Interactions between exposure to polycyclic aromatic hydrocarbons and xenobiotic metabolism genes, and risk of breast cancer.

PURPOSE: Polycyclic aromatic hydrocarbons (PAHs) are a group of environmental pollutants associated with multiple cancers, including female breast cancer. Several xenobiotic metabolism genes (XMGs), including the CYP450 family, play an important role in activating and detoxifying PAHs, and variations in the activity of the enzymes they encode can impact this process. This study aims to examine the association between XMGs and breast cancer, and to assess whether these variants modify the effects of PAH exposure on breast cancer risk. METHODS: In a case-control study in Vancouver, British Columbia, and Kingston, Ontario, 1037 breast cancer cases and 1046 controls had DNA extracted from blood or saliva and genotyped for 138 single nucleotide polymorphisms (SNPs) and tagSNPs in 27 candidate XMGs. Occupational PAH exposure was assessed using a measurement-based job-exposure matrix. RESULTS: An association between genetic variants and breast cancer was observed among six XMGs, including increased risk among the minor allele carriers of AKR1C3 variant rs12387 (OR 2.71, 95% CI 1.42-5.19) and AKR1C4 variant rs381267 (OR 2.50, 95% CI 1.23-5.07). Heterogeneous effects of occupational PAH exposure were observed among carriers of AKR1C3/4 variants, as well as the PTGS2 variant rs5275. CONCLUSION: Our findings support an association between SNPs of XMGs and female breast cancer, including novel genetic variants that modify the toxicity of PAH exposure. These results highlight the interplay between genetic and environmental factors, which can be helpful in understanding the modifiable risks of breast cancer and its complex etiology.

Tattoos and Hematologic Malignancies in British Columbia, Canada.

BACKGROUND: Tattoos may cause a variety of adverse reactions in the body, including immune reactions and infections. However, it is unknown whether tattoos may increase the risk of lymphatic cancers such as non-Hodgkin lymphoma (NHL) and multiple myeloma. METHODS: Participants from two population-based case-control studies were included in logistic regression models to examine the association between tattoos and risk of NHL and multiple myeloma. RESULTS: A total of 1,518 participants from the NHL study (737 cases) and 742 participants from the multiple myeloma study (373 cases) were included in the analyses. No statistically significant associations were found between tattoos and risk of NHL or multiple myeloma after adjusting for age, sex, ethnicity, education, body mass index, and family history. CONCLUSIONS: We did not identify any significant associations between tattoos and risk of multiple myeloma, NHL, or NHL subtypes in these studies. IMPACT: Though biologically plausible, tattoos were not associated with increased risk of NHL or multiple myeloma in this study. Future studies with greater detail regarding tattoo exposure may provide further insights.

Mammographic density parameters and breast cancer tumor characteristics among postmenopausal women.

PURPOSE: Mammographic density is an important breast cancer risk factor, although it is not clear whether the association differs across breast cancer tumor subtypes. We examined the association between indicators of mammographic density and breast cancer risk by tumor subtype among postmenopausal women by investigating heterogeneity across tumor characteristics. METHODS: Mammographic density measures were determined for 477 breast cancer cases and 588 controls, all postmenopausal, in Vancouver, British Columbia, using digitized screening mammograms and Cumulus software. Mammographic dense (DA), non-dense (NDA), and percent dense (PDA) areas were treated as continuous covariates and categorized into quartiles according to the distribution in controls. For cases only, tests for heterogeneity between tumor subtypes were assessed by multinomial logistic regression. Associations between mammographic density and breast cancer risk were modeled for each subtype separately through unconditional logistic regression. RESULTS: Heterogeneity was apparent for the association of PDA with tumor size (p-heterogeneity=0.04). Risk did not differ across the other assessed tumor characteristics (p-heterogeneity values >0.05). CONCLUSION: These findings do not provide strong evidence that mammographic density parameters differentially affect specific breast cancer tumor characteristics.

Genetic variants in genes related to inflammation, apoptosis and autophagy in breast cancer risk.

BACKGROUND: Inflammation contributes to breast cancer development through its effects on cell damage. This damage is usually dealt with by key genes involved in apoptosis and autophagy pathways. METHODS: We tested 206 single nucleotide polymorphisms (SNPs) in 54 genes related to inflammation, apoptosis and autophagy in a population-based breast cancer study of women of European (658 cases and 795 controls) and East Asian (262 cases and 127 controls) descent. Logistic regression was used to estimate odds ratios for breast cancer risk, and case-only analysis to compare breast cancer subtypes (defined by ER/PR/HER2 status), with adjustment for confounders. We assessed statistical interactions between the SNPs and lifestyle factors (smoking status, physical activity and body mass index). RESULTS AND CONCLUSION: Although no SNP was associated with breast cancer risk among women of European descent, we found evidence for an association among East Asians for rs1800925 (IL-13) and breast cancer risk (OR = 2.08; 95% CI: 1.32-3.28; p = 0.000779), which remained statistically significant after multiple testing correction (padj = 0.0350). This association was replicated in a meta-analysis of 4305 cases and 4194 controls in the Shanghai Breast Cancer Genetics Study (OR 1.12, 95% CI: 1.03-1.21, p = 0.011). Further, we found evidence of an interaction between rs7874234 (TSC1) and physical activity among women of East Asian descent.

Women's occupational exposure to polycyclic aromatic hydrocarbons and risk of breast cancer.

OBJECTIVE: To estimate the association between occupational polycyclic aromatic hydrocarbon (PAH) exposure and female breast cancer. METHODS: Lifetime work histories for 1130 cases and 1169 controls from British Columbia and Ontario (Canada) were assessed for PAH exposure using a job-exposure matrix based on compliance measurements obtained during US Occupational Safety and Health Administration workplace safety inspections. RESULTS: Exposure to any level of PAHs was associated with an increased risk of breast cancer (OR=1.32, 95% CI: 1.10 to 1.59), as was duration at high PAH exposure (for >7.4 years: OR=1.45, 95% CI: 1.10 to 1.91; ptrend=0.01), compared with women who were never exposed. Increased risk of breast cancer was most strongly associated with prolonged duration at high occupational PAH exposure among women with a family history of breast cancer (for >7.4 years: OR=2.79, 95% CI: 1.25 to 6.24; ptrend<0.01). CONCLUSIONS: Our study suggests that prolonged occupational exposure to PAH may increase breast cancer risk, especially among women with a family history of breast cancer.

Mammographic non-dense area and breast cancer risk in postmenopausal women: a causal inference approach in a case-control study.

PURPOSE: The association between high mammographic density (MD) and elevated breast cancer risk is well established. However, the role of absolute non-dense area remains unclear. We estimated the effect of the mammographic non-dense area and other density parameters on the risk of breast cancer. METHODS: This study utilizes data from a population-based case-control study conducted in Greater Vancouver, British Columbia, with 477 female postmenopausal breast cancer cases and 588 female postmenopausal controls. MD measures were determined from digitized screening mammograms using computer-assisted software (Cumulus). Marginal odds ratios were estimated by inverse-probability weighting using a causal diagram for confounder selection. Akaike information criteria and receiver operating characteristic curves were used to assess the goodness of fit and predictive power of unconditional logistic models containing MD parameters. RESULTS: The risk of breast cancer is 60% lower for the highest quartile compared to the lowest quartile of mammographic non-dense area (marginal OR 0.40, 95% CI 0.26-0.61, p-trend < 0.001). The cancer risk almost doubles for the highest quartile compared to the lowest quartile of dense area (marginal OR 1.81, 95% CI 1.19-2.43, p-trend < 0.001). For the highest quartile of percent density, breast cancer risk was more than three times higher than for the lowest quartile (marginal OR 3.15, 95% CI 1.90-4.40, p-trend < 0.001). No difference was seen in predictive accuracy between models using percent density alone, dense area alone, or non-dense area plus dense area. CONCLUSIONS: In this study, non-dense area is an independent risk factor after adjustment for dense area and other covariates, inversely related with the risk of breast cancer. However, non-dense area does not improve prediction over that offered by percent density or dense area alone.

Polymorphisms of Insulin-Like Growth Factor 1 Pathway Genes and Breast Cancer Risk.

Genetic variants of insulin-like growth factor 1 (IGF1) pathway genes have been shown to be associated with breast density and IGF1 levels and, therefore, may also influence breast cancer risk via pro-survival signaling cascades. The aim of this study was to investigate associations between IGF1 pathway single nucleotide polymorphisms (SNPs) and breast cancer risk among European and East Asian women, and potential interactions with menopausal status and breast tumor subtype. Stratified analyses of 1,037 cases and 1,050 controls from a population-based case-control study were conducted to assess associations with breast cancer for 22 SNPs across 5 IGF1 pathway genes in European and East Asian women. Odds ratios were calculated using logistic regression in additive genetic models. Polytomous logistic regression was used to assess heterogeneity by breast tumor subtype. Two SNPs of the IGF1 gene (rs1019731 and rs12821878) were associated with breast cancer risk among European women. Four highly linked IGF1 SNPs (rs2288378, rs17727841, rs7136446, and rs7956547) were modified by menopausal status among East Asian women only and associated with postmenopausal breast cancers. The association between rs2288378 and breast cancer risk was also modified by breast tumor subtype among East Asian women. Several IGF1 polymorphisms were found to be associated with breast cancer risk and some of these associations were modified by menopausal status or breast tumor subtype. Such interactions should be considered when assessing the role of these variants in breast cancer etiology.

Genetic variation in vitamin D-related genes and risk of breast cancer among women of European and East Asian descent.

Studies of vitamin D-related genetic variants and breast cancer have been inconsistent. This study aimed to investigate associations of vitamin D-related polymorphisms and breast cancer risk among European and East Asian women and potential interactions with menopausal status and breast tumour subtypes. Data from a case-control study of breast cancer (1037 cases and 1050 controls) were used to assess relationships between 21 polymorphisms in two vitamin D-related genes (GC and VDR) and breast cancer risk. Odds ratios were calculated in stratified analyses of European and East Asian women, using logistic regression in an additive genetic model. An interaction term was used to explore modification by menopausal status. Polytomous regression was used to assess heterogeneity by breast tumour subtype. False discovery rate adjustments were conducted to account for multiple testing. No association was observed between GC or VDR polymorphisms and breast cancer risk. Modification of these relationships by menopausal status was observed for select polymorphisms in both Europeans (VDR rs4328262 and rs11168292) and East Asians (GC rs7041 and VDR rs11168287). Heterogeneity by tumour subtype was seen for three VDR polymorphisms (rs1544410, rs7967152 and rs2239186) among Europeans, in which associations with ER-/PR-/HER2+ tumours, but not with other subtypes, were observed. In conclusion, associations between vitamin D-related genetic variants and breast cancer were not observed overall, although the relationships between vitamin D pathway polymorphisms and breast cancer may be modified by menopausal status and breast tumour subtype.

A case-control study of lifetime light intensity physical activity and breast cancer risk.

PURPOSE: Physical activity reduces breast cancer risk, although most evidence is for activity in the moderate-to-vigorous intensity range. The effect of light intensity physical activity (LIPA) is unknown. We aimed to determine the association between self-reported lifetime LIPA and pre- and post-menopausal breast cancer risk. Our secondary objective was to analyze risk stratified by estrogen and progesterone tumor receptor status. METHODS: Data were from a case-control study of 1,110 incident breast cancer cases (388 pre-menopausal; 722 post-menopausal) and 1,172 controls (442 pre-menopausal; 730 post-menopausal) recruited at two Canadian sites. Lifetime leisure-time, household, and occupational physical activity and covariates were assessed by questionnaire. Mean minutes per day of LIPA for each of the age periods 12-17, 18-34, 35-49, ≥50, and the total lifetime were calculated. Odds ratios were calculated using unconditional logistic regression for overall breast cancer risk and using polytomous logistic regression for estrogen receptor (ER)/progesterone receptor (PR)-defined tumor subtypes and were adjusted for moderate-to-vigorous physical activity and other confounders. RESULTS: LIPA was not associated with breast cancer risk at any age period across the life course: odds ratio (OR) = 0.81; 95 % CI 0.53-1.24 for pre-menopausal women and OR = 0.87; 95 % CI 0.64-1.19 for post-menopausal women in the highest vs. lowest categories of total lifetime LIPA. No heterogeneity in risk by ER/PR tumor status was observed. CONCLUSIONS: Our results suggest that light intensity physical activity is not associated with breast cancer risk reduction. This finding is important for physical activity recommendations for breast cancer prevention.

Increased risk of breast cancer associated with long-term shift work in Canada.

OBJECTIVES: Long-term night work has been suggested as a risk factor for breast cancer; however, additional studies with more comprehensive methods of exposure assessment to capture the diversity of shift patterns are needed. As well, few previous studies have considered the role of hormone receptor subtype. METHODS: Relationships between night shift work and breast cancer were examined among 1134 breast cancer cases and 1179 controls, frequency-matched by age in Vancouver, British Columbia, and Kingston, Ontario. Self-reported lifetime occupational histories were assessed for night shift work, and hormone receptor status obtained from tumour pathology records. RESULTS: With approximately one-third of cases and controls ever employed in night shift work, associations with duration demonstrated no relationship between either 0-14 or 15-29 years, while an association was apparent for ≥30 years (OR=2.21, 95% CI 1.14 to 4.31). This association with long-term night shift work is robust to alternative definitions of prolonged shift work, with similar results for both health and non-health care workers. CONCLUSIONS: Long-term night shift work in a diverse mix of occupations is associated with increased breast cancer risk and not limited to nurses, as in most previous studies.

Moderate-to-vigorous intensity physical activity across the life course and risk of pre- and post-menopausal breast cancer.

Moderate-to-vigorous intensity physical activity (MVPA) reduces breast cancer risk, although the effects of MVPA in different settings across the life course and how they may differ by menopausal status are unclear. This gap was addressed using data from a case-control study of 1,110 incident breast cancer cases and 1,172 cancer-free controls, frequency matched by age, from Vancouver and Kingston, Canada. In Vancouver, cases were recruited from the British Columbia Cancer Registry and controls from the Screening Mammography Program of British Columbia and in Kingston cases and controls were recruited from a breast assessment center. Lifetime leisure-time, household, and occupational MVPA energy expenditures were assessed in an open-ended questionnaire and mean weekly metabolic equivalent hours (MET-h/week) were calculated for the age periods 12-17, 18-34, 35-49, and ≥50 years and for the total lifetime. Odds ratios were estimated separately for pre- and for post-menopausal women using unconditional logistic regression. Among post-menopausal women, each of >22.9 MET-h/week of mean lifetime leisure-time MVPA (equivalent to running for 3 h) and >61.1 MET-h/week of mean lifetime household MVPA (equivalent to 24 h of moderate household work) reduced breast cancer risk by 40 %, compared to 0 MET-h/week of each. The respective ORs were 0.63 (95 % CI 0.42-0.94) and 0.58 (95 % CI 0.43-0.79). Among post-menopausal women, leisure-time MVPA after age 35 was more strongly associated with reduced breast cancer risk than MVPA in early life, while household MVPA was associated with reduced risk at all adulthood age periods. The weekly volume of leisure-time MVPA required to reduce post-menopausal breast cancer risk was consistent with amount recommended in the World Cancer Research Fund/American Institute for Cancer Research guidelines for cancer prevention.

Shift work, circadian gene variants and risk of breast cancer.

Circadian (clock) genes have been linked with several functions relevant to cancer, and epidemiologic research has suggested relationships with breast cancer risk for variants in NPAS2, CLOCK, CRY2 and TIMELESS. Increased breast cancer risk has also been observed among shift workers, suggesting potential interactions in relationships of circadian genes with breast cancer. Relationships with breast cancer of 100 SNPs in 14 clock-related genes, as well as potential interactions with shift work history, were investigated in a case-control study (1042 cases, 1051 controls). Odds ratios in an additive genetic model for European-ancestry participants (645 cases, 806 controls) were calculated, using a two-step correction for multiple testing: within each gene through permutation testing (10,000 permutations), and correcting for the false discovery rate across genes. Interactions of genotypes with ethnicity and shift work (<2 years vs ≥2 years) were evaluated individually. Following permutation analysis, two SNPs (rs3816360 in ARNTL and rs11113179 in CRY1) displayed significant associations with breast cancer and one SNP (rs3027188 in PER1) was marginally significant; however, none were significant following adjustment for the false discovery rate. No significant interaction with shift work history was detected. If shift work causes circadian disruption, this was not reflected in associations between clock gene variants and breast cancer risk in this study. Larger studies are needed to assess interactions with longer durations (>30 years) of shift work that have been associated with breast cancer.

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.

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.

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.

Hepatitis C virus and risk of non-Hodgkin lymphoma in British Columbia, Canada.

We investigated Hepatitis C virus (HCV) seropositivity and the risk of non-Hodgkin lymphoma (NHL) in a population-based case-control study in British Columbia, Canada. Cases were aged 20-79, diagnosed between March 2000 and February 2004, and resident in greater Vancouver or Victoria. Cases with HIV or a prior transplant were excluded. Controls were chosen from the Client Registry of the British Columbia (BC) Ministry of Health, and were age/sex/region frequency matched to cases. Antibodies for HCV were measured in 795 cases and 697 control subjects. HCV seropositivity was 2.4% in cases and 0.7% in controls [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 0.9-7.4]. A significantly elevated risk was observed for B-cell lymphoma (OR = 2.9, 95%CI = 1.0-8.6). The highest risks were associated with diffuse large B-cell lymphoma (OR = 7.3, 95%CI = 2.1-25.0) and marginal zone lymphoma (OR = 6.1, 95%CI = 1.1-33.9). Our results provide further evidence that HCV infection contributes to NHL risk.

Organochlorines and risk of non-Hodgkin lymphoma.

Organochlorine chemicals and polychlorinated biphenyls (PCBs) have been suspected as possible risk factors for non-Hodgkin lymphoma (NHL). We investigated PCBs and organochlorine pesticides and risk of NHL in a population-based case-control study in British Columbia, Canada. Congeners of PCBs (including dioxinlike congeners) and pesticides or pesticide metabolites were measured in plasma of 422 pretreatment cases and 460 control subjects. This is so far the largest study to examine organochlorines in plasma to date. Several dioxin-like PCB congeners were associated with increased risk of NHL, including dioxin-like PCB nos. 118 and 156 with odds ratios (OR) for the highest versus lowest quartile between 1.6 and 1.8. Several non-dioxin-like congeners also showed significant associations. The PCB congener with the strongest association was no. 180 with an OR for the highest versus the lowest quartile of 1.83 (95% confidence interval = 1.18-2.84). Six pesticide analytes also showed a significant association with NHL; beta-hexachlorocyclohexane, p,p'-DDE, hexachlorobenzene, mirex, oxychlordane and trans-nonachlor. The strongest association was found for oxychlordane, a metabolite of the pesticide chlordane (highest vs. lowest quartile OR = 2.68, 95% confidence interval = 1.69-4.24). Our results provide further evidence that organochlorines contribute to NHL risk.