Amy C. MacArthur

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

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.

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.

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

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.

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. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1098–106)

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.

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

BackgroundTranslocations 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.MethodsWe 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.Results114 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.ConclusionThese 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.

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.

Polychlorinated biphenyls (PCB), UV radiation, and cutaneous malignant melanoma

Several older epidemiologic studies have suggested that exposure to polychlorinated biphenyls (PCBs) may increase risk of cutaneous malignant melanoma (CMM). These investigations, however, have not been able to control for sun exposure, and sun sensitivity, which are major risk factors for this cancer. We conducted a pilot study to examine the possible association between plasma levels of PCBs and risk of CMM, controlling for sun exposure and sun sensitivity. Our case-control study compared levels of 14 PCB congeners in the plasma of 80 Caucasian CMM patients, and 310 Caucasian controls frequency matched by age group and gender. Assays were conducted using gas chromatography and values were lipid-adjusted. Data concerning sun exposure history, sun sensitivity, and host pigmentation variables such as skin, eye and hair colour were also collected using standardized questionnaires. Odds ratios and 95% confidence intervals were calculated for total PCBs, dioxin-like and non-dioxin like PCBs, as well as individual congeners using unconditional logistic regression. A strong association was seen between melanoma risk and plasma levels of total PCBs, (OR highest quartile: 6.02; 95% CI = 2.00-18.17); non-dioxin-like PCBs (OR highest quartile:7.02; 95%CI = 2.30-21.43); and many of the single congeners. These associations persisted after adjustment for recreational sun exposure, sun sensitivity and pigmentation factors. Although the study results will require independent confirmation in larger case-control or cohort investigations, they suggest that potential environmental factors other than UV radiation may be involved in melanoma.