Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study.

Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics.

Nevus count associations with pigmentary phenotype, histopathological melanoma characteristics and survival from melanoma.

Although nevus count is an established risk factor for melanoma, relationships between nevus number and patient and tumor characteristics have not been well studied and the influence of nevus count on melanoma-specific survival is equivocal. Using data from the Genes, Environment and Melanoma (GEM) study, a large population-based study of primary cutaneous melanoma, we evaluated associations between number of nevi and patient features, including sun-sensitivity summarized in a phenotypic index, and tumor characteristics. We also assessed the association of nevus count with melanoma-specific survival. Higher nevus counts were independently and positively associated with male gender and younger age at diagnosis, and they were inversely associated with lentigo maligna histology. We observed a borderline significant trend of poorer melanoma-specific survival with increasing quartile of nevus count, but little or no association between number of nevi and pigmentary phenotypic characteristics or prognostic tumor features.

Adult lifetime alcohol consumption and invasive epithelial ovarian cancer risk in a population-based case-control study.

OBJECTIVE: Meta-analyses report a null association between recent alcohol consumption and ovarian cancer risk. However, because few studies investigated different types of alcohol over adult ages, we investigated adult lifetime and type (beer, wine, spirits) of consumption and risk. METHODS: Consumption after age 20years was ascertained in 1144 invasive epithelial ovarian cancer cases and 2513 controls in a population-based case-control study (Alberta and British Columbia, Canada, 2001-2012). Non-drinkers consumed any types of alcohol <12 times per year on average. Logistic regression was use to estimate adjusted odds ratios [aOR] and 95% confidence intervals [CIs]. RESULTS: Wine consumption was associated with a risk reduction (aOR=0.67, 95% CI: 0.50-0.88) relative to non-drinkers, but not beer (aOR=1.06, 95% CI: 0.71-1.58) or spirits (aOR=0.98, 95% CI: 0.69-1.39). The reduced risk was stronger for exclusive red wine drinkers (aOR=0.44, 95% CI: 0.19-0.92) than white wine drinkers (aOR=0.79, 95% CI: 0.46-1.34), although most women drank both types of wine. Risk decreased with increasing cumulative consumption of any wine (P-trend<0.05) and was evident for the serous histotype. Wine consumption initiated prior to age 50 was associated with a risk reduction (e.g., at 40-49years, aOR=0.58, 95% CI: 0.42-0.78), but not drinking initiated after 50years of age. For any type, level, or age at initiation of alcohol consumption, we found no increased risks. CONCLUSIONS: For the moderate consumption in this study, higher levels of wine consumption were generally associated with risk reductions; reductions may be stronger for red wine. Our results suggest that alcohol consumption that is guideline concordant will not increase epithelial ovarian cancer risk.

Inherited variation at MC1R and ASIP and association with melanoma-specific survival.

Melanocortin-1 receptor (MC1R) is a marker of melanoma risk in populations of European ancestry. However, MC1R effects on survival are much less studied. We investigated associations between variation at MC1R and survival in an international, population-based series of single primary melanoma patients enrolled into the Genes, Environment, and Melanoma study. MC1R genotype data was available for 2,200 participants with a first incident primary melanoma diagnosis. We estimated the association of MC1R genotypes with melanoma-specific survival (i.e., death caused by melanoma) and overall survival using COX proportional hazards modeling, adjusting for established prognostic factors for melanoma. We also conducted stratified analyses by Breslow thickness, tumor site, phenotypic index, and age. In addition, we evaluated haplotypes involving polymorphisms near the Agouti signaling protein gene (ASIP) locus for their impacts on survival. Melanoma-specific survival was inversely associated with carriage of MC1R variants in the absence of consensus alleles compared to carriage of at least one consensus allele (hazard ratio (HR) = 0.60; 95% confidence interval (CI): 0.40, 0.90). MC1R results for overall survival were consistent with no association. We did not observe any statistical evidence of heterogeneity of effect estimates in stratified analyses. We observed increased hazard of melanoma-specific death among carriers of the risk haplotype TG near the ASIP locus (HR = 1.37; 95% CI: 0.91, 2.04) when compared to carriers of the most common GG haplotype. Similar results were noted for overall survival. Upon examining the ASIP TG/TG diplotype, we observed considerably increased hazard of melanoma-specific death (HR = 5.11; 95% CI: 1.88, 13.88) compared to carriers of the most common GG/GG diplotype. Our data suggest improved melanoma-specific survival among carriers of two inherited MC1R variants.

Occupational exposure and ovarian cancer risk.

PURPOSE: Relatively little work has been done concerning occupational risk factors in ovarian cancer. Although studies conducted in occupational settings have reported positive associations, their usefulness is generally limited by the lack of information on important confounders. In a population-based case-control study, we assessed risk for developing epithelial ovarian cancer (EOC) associated with occupational exposure while accounting for important confounders. METHODS: Participants were identified through provincial population-based registries. Lifetime occupational history and information on potential confounding factors were obtained through a self-administered questionnaire. Unconditional logistic regression and the likelihood ratio test were used to assess EOC risk with each occupation (or industry), relative to all other occupations (or industries), adjusting for potential confounders including body mass index, oral contraceptive use, menopausal hormone therapy, parity, age at first childbirth, age at menarche, age at menopause, family history of breast and ovarian cancer in mother and sister(s), tubal ligation, partial oophorectomy, and hysterectomy. Occupations and industries were coded according to the Canadian Standard Occupational Classification (SOC) and Standard Industrial Classification (SIC). RESULTS: Significant excess risk was observed for several groups of teaching occupations, including SOC 27, teaching and related (adjusted OR 1.77, 95% CI 1.15-2.81) and SOC 279, other teaching and related (adjusted OR 3.11, 95% CI 1.35-8.49). Significant excess was also seen for a four-digit occupational group SOC 4131, bookkeepers and accounting clerks (adjusted OR 2.80, 95% CI 1.30-6.80). Industrial sub-groups showing significant excess risk included SIC 65, other retail stores (adjusted OR 2.19, 95 % CI 1.16-4.38); SIC 85, educational service (adjusted OR 1.45, 95% CI 1.00-2.13); and SIC 863, non-institutional health services (adjusted OR 2.54, 95% CI 1.13-6.52). CONCLUSIONS: Our study found an elevated EOC risk for teaching occupations and is the first study to observe such an increased risk after adjustment for potential confounders. Further studies with more detailed assessment of the work environment and unique lifestyle characteristics may be fruitful in elucidating this etiology.

Fasting insulin and endogenous hormones in relation to premenopausal breast density (Canada).

PURPOSE: Mammographic breast density (BD) is associated with increased risk of breast cancer. This study asks which circulating metabolic and reproductive biomarkers are associated with BD, particularly dense breast area, in premenopausal women not taking exogenous hormones. METHODS: In a cross-sectional study, 299 premenopausal women aged 40-49 completed questionnaires, provided a fasting blood sample, had height, weight, percentage body fat, waist and hip measurements taken, and attended a screening mammogram. Multivariate linear regression was used to calculate adjusted means for percentage BD, absolute dense and non-dense area, across categories of covariates, adjusted for day of menstrual cycle, age, parity, body mass index, percentage body fat, and ethnicity. RESULTS: Fasting insulin levels were inversely associated, and insulin-like growth factor-binding protein 1 levels directly associated with percentage BD, but lost statistical significance after multivariate adjustment. Sex hormone-binding globulin levels were directly associated with percentage BD, still significant after multivariate adjustment (p = 0.03). A significant inverse dose-response association was observed between progesterone levels and dense area (p < 0.01). CONCLUSIONS: Breast density in premenopausal women seems unrelated or inversely related to insulin resistance, levels of insulin-like growth factor 1 and its binding proteins, and levels of sex steroids; therefore, the mechanism by which radiodensity on a mammogram is related to breast cancer risk remains unclear.

Association of functional, inherited vitamin D-binding protein variants with melanoma-specific death.

BACKGROUND: It is unclear whether genetic variants affecting vitamin D metabolism are associated with melanoma prognosis. Two functional missense variants in the vitamin D-binding protein gene (GC), rs7041 and rs4588, determine 3 common haplotypes, Gc1s, Gc1f, and Gc2, of which Gc1f may be associated with decreased all-cause death among melanoma patients based on results of a prior study, but the association of Gc1f with melanoma-specific death is unclear. METHODS: We investigated the association of the Gc1s, Gc1f, and Gc2 haplotypes with melanoma-specific and all-cause death among 4490 individuals with incident, invasive primary melanoma in 2 population-based studies using multivariable Cox-proportional hazards regression. RESULTS: In the pooled analysis of both datasets, the patients with the Gc1f haplotype had a 37% lower risk of melanoma-specific death than the patients without Gc1f (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.47 to 0.83, P = .001), with adjustments for age, sex, study center, first- or higher-order primary melanoma, tumor site, pigmentary phenotypes, and Breslow thickness. Associations were similar in both studies. In pooled analyses stratified by Breslow thickness, the corresponding melanoma-specific death HRs for those patients with the Gc1f haplotype compared with those without Gc1f were 0.89 (95% CI = 0.63 to 1.27) among participants with tumor Breslow thickness equal to or less than 2.0 mm and 0.40 (95% CI = 0.25 to 0.63) among participants with tumor Breslow thickness greater than 2.0 mm (Pinteraction = .003). CONCLUSIONS: Our findings suggest that individuals with the GC haplotype Gc1f may have a lower risk of dying from melanoma-specifically from thicker, higher-risk melanoma-than individuals without this Gc1f haplotype.

Sex-Specific Associations of MDM2 and MDM4 Variants with Risk of Multiple Primary Melanomas and Melanoma Survival in Non-Hispanic Whites.

MDM2-SNP309 (rs2279744), a common genetic modifier of cancer incidence in Li-Fraumeni syndrome, modifies risk, age of onset, or prognosis in a variety of cancers. Melanoma incidence and outcomes vary by sex, and although SNP309 exerts an effect on the estrogen receptor, no consensus exists on its effect on melanoma. MDM2 and MDM4 restrain p53-mediated tumor suppression, independently or together. We investigated SNP309, an a priori MDM4-rs4245739, and two coinherited variants, in a population-based cohort of 3663 primary incident melanomas. Per-allele and per-haplotype (MDM2_SNP309-SNP285; MDM4_rs4245739-rs1563828) odds ratios (OR) for multiple-melanoma were estimated with logistic regression models. Hazard ratios (HR) for melanoma death were estimated with Cox proportional hazards models. In analyses adjusted for covariates, females carrying MDM4-rs4245739*C were more likely to develop multiple melanomas (ORper-allele = 1.25, 95% CI 1.03-1.51, and Ptrend = 0.03), while MDM2-rs2279744*G was inversely associated with melanoma-death (HRper-allele = 0.63, 95% CI 0.42-0.95, and Ptrend = 0.03). We identified 16 coinherited expression quantitative loci that control the expression of MDM2, MDM4, and other genes in the skin, brain, and lungs. Our results suggest that MDM4/MDM2 variants are associated with the development of subsequent primaries and with the death of melanoma in a sex-dependent manner. Further investigations of the complex MDM2/MDM4 motif, and its contribution to the tumor microenvironment and observed associations, are warranted.

Vitamin D receptor polymorphisms in patients with cutaneous melanoma.

The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38 VDR gene single nucleotide polymorphisms (SNPs) in a large international multicenter population-based case-control study of melanoma. Buccal DNAs were obtained from 1,207 people with incident multiple primary melanoma and 2,469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, haplotype tagging SNPs with ≥ 10% minor allele frequency in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP. Eight of 38 SNPs in the promoter, coding, and 3' gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25 to 33% for six polymorphisms: rs10875712 (odds ratios [OR] 1.28; 95% confidence interval (CI), 1.01-1.62), rs4760674 (OR 1.33; 95% CI, 1.06-1.67), rs7139166 (OR 1.26; 95%CI, 1.02-1.56), rs4516035 (OR 1.25; 95%CI, 1.01-1.55), rs11168287 (OR 1.27; 95%CI, 1.03-1.57) and rs1544410 (OR 1.30; 95%CI, 1.04-1.63); for two polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65-1.02) and rs7965281 (OR, 0.78; 95%CI, 0.62-0.99). We recognize the potential false positive findings because of multiple comparisons; however, the eight significant SNPs in our study outnumbered the two significant tests expected to occur by chance. The VDR may play a role in melanomagenesis.

Persistent organic pollutants and risk of cutaneous malignant melanoma among women.

BACKGROUND: Despite the increasing trend of cutaneous malignant melanoma (CMM) incidence in Canada, especially among females, few risk factors other than ultraviolet radiation exposure, have been identified. AIM: We conducted a case-control study of 406 CMM cases and 181 controls to evaluate the potential impact of body burdens of various persistent organic pollutants on CMM risk. METHODS: Detailed data on potential confounding factors, including lifetime repeated sun exposure and skin reaction to repeated sun exposure, were collected. Gas chromatography tandem mass spectrometry was used to assay plasma levels of 14 polychlorinated biphenyl (PCB) congeners and 11 organochlorine (OC) pesticides among cases and controls. RESULTS: Statistically significant trends of increased CMM risk were observed with increasing plasma concentrations of multiple PCB congeners, including PCBs 138, 153, 170, 180, 183 and 187. For example, compared to lowest plasma concentration quartile of PCB-138, the second, third and fourth quartiles were associated with 1.7 (95% CI: 0.9-2.9), 2.3 (95% CI: 1.3-4.1) and 2.4 (95% CI: 1.3-4.5) -fold increased risks of CMM, respectively. Similarly, increasing plasma concentrations of several OC pesticides (i.e., ß-HCH, HCB, Mirex, oxychlordane and trans-Nonachlor) showed statistically significant trends with increased CMM risk. For example, compared to lowest plasma concentration quartile of ß-HCH, the second, third and fourth quartiles were associated with 1.3 (95% CI: 0.7-2.3), 2.1 (95% CI: 1.2-3.7) and 2.3 (95% CI: 1.2-4.4) -fold increased risks of CMM, respectively. CONCLUSION: Plasma levels of several persistent organic pollutants were highly correlated, suggesting that observed associations were not necessarily independent of each other. Given the highly correlated nature of exposure to PCB and OC analytes, sophisticated analyses that consider complex mixtures should be considered in future studies.

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.

Prostate cancer risk and exposure to pesticides in British Columbia farmers.

BACKGROUND: Several epidemiologic studies have reported an increased risk of prostate cancer among farmers. Our aim was to assess the risk of developing prostate cancer in relation to exposure to specific active compounds in pesticides. METHOD: A case-control approach was used with 1,516 prostate cancer patients and 4,994 age-matched internal controls consisting of all other cancer sites excluding lung cancer and cancers of unknown primary site. Lifetime occupational history was obtained through a self-administered questionnaire and used in conjunction with a job exposure matrix to estimate the participants' lifetime cumulative exposure to approximately 180 active compounds in pesticides. Conditional logistic regression was used to assess prostate cancer risk, adjusting for potential confounding variables and effect modifiers. These include age, ethnicity, alcohol consumption, smoking, education, and proxy respondent. RESULTS AND CONCLUSIONS: The significant association between prostate cancer risk and exposure to DDT (OR = 1.68; 95% CI: 1.04-2.70 for high exposure), simazine (OR = 1.89; 95% CI: 1.08-3.33 for high exposure), and lindane (OR = 2.02; 95% CI: 1.15-3.55 for high exposure) is in keeping with those previously reported in the literature. We also observed a significant excess risk for several active ingredients that have not been previously reported in the literature such as dichlone, dinoseb amine, malathion, endosulfan, 2,4-D, 2,4-DB, and carbaryl. Some findings in our study were not consistent with those reported in the literature, including captan, dicamba, and diazinon. It is possible that these findings showed a real association and the inconsistencies reflected differences of characteristics between study populations.

Exposure to anesthetic gases and congenital anomalies in offspring of female registered nurses.

BACKGROUND: Studies of offspring of mothers exposed to anesthetic gases have shown associations with congenital anomalies reported by the mothers, but rarely in studies with objectively ascertained outcomes. We conducted a retrospective cohort study to examine associations between registry-ascertained congenital anomalies in offspring and anesthetic gas exposure of mothers employed as nurses. METHODS: A cohort of registered nurses in British Columbia, Canada, was linked to records of births and congenital anomalies from 1990 to 2000. Exposures were assessed via a survey of anesthetic gas use in all hospitals in the province and records of nurses' jobs, departments, and hospitals. RESULTS: Departments most frequently reporting anesthetic gas use were operating rooms, post-anesthetic recovery rooms, and maternity units. In the cohort of 15,317 live-borne children of 9,433 mothers, 1,079 had congenital anomalies. Anomalies were associated with ever and probable maternal exposure to halogenated gases (ORs: 1.49, 95% CI: 1.04-2.13; and 2.61, 95% CI: 1.31-5.18, respectively) and to nitrous oxide (ORs: 1.42, 95% CI: 1.05-1.94; and 1.82, 95% CI: 1.11-2.99). Anomalies most frequently associated with exposure were those of the heart (OR, halogenated gases: 2.31, 95% CI: 1.07-4.97) and integument (OR, halogenated gases: 3.56, 95% CI: 1.53-8.32; OR, nitrous oxide: 3.02, 95% CI: 1.37-6.64). Gases most frequently associated with anomalies were halothane (predominantly used early in the study period), isoflurane, and sevoflurane (predominantly used later in the period). CONCLUSIONS: In this study, where both exposures and outcomes were assessed objectively, certain congenital anomalies were associated with estimated anesthetic gas exposure.

Congenital anomalies in the offspring of nurses: association with area of employment during pregnancy.

The purpose of this study was to determine whether registered nurses in specific areas of employment during pregnancy had a higher risk for congenital anomalies in their offspring. An offspring cohort (n = 22,611) was created through linkage of the British Columbia Vital Statistics Agency live and stillbirth records from 1986 to 2000, to a female cohort database of registered nurses. Of these, 16,005 (70.8%) were registered in a specific area of employment when pregnant. Odds ratios were calculated using generalized estimating equations (GEE), binary logistic regression with adjustment for sex, mother's age, and year of birth. Elevated risks of congenital anomalies were found for the singleton offspring of nurses employed in the following areas: operating rooms and pediatric nursing units (heart anomalies); maternal newborn units (integument); emergency room (respiratory system); and psychiatry (upper alimentary tract). Further research is needed to determine whether these are chance or consistent findings and whether exposure patterns might provide biological plausibility.

Disease-Associated Risk Variants in ANRIL Are Associated with Tumor-Infiltrating Lymphocyte Presence in Primary Melanomas in the Population-Based GEM Study.

BACKGROUND: Genome-wide association studies have reported that genetic variation at ANRIL (CDKN2B-AS1) is associated with risk of several chronic diseases including coronary artery disease, coronary artery calcification, myocardial infarction, and type 2 diabetes mellitus. ANRIL is located at the CDKN2A/B locus, which encodes multiple melanoma tumor suppressors. We investigated the association of these variants with melanoma prognostic characteristics. METHODS: The Genes, Environment, and Melanoma Study enrolled 3,285 European origin participants with incident invasive primary melanoma. For each of ten disease-associated SNPs at or near ANRIL, we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and ORs for presence of ulceration and tumor-infiltrating lymphocytes (TIL). We also assessed effect modification by tumor NRAS/BRAF mutational status. RESULTS: Rs518394, rs10965215, and rs564398 passed false discovery and were each associated (P ≤ 0.005) with TILs, although only rs564398 was independently associated (P = 0.0005) with TILs. Stratified by NRAS/BRAF mutational status, rs564398*A was significantly positively associated with TILs among NRAS/BRAF mutant, but not wild-type, cases. We did not find SNP associations with Breslow thickness or ulceration. CONCLUSIONS: ANRIL rs564398 was associated with TIL presence in primary melanomas, and this association may be limited to NRAS/BRAF-mutant cases. IMPACT: Pathways related to ANRIL variants warrant exploration in relationship to TILs in melanoma, especially given the impact of TILs on immunotherapy and survival.

Association of Melanoma-Risk Variants with Primary Melanoma Tumor Prognostic Characteristics and Melanoma-Specific Survival in the GEM Study.

Genome-wide association studies (GWAS) and candidate pathway studies have identified low-penetrant genetic variants associated with cutaneous melanoma. We investigated the association of melanoma-risk variants with primary melanoma tumor prognostic characteristics and melanoma-specific survival. The Genes, Environment, and Melanoma Study enrolled 3285 European origin participants with incident invasive primary melanoma. For each of 47 melanoma-risk single nucleotide polymorphisms (SNPs), we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and odds ratios for presence of ulceration, mitoses, and tumor-infiltrating lymphocytes (TILs). We also used Cox proportional hazards regression modeling to estimate the per allele hazard ratios for melanoma-specific survival. Passing the false discovery threshold (p = 0.0026) were associations of IRF4 rs12203592 and CCND1 rs1485993 with log of Breslow thickness, and association of TERT rs2242652 with presence of mitoses. IRF4 rs12203592 also had nominal associations (p < 0.05) with presence of mitoses and melanoma-specific survival, as well as a borderline association (p = 0.07) with ulceration. CCND1 rs1485993 also had a borderline association with presence of mitoses (p = 0.06). MX2 rs45430 had nominal associations with log of Breslow thickness, presence of mitoses, and melanoma-specific survival. Our study indicates that further research investigating the associations of these genetic variants with underlying biologic pathways related to tumor progression is warranted.

GBV-C/hepatitis G virus infection and non-Hodgkin lymphoma: a case control study.

We investigated whether there was an association between GBV-C viremia and the development of non-Hodgkin lymphoma (NHL) in 553 NHL cases and 438 controls from British Columbia, Canada. Cases were aged 20-79, diagnosed between March 2000 and February 2004, and resident in Greater Vancouver or Victoria. Cases and controls were tested for GBV-C RNA by RT-PCR and positive samples were genotyped. Overall, GBV-C RNA was detected in 4.5% of NHL cases vs. 1.8% of controls [adjusted odds ratio (OR) = 2.72, 95% confidence interval (CI) = 1.22-6.69]. The association between GBV-C RNA detection and NHL remained even after individuals with a history of prior transfusion, injection drug use and hepatitis C virus sero-positivity were excluded. GBV-C viremia showed the strongest association with diffuse large B cell lymphoma (adjusted OR = 5.18, 95% CI = 2.06-13.71). Genotyping was performed on 29/33 GBV-C RNA positive individuals; genotypes 2a (n = 22); 2b (n = 5) and 3 (n = 2) were identified, consistent with the distribution of genotypes found in North America. This is the largest case-control study to date associating GBV-C viremia and NHL risk. As GBV-C is known to be transmitted through blood products this may have important implications for blood safety.

MC1R genotype may modify the effect of sun exposure on melanoma risk in the GEM study.

We investigated whether MC1R genotype modifies the effect of sun exposure on melanoma risk in 1,018 cases with multiple melanomas (MPM) and 1,875 controls with one melanoma (SPM). There was some suggestion that MC1R genotype modified the effect of beach and water activities on MPM risk: ORs were 1.94 (95% CI 1.40-2.70) for any activities for no R variants and 1.39 (95% CI 1.05-1.84) with R variants (R151C, R160W, D294H, and D84E) (p for interaction 0.08). MC1R modification of sun exposure effects appeared most evident for MPM of the head and neck: for early life ambient UV, the OR was 4.23 (95% CI 1.76-10.20) with no R and 1.04 (95% CI 0.40-2.68) with R (p for interaction = 0.01; p for three-way interaction = 0.01). Phenotype modified the effect of sun exposure and MPM in a similar manner. We conclude that MC1R and pigmentary phenotype may modify the effects of sun exposure on melanoma risk on more continuously sun-exposed skin. Possible explanations include that risk may saturate with higher sun sensitivity for melanomas on continuously sun-exposed sites but continue to increase as sun exposure increases with lower sun sensitivity, or that sun-sensitive people adapt their behavior by increasing sun protection when exposed.

Interaction between organochlorines and the AHR gene, and risk of non-Hodgkin lymphoma.

BACKGROUND: Plasma organochlorines have been implicated to increase the risk of non-Hodgkin lymphoma (NHL), and interaction with the aryl hydrocarbon receptor gene (AHR) may modify this risk. METHODS: In this case-control study conducted in British Columbia, Canada, five single nucleotide polymorphisms (SNPs) of AHR were genotyped in 422 NHL cases and 459 controls to measure the association between individual SNPs, haplotypes, and risk of NHL. Pre-chemotherapy organochlorine levels were measured and gene-environment interaction analysis was performed. RESULTS: The IVS1 + 4640G/A SNP was significantly associated with NHL risk, with an odds ratio of 1.32 (95% CI = 1.05-1.65) for G/A or A/A genotypes compared to the G/G genotype. Interactions were observed with PCB 118, a known inducer of AHR, and chlordane-related analytes oxychlordane and trans-nonachlor, although no interactions were statistically significant after controlling for multiple comparisons. The observed interactions were consistent across NHL subtypes. CONCLUSION: Results suggest that the AHR gene may play a role in determining the risk of NHL with exposure to organochlorines, and highlight the importance of understanding gene-environment interactions.

Ultraviolet radiation.

The major source of ultraviolet radiation is solar radiation or sunlight. However, exposure to artificial sources particularly through tanning salons is becoming more important in terms of human health effects, as use of these facilities by young people, has increased. The International Agency for Research on Cancer has noted that there is sufficient evidence from studies in animals and in man to establish ultraviolet radiation as a human carcinogen. Skin cancer has been the most commonly studied cancer site with respect to UV radiation. The nature and timing of sun exposure appear to be important determinants of both the degree of risk and the type of skin cancer. Cutaneous malignant melanoma and basal cell cancer are much more strongly related to measures of intermittent ultraviolet exposure (particularly those of childhood or adolescence) than to measures of cumulative exposure. In contrast, squamous cell cancer is more strongly related to constant or cumulative sun exposure. Lip cancer is causally related to lifetime sun exposure. It has been estimated that solar ultraviolet radiation accounts for approximately 93 percent of skin cancers and about half of lip cancers. This translates to approximately 4,500 life-threatening cancers (cutaneous malignant melanoma) per year in Canada, as well as 65,000 less serious cancers (basal cell cancer, squamous cell cancer and lip cancer). Appropriate clothing use, care not to sunburn and judicious use of sunscreens could prevent at least half of these and save approximately 450 lives per year. In addition, physician and public education programs can significantly increase the proportion of melanomas diagnosed early. Lesions that have not yet penetrated deeply are associated with a mortality rate of less than five percent. Several recent studies suggest a possible inverse relationship between ultraviolet radiation exposure and risk of non-Hodgkin lymphoma, colon, breast and prostate cancer, and investigators have speculated that this might be due to the higher serum levels of vitamin D stimulated by high lifetime sun exposure. Further, studies conducted within cohorts using stored pre-diagnostic serum suggest that those with high levels of vitamin D have lower incidence rates of a number of malignancies, particularly colon cancer. However, since serum vitamin D levels can be raised through the use of supplements without increasing risk for skin lip and other known UV-related cancers, changes to health policy with regard to exposure are not merited at this point. Further research is needed in this area.