Plasma levels of polychlorinated biphenyls and risk of cutaneous malignant melanoma: a preliminary study.

A number of epidemiologic studies have suggested that exposure to polychlorinated biphenyls (PCB) and other organochlorine compounds (OCC) increase risk of cutaneous malignant melanoma (CMM). However, these studies have generally had no biologic measure of OCC exposure, and have been unable to control for sun exposure, the major known environmental risk factor for this disease. This preliminary study examined the relationship between OCC residues in plasma and risk of CMM adjusting for sun sensitivity and sun exposure. A case-control study of 80 CMM patients and 310 control subjects was conducted. Lifetime sun exposure information, along with data on pigmentation variables and sun sensitivity data was collected, along with a blood sample. Cases and controls were assayed for plasma levels of 14 PCB congeners and 11 organochlorine pesticide residues using gas chromatography. Strong associations were seen between risk of CMM and plasma levels of non-dioxin-like PCBs (Adjusted OR = 7.02; 95% CI: 2.30-21.43 for highest quartile) and several PCB congeners, organochlorine pesticides or metabolites. These associations persisted after control for sun sensitivity and sun exposure. Results from this investigation require independent confirmation in larger studies. However, they suggest that environmental factors other than UV radiation may play a role in genesis of CMM, and indicate that it may be productive to search for further agents which might increase risk.

Genetic variation in the NBS1, MRE11, RAD50 and BLM genes and susceptibility to non-Hodgkin lymphoma.

BACKGROUND: Translocations are hallmarks of non-Hodgkin lymphoma (NHL) genomes. Because lymphoid cell development processes require the creation and repair of double stranded breaks, it is not surprising that disruption of this type of DNA repair can cause cancer. The members of the MRE11-RAD50-NBS1 (MRN) complex and BLM have central roles in maintenance of DNA integrity. Severe mutations in any of these genes cause genetic disorders, some of which are characterized by increased risk of lymphoma. METHODS: We surveyed the genetic variation in these genes in constitutional DNA of NHL patients by means of gene re-sequencing, then conducted genetic association tests for susceptibility to NHL in a population-based collection of 797 NHL cases and 793 controls. RESULTS: 114 SNPs were discovered in our sequenced samples, 61% of which were novel and not previously reported in dbSNP. Although four variants, two in RAD50 and two in NBS1, showed association results suggestive of an effect on NHL, they were not significant after correction for multiple tests. CONCLUSION: These results suggest an influence of RAD50 and NBS1 on susceptibility to diffuse large B-cell lymphoma and marginal zone lymphoma. Larger association and functional studies could confirm such a role.

Occupational physical activity and risk of malignant melanoma: the Western Canada Melanoma Study.

The relationship between physical activity and cutaneous malignant melanoma has not been fully investigated; in particular, many previous studies have not controlled for sunlight exposure, which is an important environmental risk factor for melanoma. The aim of this study was to examine the relationship between occupational physical activity and melanoma risk. The data were collected for a population-based case-control study that consisted of 595 melanoma patients diagnosed between 1979 and 1981. Five hundred and ninety-five controls matched on sex, age and area of residence were selected from provincial government health insurance rolls. Lifetime job histories, sun exposure and other host factors were obtained from personal interviews with each individual. Logistic regression analysis was used to examine the relationship between melanoma risk and occupational activity levels, measured as total metabolic equivalent hours, with adjustment for occupational sun exposure, recreational sun exposure and host factors. Risk estimates were elevated above one for each occupational activity quintile compared with those with sedentary jobs. However, the pattern of risk ratios was irregular and statistical significance was reached only by the highest quintile (odds ratio: 1.59, 95% confidence interval: 1.02-2.47) and the second lowest quintile (odds ratio: 1.62, 95% confidence interval: 1.10-2.39). Our data showed an elevated risk for cutaneous malignant melanoma among those with higher levels of physical activity, although no clear dose-response relationship was observed. Further studies examining lifetime physical activity histories and sunlight exposure are required to explicate these findings.

Identification of occupational cancer risk in British Columbia: a population-based case-control study of 2,998 lung cancers by histopathological subtype.

BACKGROUND: Few studies have investigated occupational lung cancer risk in relation to specific histopathological subtypes. METHODS: A case-control study was conducted to evaluate the relationship between lung cancer and occupation/industry of employment by histopathological subtype. A total of 2,998 male cases and 10,223 cancer controls, diagnosed between 1983 and 1990, were identified through the British Columbia Cancer Registry. Matched on age and year of diagnosis, conditional logistic regression analyses were performed for two different estimates of exposure with adjustment for potentially important confounding variables, including tobacco smoking, alcohol consumption, marital status, educational attainment, and questionnaire respondent. RESULTS: For all lung cancers, an excess risk was observed for workers in the primary metal (OR = 1.31, 95% CI, 1.01-1.71), mining (OR = 1.53, 95% CI, 1.20-1.96), machining (OR = 1.33, 95% CI, 1.09-1.63), transport (OR = 1.50, 95% CI, 1.08-2.07), utility (OR = 1.60, 95% CI, 1.22-2.09), and protective services (OR = 1.27, 95% CI, 1.05-1.55) industries. Associations with histopathological subtypes included an increased risk of squamous cell carcinoma in construction trades (OR = 1.25, 95% CI, 1.06-1.48), adenocarcinoma for professional workers in medicine and health (OR = 1.73, 95% CI, 1.18-2.53), small cell carcinoma in railway (OR = 1.62, 95% CI, 1.06-2.49), and truck transport industries (OR = 1.51, 95% CI, 1.00-2.28), and large cell carcinoma for employment in the primary metal industry (OR = 2.35, 95% CI, 1.11-4.96). CONCLUSIONS: Our results point to excess lung cancer risk for occupations involving exposure to metals, polyaromatic hydrocarbons and asbestos, as well as several new histopathologic-specific associations that merit further investigation.

Risk of childhood leukemia associated with parental smoking and alcohol consumption prior to conception and during pregnancy: the cross-Canada childhood leukemia study.

OBJECTIVE: As part of a larger case-control study, the authors evaluated risk of childhood leukemia relative to parental self-reported smoking and alcohol consumption. METHODS: Children 0-14 years of age diagnosed with leukemia between 1990 and 1994 were ascertained through population-based sources at the time of diagnosis. For each participating case, an age, gender, and area-matched control was randomly selected from provincial government health insurance rolls. Risk factor information was obtained through personal interviews with each child's parents. Conditional logistic regression models were used to examine risk of leukemia associated with parental smoking and drinking. RESULTS: Maternal alcohol consumption prior to conception (OR = 1.37, 95% CI, 0.99-1.90) and during pregnancy (OR = 1.39, 95% CI, 1.01-1.93) was associated with an excess risk of childhood leukemia, with a positive dose-response trend for increasing weekly consumption (p < 0.05). Similar results were observed for children diagnosed with acute lymphoblastic leukemia (ALL). Odds ratios for maternal cigarette smoking before and during pregnancy were consistently elevated above one, but not statistically significant. No relationship was observed with paternal drinking or smoking in the perinatal period. CONCLUSIONS: Our study suggests that maternal alcohol drinking before or during pregnancy may contribute to an increased risk of childhood leukemia.

Risk of childhood leukemia associated with vaccination, infection, and medication use in childhood: the Cross-Canada Childhood Leukemia Study.

Current hypotheses consonant with the peak in leukemia incidence in early childhood point to an infectious etiology. The authors examined the effect of postnatal exposures predicted to affect early immune functioning, including childhood vaccinations, illness, medication use, and breastfeeding patterns. Children 0-15 years of age diagnosed with leukemia from 1990 to 1994 and resident within principal cities across Canada were eligible for inclusion. Through pediatric oncology centers and population-based cancer registries, 399 cases were ascertained at the time of diagnosis. For each participating case, an age-, gender-, and area-matched control was randomly selected from government health insurance rolls. Risk factor information was obtained through personal interviews with each child's parents or guardians. Conditional logistic regression was used to calculate odds ratios, with adjustment for potential confounders. Use of immunosuppressant medication by the index child led to a deficit of risk (odds ratio = 0.37, 95% confidence interval: 0.16, 0.84), while vitamin intake was positively associated with leukemia (odds ratio = 1.66, 95% confidence interval: 1.18, 2.33). Breastfeeding for more than 6 months was also protective (p < 0.05). Results persisted for cases diagnosed with acute lymphoblastic leukemia and for children diagnosed at 1-5 years of age. These findings suggest a role for early immunologic challenge in the expression of childhood leukemia.

A systematic evaluation of the ataxia telangiectasia mutated gene does not show an association with non-Hodgkin lymphoma.

The ataxia telangiectasia mutated (ATM) gene is critical for the detection and repair of DNA double-stranded breaks. Mutations in this gene cause the autosomal recessive syndrome ataxia telangiectasia (AT), an attribute of which is an increased risk of cancer, particularly lymphoma. We have undertaken a population-based case/control study to assess the influence of genetic variation in ATM on the risk of non-Hodgkin lymphoma (NHL). A number of the subtypes that constitute NHL have in common the occurrence of specific somatic translocations that contribute to lymphomagenesis. We hypothesize that ATM function is slightly attenuated by some variants, which could reduce double-stranded break repair capacity, contributing to the occurrence of translocations and subsequent lymphomas. We sequenced the promoter and all exons of ATM in the germline DNA of 86 NHL patients and identified 79 variants. Eighteen of these variants correspond to nonsynonymous amino acid differences, 6 of which were predicted to be deleterious to protein function; these variants were all rare. Eleven common variants make up 10 haplotypes that are specified by 7 tagSNPs. Linkage disequilibrium across the ATM gene is high but incomplete. TagSNPs and the 6 putatively deleterious variants were genotyped in 798 NHL cases and 793 controls. Our results indicate that common variants of ATM do not significantly contribute to the risk of NHL in the general population. However, some rare, functionally deleterious variants may contribute to an increased risk of development of rare subtypes of the disease.

Genetic variation in H2AFX contributes to risk of non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) comprises a group of lymphoid tumors that have in common somatic translocations. H2AFX encodes a key histone involved in the detection of the DNA double-stranded breaks that can lead to translocations. H2afx is a dosage-dependent gene that protects against B-cell lymphomas in mice, making its human orthologue an ideal candidate gene for susceptibility to lymphoma. We did a population-based genetic association study of H2AFX variants in 487 NHL cases and 531 controls. Complete resequencing of the human H2AFX gene in 95 NHL cases was done to establish the spectrum of variation in affected individuals; this was followed by both direct and indirect tests for association at the level of individual single nucleotide polymorphisms (SNP) and as haplotypes. Homozygosity for the AA genotype of a SNP 417 bp upstream of the translational start of H2AFX is strongly associated [odds ratio (OR), 0.54; P = 0.001] with protection from NHL. We find a strong association of this SNP with the follicular lymphoma subtype of NHL (AA genotype: OR, 0.40; P = 0.004) and with mantle cell lymphoma (AA genotype: OR, 0.20; P = 0.01) that remains significant after adjustment for the false discovery rate, but not with diffuse large B-cell lymphoma. These data support the hypothesis that genetic variation in the H2AFX gene influences genetic susceptibility or resistance to some subtypes of NHL by contributing to the maintenance of genome stability.

Occupational female breast and reproductive cancer mortality in British Columbia, Canada, 1950-94.

BACKGROUND: It has been postulated that recent increases in female breast and reproductive cancers may be, in part, attributable to occupational exposures. AIM: We aimed to identify occupational associations with female breast and reproductive cancer mortality among women living in British Columbia (BC), Canada. METHODS: Case-control methods were used to calculate mortality odds ratios for occupation and cause of death information obtained from the provincial death registry. Cases included women 20 years of age or older who died from breast or reproductive cancer between 1950 and 1994 and resident in BC, Canada. Controls were randomly selected from non-cancer deaths, matched according to age at death and year of death. In a subsequent, stratified analysis, we also identified changes over time to breast and reproductive cancer mortality among each worker group. RESULTS: There was excess mortality from breast and ovarian cancer among teachers, nurses, secretaries, librarians, retail sales clerks and religious workers. An elevated risk of breast cancer mortality was also found among professionals employed as owners, managers and government officials, financial saleswomen, scientists, physicians, medical and dental technicians and accountants. Secretaries, telephone operators and musicians were at increased risk of death from endometrial cancer. Cervical cancer mortality was not significantly increased for any occupational classification. CONCLUSIONS: Our study was aimed primarily at hypothesis generation. More systematic reviews, including cancer registry studies, will prove useful for confirming the relationships we have observed, including a possible increase in the risk of breast and ovarian cancer mortality among women employed in professional occupations.

Mortality among 5-year survivors of cancer diagnosed during childhood or adolescence in British Columbia, Canada.

BACKGROUND: Ongoing monitoring of late mortality among survivors of a childhood or adolescent cancer is essential to appropriately evaluate risk in more recent cohorts and with longer follow-up. We examined overall and cause-specific mortality in a population-based cohort of 2,354 individuals diagnosed with a cancer or tumor prior to 20 years of age between 1970 and 1995 in British Columbia (BC), Canada who survived at least 5 years. PROCEDURE: Late deaths in a survivor cohort ascertained from the BC Cancer Registry were identified using death registrations. Standardized mortality ratios, absolute excess risk of death, and cumulative risk of death were determined. Demographic, temporal, and disease-related factors in risk of late mortality were also assessed. RESULTS: After 24,491 person-years of follow-up, there were 181 deaths, 139 of which were cancer related. Excess risk of late mortality among survivors was 7 deaths per 1,000 person-years at risk (AER = 6.6). Standardized mortality ratio (SMR) was ninefold higher relative to the underlying BC population (SMR = 9.1, 95% CI, 7.8-10.5), and was greatest for those with a recurrence within 5 years of diagnosis, and for those diagnosed with acute lymphoblastic leukemia and nervous system tumors. Absolute excess risk of late death was significantly higher for males and for those diagnosed prior to 1980, but did not vary according to age at diagnosis. Relative mortality was significantly increased due to cancer-related causes of death (SMR = 81.7, 95% CI, 68.6-95.8), as well as circulatory (SMR = 9.7, 95% CI, 4.2-19.1) and respiratory (SMR = 16.8, 95% CI, 4.6-43.0) diseases. CONCLUSIONS: In this population-based cohort with long follow-up, there continues to be excess late mortality among childhood and adolescent cancer survivors due to both cancer and non-cancer causes, even among more recently diagnosed survivors.

Risk of a second malignant neoplasm among 5-year survivors of cancer in childhood and adolescence in British Columbia, Canada.

BACKGROUND: We examined second malignancies, a recognized late effect of therapy among survivors of childhood and adolescent cancer, among a recent, population-based cohort of 2,322 5-year survivors diagnosed before 20 years of age in British Columbia (BC), Canada between 1970 and 1995. PROCEDURE: Survivors and second malignancies were identified from the BC Cancer Registry. Risk of second malignancy was evaluated using standardized incidence ratios (SIRs), absolute excess risk (AER), and cumulative risk. The effect of demographic, temporal, and disease-related characteristics on risk was assessed. RESULTS: Fifty-five second malignancies were observed after 26,071 person-years of follow-up. Relative rate of developing a second malignancy among survivors was 5 times higher than expected (SIR = 5.0, 95% CI, 3.8-6.5), and absolute excess risk was 1.7 deaths per 1,000 person-years. Cumulative incidence of a second malignancy was 5.1% at 25 years after diagnosis of the first cancer. SIRs and absolute excess risk of subsequent cancer was higher among females (SIR = 5.9, 95% CI, 4.5-8.3 and AER = 2.66). While relative risk of second cancer was higher for those diagnosed before 10 years of age (SIR = 10.6, 95% CI, 7.1-16.0), absolute excess risk was slightly higher for those diagnosed after 10 years of age. SIRs were significantly elevated for all follow-up periods, but absolute excess risk of a second cancer was highest among patients surviving more than 15 years. CONCLUSIONS: Increased risk of a subsequent neoplasm is evident among childhood cancer survivors diagnosed in more recent periods than has been previously reported, continues years after diagnosis, and varies according to several risk factors. Continued surveillance is essential to quantify and characterize long-term and changing risks for appropriate follow-up.

Identification of occupational cancer risks in British Columbia: a population-based case-control study of 1129 cases of bladder cancer.

OBJECTIVE: We collected information on lifetime occupational histories, smoking, and alcohol consumption from 15,463 incident cancer cases. Occupational risk factors for bladder cancer are presented in this report. METHOD: A matched case-control design was used. All cases were diagnosed with bladder cancers, with controls being internal controls consisting of all other cancer sites, excluding lung and unknown primary. Data were analyzed using conditional logistic regression for matched sets data and the likelihood ratio test. RESULTS: Excess bladder cancer risks was observed in a number of occupation and industries, particularly those involving exposure to metals, including aluminum, paint and solvents, polycyclic aromatic hydrocarbons, diesel engine emissions, and textiles. CONCLUSIONS: The results of our study are in line with those from the literature and further suggest that exposure to silica and to electromagnetic fields may carry an increased risk of bladder cancer.