0.007)]. We did not find ethnic difference in the frequency of XPC-PAT+ allele among four groups aged between 19 and 75 years: non-Hispanic whites, 294; African-Americans, 178; Hispanic-Americans, 103; and native Chinese, 119 (0.333, 0.281, 0.296, and 0.353, respectively). The case-control findings support the hypothesis that the XPC-PAT+ allele may contribute to the risk of developing SCCHN.

p53 mutations in nonmelanoma skin cancer of the head and neck: molecular evidence for field cancerization.

Multiple and distinct p53 mutations were detected by DNA sequence analysis in tumor and adjacent nonmalignant skin samples from eight patients with nonmelanoma skin cancer of the head and neck, providing unambiguous evidence for field cancerization. The mutations consisted of C-->T transitions at dipyrimidine sequences (30% of all single base substitutions), T-->C transitions (47%), and G-->T transversions (12%), suggesting that other carcinogens may act along with UV radiation in the development of nonmelanoma skin cancer. Patient interviews revealed that, in addition to substantial exposure to solar UV radiation, most had a history of smoking and were exposed to carcinogens from industrial or agricultural sources. These data show that extensive molecular epidemiological investigations are necessary to elucidate risk factors associated with the disease in localities where patients often report substantial exposure to environmental carcinogens.

Limiting the location of a putative human prostate cancer tumor suppressor gene at chromosome 13q14.3.

We studied loss of heterozygosity (LOH) on human chromosome 13q in prostate cancer specimens to determine the location of a putative tumor suppressor gene (TSG) and to correlate these losses with the clinicopathological stage of the disease. Overall 13 (21%) of 61 specimens analysed had an allele loss on the long arm of chromosome 13. The most frequent (37%) LOH among the informative cases with allele losses was detected at the D13S284 locus on chromosome 13q14. 3. A portion of the DNA segment that spans this locus and is flanked by the microsatellite loci D13S153 and D13S163 was lost in 85% of the specimens with allele losses and was designated as a LOH cluster region (LCR). The LCR spans more than 6 Mbp of DNA. The results suggest that a TSG relevant for the development of prostate cancer is located telomeric to the RB locus. There was a significant correlation (P=0.0024) between chromosome 13q LOH and advanced metastatic disease, suggesting that loss of 13q14.3 region is associated with prostate cancer progression. However, further research must be conducted to establish the identity and function of this putative TSG.

Limiting the location of putative human prostate cancer tumor suppressor genes on chromosome 18q.

We studied loss of heterozygosity (LOH) on the long arm of human chromosome 18 in prostate cancer to determine the location of a putative tumor suppressor gene (TSG) and to correlate these losses with the pathological grade and stage of the cancer. Of 48 specimens analysed 17 (35.4%) lost at least one allele on chromosome 18q. All the specimens with allelic losses lost at least one allele within chromosomal region 18q21. Allelic losses picked at D18S51 (19%) and D18S858 (17%). A 0.58 cM DNA segment that includes the D18S858 locus and is flanked by the microsatellite loci D18S41 and D18S381, was lost in eight (47%) of 17 specimens with allelic losses. This segment was designated as a LOH cluster region 1 (LCR 1). Although Smad2 resides within LCR 1, it was not mutated in any of the six prostate cell lines (five prostate cancer cell lines and one immortalized prostate epithelial cell line) analysed, suggesting that it is not a candidate TSG in prostate cancer. A second LCR at 18q21, LCR 2, includes the D18S51 locus and is flanked by the D18S1109 and D18S68 loci, which are separated by 7.64 cM. LCR 2 was lost in six (35%) of the 17 specimens with chromosome 18q losses. These results suggest that chromosome 18q21 may harbor two candidate prostate cancer TSGs. The candidate TSGs DCC and Smad4 are located centromeric to the LCRs. No alleles were lost within or in close proximity to these genes, suggesting that they are not targets for inactivation by allelic losses in prostate cancer. Although there was no obvious correlation between chromosome 18q LOH and the pathological grade or stage, three (37.5%) of eight low-grade cancers and nine (32.1%) of 28 organ-confined cancers lost alleles at 18q21, suggesting that allelic losses are relatively early events in the development of invasive prostate cancer.

Second cancer risk in hairy cell leukemia: analysis of 350 patients.

PURPOSE: The discovery of effective therapy for hairy cell leukemia (HCL) has increased the relevance of long-term outcome. We have therefore examined the incidence of second cancers. PATIENTS AND METHODS: Data on 350 HCL patients was obtained from the M.D. Anderson Cancer Center Cancer Registry's computerized data base and from chart review. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) (observed/expected [O/E]) were calculated with the expected number determined using age, sex, and calendar-year-specific rates from the Connecticut Tumor Registry and from national mortality data, respectively. RESULTS: The median age of the patients was 50 years and the median follow-up duration was 6 years. Twenty-six patients developed a second cancer at least 6 months after the HCL diagnosis (O/E ratio, 1.34; P = .08). There was no excess of malignancy among patients treated with interferon alfa (IFN-alpha; P = .27), 2-chlorodeoxyadenosine (2CDA; P = .37), or deoxycoformycin (DCF; P = .7). However, an excess of myeloma-related neoplasms (O/E, 13.04; P < .001) and lymphomas (O/E, 8.7; P = .03) was observed. Survival from the advent of systemic therapy for HCL was better than before this time (P = .0009). Nevertheless, mortality remained excessive (O/E, 6.17; P < .001), mainly because of HCL-related infections and secondary malignancy. CONCLUSION: Among 350 patients with HCL, there was an increase in the number of second cancers; however, it did not reach statistical significance and was not associated with therapy. The incidence of lymphoid neoplasms was significantly higher than expected. Survival since the advent of effective systemic therapy was excellent, although excess mortality was still observed.

Lung cancer, smoking patterns, and mutagen sensitivity in Mexican-Americans.

BACKGROUND: Mexican-Americans have lower age-adjusted lung cancer incidence rates than non-Hispanic whites and African-Americans. Since 87% of lung cancers are attributed to tobacco exposure, this difference could be explained partly by lower prevalence of cigarette smoking. However, only a fraction of exposed individuals will develop smoking-related cancer, and genetically determined differences in modulation of environmental exposures could also explain some of this ethnic risk differential in lung cancer incidence in the United States. However, little research on genetic susceptibility has been focused on Hispanic populations in the United States. METHODS: We are conducting a case-control study of lung cancer in a high-risk group (African-Americans) and a low-risk group (Mexican-Americans) to evaluate ethnic differences in mutagen sensitivity by an in vitro assay that quantifies mutagen-induced chromosome breaks in short-term lymphocyte cultures. RESULTS: In the 174 Mexican-Americans (67 lung cancer case patients and 107 control subjects) accrued to date, all measures of cigarette smoking (intensity, duration, nicotine and tar contents, depth of inhalation, and type of cigarette) were significant predictors of lung cancer risk. There were significantly higher risks associated with mutagen sensitivity (defined as > or = 1 break/cell) for both former smokers (odds ratio [OR] = 4.5; 95% confidence interval [CI] = 0.9-21.9) and current smokers (OR = 2.6; 95% CI = 0.6-11.1). Mutagen sensitivity also appeared to be implicated in risk in patients who were less than 55 years old at diagnosis (OR = 15.0; 95% CI = 1.0-228.9) and in those with lower cigarette exposure (OR = 11.0; compared with an OR of 1.7 for the heaviest smokers). The overall OR for mutagen sensitivity adjusted for age, sex, and pack-years of smoking was 2.9 (95% CI = 0.8-9.9). Neither current smoking status nor years of exposure shifted the sensitivity profile of case patients and control subjects. CONCLUSION: Although this study showed higher percentages of nonsmokers among Mexican-Americans than our previously reported data for African-Americans, the Mexican-American case patients were heavier smokers than the African-American case patients. The prevalence of mutagen sensitivity for Mexican-Americans was 64.1% in case patients and 26.2% in control subjects. In African-Americans, mutagen sensitivity was previously reported to be 55.3% in case patients and 24.6% in control subjects. These preliminary data do not support our a priori hypothesis that a lower prevalence of mutagen sensitivity in Mexican-Americans would account for the lower incidence of lung cancer. Mutagen sensitivity, however, is only one of an array of potential susceptibility markers that we are evaluating in this unique population.

Evaluation of sister chromatid exchange and chromosome breaks in a cohort of untreated Hodgkin's disease patients.

Cytogenetic biomarkers, chromosomal breaks [spontaneous breaks (SB) and bleomycin-induced breaks (BIB)], and sister chromatid exchange (SCE) have been shown to be sensitive cytological assays to defect susceptibility to DNA-damaging effects. However, little information is available on how environmental factors and demographic and clinical characteristics influence variation among individuals. We sought to characterize interindividual variability in a cohort of 105 untreated adult Hodgkin's disease patients. SB, BIB, and SCE data were integrated with epidemiological data by using linear regression analysis. Age, sex, ethnicity, education, histology, history of mononucleosis, and family history of cancer showed no association with any biomarker. In univariate analysis, alcohol intake was significantly associated with high SCEs (P = 0.005) and SBs (P = 0.02). Current smoking was associated only with high frequencies of SCE (P = 0.05). Advanced stage of disease was related with high SBs (P = 0.01). BIBs were not associated with any of the variables studied. In multivariate modeling, current alcohol intake was associated with high SCEs (P = 0.04) and SBs (P = 0.01). Former smokers had higher SBs than nonsmokers did (P = 0.02). A small positive correlation was found among each pair of markers. The higher SCEs and SBs in patients who smoke and consume alcohol indicate the need for evaluating these exposures when interpreting these biomarkers.

Alcohol dehydrogenase 3 genotype is not associated with risk of squamous cell carcinoma of the oral cavity and pharynx.

Alcohol is one of the major risk factors for oral and pharyngeal cancer. The rate-limiting step in alcohol metabolism is the oxidation (activation) of ethanol to acetaldehyde by the alcohol dehydrogenases (ADHs). It has been hypothesized that individuals who are homozygous for the fast allele (ADH(1-1)(3)) are at greater risk for alcohol-related cancers. To test this hypothesis, we investigated the association between the ADH3 genotype and oral and pharyngeal cancer risk in a large racially homogeneous case-control study of 229 patients and 575 matched control subjects with frequency matching on age, sex, and smoking status. Although the smoking status was matched between cases and controls, current and former alcohol use remained a significant risk factor, compared with never use (odds ratio, 2.08; 95% confidence interval, 1.37-3.17; odds ratio, 1.97; 95% confidence interval, 1.25-3.09; and odds ratio, 1.00, respectively). The ADH1(3) allele frequency of controls was 57.4%, consistent with reports of similar racial groups (50-60%). The genotype distribution in controls was also consistent with the Hardy-Weinberg equilibrium (P = 0.51). However, the ADH1(3) allele frequency and ADH(1-1)(3) genotype frequency were not significantly different between cases and controls [55.5% versus 57.4% (P = 0.52), and 30.6% versus 31.3% (P = 0.91), respectively]. There was no association between ADH3 genotypes (ADH(1-1)(3), ADH(1-2)(3), and ADH(2-2)(3)) and risk of oral and pharyngeal cancer (odds ratios, 1.00; 0.96; 95% confidence interval, 0.68-1.37; and odds ratio, 1.23; confidence interval, 0.78-1.93, respectively). Therefore, we found no evidence that supports a main effect of ADH3 genotype or a combined effect of alcohol and ADH3 genotype on risk of cancer of the oral cavity or pharynx.

Correlation between selected environmental exposures and karyotype in acute myelocytic leukemia.

Many bone marrow cytogenetic abnormalities in acute myelogenous leukemia (AML) are tumor specific, clonal, nonrandom, and related to prognosis; it has been hypothesized that they may be markers of exposure to etiological agents. A previous report from our institution revealed several such associations; the purpose of the current study was to determine whether previous findings were present in a new group of patients. Subjects included 84 newly diagnosed AML patients (French-American-British M1 and M2); exposure data were gathered using self-report questionnaires at the time of registration. Two sets of comparisons were made: (a) patients with all (AA) or some (AN) cytogenetically abnormal cells versus those with normal karyotypes (NN) and (b) patients with specific abnormalities [-5/5q-, -7/7q-, +8, t(8;21)] versus all others. Odds ratios (ORs) were 4.64 for the association between prior cytotoxic therapy and -5/5q- and 6.38 for the association with -7/7q-, but were <1.00 for +8 and t(8;21). There were no ORs > 2.0 for specific abnormalities in any of the other exposures evaluated (cigarette smoking, alcohol use, occupational exposure to organic chemicals, paints, or pesticides/herbicides), with the exception of exposure to paints and -7/7q- (OR, 7.50). The ORs for AA/AN versus NN patients were 1.43 and 3.81 for smoking and alcohol use, and weak dose-response trends were present. The most consistent positive associations between the two series were for prior cytotoxic therapy (-5/5q-; -7/7q-), cigarette smoking (AA/AN versus NN) and alcohol use (AA/AN versus NN). Reasoning from the known association between prior cytotoxic therapy and -7/7q-, we would have predicted relatively high ORs (> 4.0) if specific abnormalities acted as markers for the exposures assessed, but none were present. However, in both series, AA/AN patients were more likely to smoke and use alcohol than were NN patients, and weak dose-response patterns were present for both. This finding suggests that both smoking and alcohol use may play a role in the pathogenesis of cytogenetic abnormalities in AML-M1/M2; however, the mechanism by which they work and whether they are involved in the etiology of these diseases remain unclear.

DNA repair capacity correlates with mutagen sensitivity in lymphoblastoid cell lines.

This study describes a correlation between cellular DNA repair capacity and the frequency of mutagen-induced in vitro chromosomal breaks in selected lymphoblastoid cell lines. Two assays, host cell reactivation (HCR) assay for measuring cellular DNA repair capacity and in vitro mutagen sensitivity assay, have recently been shown to be useful biomarkers for such susceptibility. Increased in vitro mutagen sensitivity, measured by the number of induced chromatid breaks, has been postulated to reflect decreased capacity of DNA repair, as measured by the HCR assay. However, these two assays have not been examined in parallel to test this hypothesis. In this study, we performed both assays in 16 established lymphoblastoid cell lines derived from patients with xeroderma pigmentosum (n = 3), ataxia telangiectasia (n = 2), head and neck cancer (n = 3), and melanoma (n = 2), and from normal human subjects (n = 6) using UV light, 4-nitroquinoline-1-oxide (4-NQO; an UV-mimetic agent), and gamma-irradiation as the test agents. The measurements from the HCR assay correlated significantly with the frequency of chromatid breaks induced by either UV irradiation (r = -0.69; P < 0.01) or 4-NQO (r = -0.70; P < 0.01). Although published data suggest that damage induced by UV and 4-NQO may be repaired by different pathways, the two agents induced similar frequencies of chromatid breaks (r = 0.68; P < 0.01) in the tested cell lines. Our results also indicated that the HCR assay is not suitable to test agents that cause DNA strand breaks, such as gamma-irradiation, whereas the mutagen sensitivity assay is. Although reduced cellular DNA repair capacity correlated with increased frequency of mutagen-induced chromatid breaks in these cell lines, these two assays have different sensitivities in measuring the repair of damage induced by different carcinogens; therefore, the use of both assays is recommended for future molecular epidemiological studies of cancer susceptibility.

Reduced expression of hMLH1 and hGTBP/hMSH6: a risk factor for head and neck cancer.

Head and neck cancer, like lung cancer, is considered a paradigm of an environmentally induced disease. Genetically determined variation in DNA repair capacity is thought to contribute to susceptibility to tobacco-related cancers. In this molecular epidemiology study, we investigated the association between DNA mismatch-repair (MMR) gene expression and the risk of head and neck cancer. Using our newly developed multiplex reverse transcription-PCR assay, we simultaneously evaluated the relative expression levels of five MMR genes (hMSH2, hMLH1, hPMS1, hPMS2, and hGTBP/hMSH6) in the peripheral blood lymphocytes of 78 patients (mean age = 59.6 +/- 12.4 years) with newly diagnosed head and neck cancer and 86 healthy controls (mean age = 58.2 +/- 12.9 years). The relative MMR gene expression was not correlated with disease stage or tumor site in the cases or with smoking and alcohol use in the controls. The expression levels increased with age in both cases and controls, but the mean expression of hMLH1, hPMS1, and hGTBP/hMSH6 was significantly lower in the cases than in the controls (P < 0.05). Using the median expression level in controls as the cutoff value, significantly increased odds ratios (ORs) were associated only with low expression of hMLH1 (OR = 4.4; 95% confidence interval = 2.1-9.1) and hGTBP/hMSH6 (OR = 2.1; 95% confidence interval = 1.1-4.1) after adjustment for age, sex, ethnicity, smoking status, and alcohol use. The results suggest that low hMLH1 and hGTBP/hMSH6 expression is associated with an increased risk of head and neck cancer. Additional studies with a larger number of subjects are warranted to confirm these findings.

Accuracy of family history of cancer obtained through interviews with relatives of patients with childhood sarcoma.

The purpose of this study was to determine the accuracy of reporting of invasive cancer by relatives for family studies. First, we attempted to evaluate whether a lower than expected cancer rate found in second-degree relatives of children with soft-tissue sarcoma was a result of underreporting. Second, we evaluated the accuracy of reported cancer in two data sets by comparing reported cancer information with documentation by medical records and death certificates. We obtained medical histories from a primary informant, usually the proband's parent, on 346 first- and 784 second-degree relatives of 68 childhood and adolescent soft-tissue sarcoma patients. To investigate underreporting by the primary informant we conducted an individual interview with each adult relative or proxy. Primary informants reported 22 cancers in first-degree relatives, all confirmed as invasive cancer, and 71 cancers in second-degree relatives with 50 of 67 for which documentation confirmed as invasive. Of 715 individual informants contacted, 15 additional cancers were reported, including 5 confirmed as invasive. The number of first-degree relatives with confirmed invasive cancers was within the expected range; however, the number of cancers in second-degree relatives was below the expected range (observed/expected = 0.51 (54/105.5) 95% confidence interval (CI) = 0.39-0.67). Thus, the lower than expected number of cancers in second-degree relatives was not attributable to underreporting by a single informant or inability to obtain documentation. The overreporting of 25 cancers (24.5%) in second-degree relatives, indicates the need to document all reported cancers.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term follow-up of normal peripheral blood progenitor cell donors treated with filgrastim: no evidence of increased risk of leukemia development.

Data on the long-term safety of filgrastim administration in peripheral blood progenitor cell (PBPC) donors are scarce. The main theoretical risk is believed to be the possible development of leukemia. We conducted a survey of filgrastim-treated related donors to determine the incidence of leukemia after PBPC donation. Of the 343 PBPC donors eligible for inclusion in the survey, 281 (82%) were interviewed by telephone between December 1998 and February 2000. The mean age at donation was 44 years. The median time elapsed after PBPC donation was 39 months, and in 278 (99%) of the interviewed donors it was at least 1 year. At the time of the interview none of the donors had been diagnosed with acute or chronic leukemia. Although the sample size is small and the follow-up duration is limited, these data suggest that exposure to filgrastim is not associated with any notable risk of leukemia development in PBPC donors.

Gender difference in smoking effect on chromosome sensitivity to gamma radiation in a healthy population.

In the general population, there is variation in radiosensitivity associated with cancer risk. However, data on the role of epigenetic factors in the variation of radiosensitivity are scarce. Thus we investigated the effects of smoking and age on the radiosensitivity of human lymphocytes by measuring the frequency of chromosome aberrations after in vitro exposure to gamma rays in peripheral lymphocytes from 441 healthy subjects (18-95 years old). We analyzed the frequency of both spontaneous (baseline) and in vitro gamma-ray-induced (1.5 Gy) chromatid breaks in 50 well-spread metaphases per subject. The overall mean frequencies of spontaneous and induced breaks were 0.02 and 0.45 per cell, respectively. The mean frequency of induced breaks was significantly higher in men than in women (P = 0.03) but did not differ by age or ethnicity. Donors who had ever smoked showed a small but significantly increased frequency of induced breaks (mean = 0.47) compared to nonsmokers (mean = 0.41; P = 0.005). Further stratification and multivariate analyses revealed that the smoking effect was more pronounced in men than in women. These findings support a smoking effect on radiosensitivity in a healthy population, particularly in men. Therefore, when evaluating the association between radiosensitivity and susceptibility to smoking-related cancers, the effect of smoking should be taken into account.

Chromosome breaks and sister chromatid exchange as predictors of second cancers in Hodgkin's disease.

Hodgkin's disease (HD) survivors face an increased risk of developing second cancers. We evaluated baseline cytogenetic biomarkers, sister chromatid exchange (SCE) and chromosome breaks [spontaneous (SCB) and bleomycin-induced (BIB)], as predictors of second cancer risk in a cohort of 105 adult HD patients. During follow-up, seven second cancers occurred. SCBs and BIBs showed no association with risk of second primaries. Multivariate Cox regression revealed that high levels of SCEs (relative risk (RR)=11.3, p=0.02) and age (RR=1.08, p=0.02) predicted second cancer risk. Histology, stage, and treatment were not associated with elevated risk. In conclusion, baseline SCE frequencies may be a useful biomarker for identifying HD patients at increased risk of developing second cancers. These results need to be verified in a larger cohort with a longer follow-up time.

Statistical models for analysis of cytogenetic biomarkers.

BACKGROUND: Bleomycin-induced chromosomal breaks (CB) and sister chromatid exchange (SCE) in peripheral blood lymphocytes have been shown to be sensitive cytological markers for susceptibility to DNA damage in patients with various types of cancer and in healthy controls. Factors such as age, sex, smoking, and alcohol consumption could affect the values of some of these biomarkers and should be considered as covariates when analyzing cytogenetic biomarkers because these factors can affect the frequency of CB and SCE. METHODS: We propose a statistical method using negative binomial (NB) distribution to evaluate the numbers of CB and SCE. In order to determine the best model to represent the frequency of CB and SCE, we compared the NB model with the widely used Poisson model and log-transformed normal model by using generalized linear models. To demonstrate the better fit of the NB model, we analyzed three different data sets from studies conducted at The University of Texas M.D. Anderson Cancer Center. The first set was a case-control study of lung cancer in a population of African Americans and Mexican Americans (286 cases and 156 controls), the second set consisted of 311 head and neck cancer patients, and the third set consisted of 105 Hodgkin's disease patients. RESULTS: For CB; the estimates of the variability for Hodgkin's disease, head and neck, and lung cancers were 487.24, 502.82, and 520.15, respectively. For SCE, the estimates of the variability for Hodgkin's disease was 9777.01. For CB, the dispersion estimates under the three models (Poisson, NB, and Normal) for Hodgkin's disease, head and neck, and lung cancers were: 12.30, 1.20, 0.85; 8.94, 1.05, 0.22; and 10.10, 1.05, 0.25, respectively. For SCE (Hodgkin's disease only), the dispersion estimates under the three models (Poisson, NB, and Normal) were 30.91, 1.11, 0.10, respectively. CONCLUSIONS: Our results demonstrate that the NB model provides a better interpretation and fit for the frequency of CB and SCE in different cancer types. Therefore, we recommend it as a model for the analysis of cytogenetic biomarkers.