Publications by authors named "Kristan J Aronson"

86 Publications

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

Breast Cancer 2021 Aug 5. Epub 2021 Aug 5.

School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.

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.
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http://dx.doi.org/10.1007/s12282-021-01279-0DOI Listing
August 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611832PMC
August 2021

Mendelian randomisation study of smoking exposure in relation to breast cancer risk.

Br J Cancer 2021 Oct 2;125(8):1135-1145. Epub 2021 Aug 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.

Methods: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.

Results: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.

Conclusion: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
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http://dx.doi.org/10.1038/s41416-021-01432-8DOI Listing
October 2021

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.

Am J Hum Genet 2021 07 18;108(7):1190-1203. Epub 2021 Jun 18.

Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10).
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http://dx.doi.org/10.1016/j.ajhg.2021.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322933PMC
July 2021

The impact of image resolution on power, bias, and confounding: A simulation study of ambient light at night exposure.

Environ Epidemiol 2021 Apr 2;5(2):e145. Epub 2021 Apr 2.

GFZ German Research Centre for Geosciences, Potsdam, Germany.

Studies of the impact of environmental pollutants on health outcomes can be compromised by mismeasured exposures or unmeasured confounding with other environmental exposures. Both problems can be exacerbated by measuring exposure from data sources with low spatial resolution. Artificial light at night, for example, is often estimated from low-resolution satellite images, which may result in substantial measurement error and increased correlation with air or noise pollution.

Methods: Light at night exposure was considered in simulated epidemiologic studies in Vancouver, British Columbia. First, we assessed statistical power and bias for hypothetical studies that replaced true light exposure with estimates from sources with low resolution. Next, health status was simulated based on pollutants other than light exposure, and we assessed the frequency with which studies might incorrectly attribute negative health impacts to light exposure as a result of unmeasured confounding by the other environmental exposures.

Results: When light was simulated to be the causal agent, studies relying on low-resolution data suffered from lower statistical power and biased estimates. Additionally, correlations between light and other pollutants increased as the spatial resolution of the light exposure map decreased, so studies estimating light exposure from images with lower spatial resolution were more prone to confounding.

Conclusions: Studies estimating exposure to pollutants from data with lower spatial resolution are prone to increased bias, increased confounding, and reduced power. Studies examining effects of light at night should avoid using exposure estimates based on low-resolution maps, and should consider potential confounding with other environmental pollutants.
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http://dx.doi.org/10.1097/EE9.0000000000000145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043729PMC
April 2021

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Nat Commun 2021 02 17;12(1):1078. Epub 2021 Feb 17.

Copenhagen General Population Study, Herlev and Gentofte Hospital Copenhagen University Hospital, Herlev, Denmark.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1038/s41467-020-20496-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890067PMC
February 2021

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.

Br J Cancer 2021 02 26;124(4):842-854. Epub 2021 Jan 26.

Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.

Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.

Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10).

Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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http://dx.doi.org/10.1038/s41416-020-01185-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884683PMC
February 2021

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Am J Hum Genet 2020 11 5;107(5):837-848. Epub 2020 Oct 5.

Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong; Hong Kong Sanatorium and Hospital, Department of Pathology, Happy Valley, Hong Kong.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS was quantified using Cox regression analyses. We assessed PRS interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10 percentile and 20.5% at the 90 percentile of PRS. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675034PMC
November 2020

The Associations of Shift Work, Sleep Quality, and Incidence of Hypertension in Ontario Adults: A Population-Based Study.

Can J Cardiol 2021 03 12;37(3):513-518. Epub 2020 Sep 12.

School of Nursing, Queen's University, Kingston, Ontario, Canada. Electronic address:

Background: Relatively few population-based studies have explored the relationship and potential mechanisms between exposure to shift work and hypertension. The study objectives for this study were to determine 1) if history of shift work was associated with increased rates of hypertension among working adults, and 2) if sleep quality mediated this relationship.

Methods: We conducted a population-based cohort study using data from Ontario respondents (aged 35-69 y) in the 2000-2001 Canadian Community Health Survey, which was linked to administrative health data housed at the Institute for Clinical Evaluative Sciences. Our sample included survey participants who were employed with no previous diagnosis of hypertension (n = 7420). During a 12-year follow-up window, we determined the time of hypertension diagnosis based on a previously validated algorithm; and explored the mediating effect of sleep quality using marginal structural effect models.

Results: The study sample included 2079 shift workers and 5341 day workers. Shift workers reported less refreshing sleep, more trouble sleeping, and poorer sleep quality overall compared with day workers. In 12 years of follow-up, 31.3% of workers developed hypertension. History of shift work was associated with higher hypertension rates in both men (hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.02-1.44) and women (HR 1.26, 95% CI 1.03-1.55). There was no evidence that these associations were mediated by past sleep quality.

Conclusions: History of shift work schedules is associated with increased rates of hypertension. Shift work disrupts sleep, but further longitudinal studies are needed to determine if sleep quality mediates the association between shift work and hypertension.
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http://dx.doi.org/10.1016/j.cjca.2020.09.003DOI Listing
March 2021

European polygenic risk score for prediction of breast cancer shows similar performance in Asian women.

Nat Commun 2020 07 31;11(1):3833. Epub 2020 Jul 31.

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore, Singapore.

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.
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http://dx.doi.org/10.1038/s41467-020-17680-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395776PMC
July 2020

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.

Sci Rep 2020 06 16;10(1):9688. Epub 2020 Jun 16.

Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
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http://dx.doi.org/10.1038/s41598-020-65665-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297796PMC
June 2020

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Nat Genet 2020 06 18;52(6):572-581. Epub 2020 May 18.

Molecular Medicine Unit, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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http://dx.doi.org/10.1038/s41588-020-0609-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808397PMC
June 2020

Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.

J Natl Cancer Inst 2021 03;113(3):329-337

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
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http://dx.doi.org/10.1093/jnci/djaa056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936056PMC
March 2021

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants.

Nat Commun 2020 03 5;11(1):1217. Epub 2020 Mar 5.

Departments of Health Research and Policy, School of Medicine, Stanford University, California, CA, USA.

Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women.
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http://dx.doi.org/10.1038/s41467-020-15046-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057957PMC
March 2020

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Genet Epidemiol 2020 07 1;44(5):442-468. Epub 2020 Mar 1.

Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
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http://dx.doi.org/10.1002/gepi.22288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987299PMC
July 2020

Outdoor light at night at residences and breast cancer risk in Canada.

Eur J Epidemiol 2020 Jun 6;35(6):579-589. Epub 2020 Feb 6.

Department of Public Health Sciences, Queen's University, Kingston, ON, Canada.

Experimental and epidemiologic studies suggest that light at night (LAN) exposure disrupts circadian rhythm, and this disruption may increase breast cancer risk. We investigated the potential association between residential outdoor LAN and breast cancer risk. A population-based case-control study was conducted in Vancouver, British Columbia and Kingston, Ontario, Canada with incident breast cancer cases, and controls frequency matched by age in the same region. This analysis was restricted to 844 cases and 905 controls who provided lifetime residential histories. Using time-weighted average duration at each home 5-20 years prior to study entry, two measures of cumulative average outdoor LAN were calculated using two satellite data sources. Logistic regression was used to estimate the relationship between outdoor LAN and breast cancer risk, considering interactions for menopausal status and night shift work. We found no association between residential outdoor LAN and breast cancer for either measure of LAN [OR comparing highest vs. lowest tertile (DNB) = 0.95, 95% CI 0.70-1.27]. We also found no association when considering interactions for menopausal status and past/current night work status. These findings were robust to changes to years of residential data considered, residential mobility, and longer exposure windows. Our findings are consistent with studies reporting that outdoor LAN has a small effect or no effect on breast cancer risk.
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http://dx.doi.org/10.1007/s10654-020-00610-xDOI Listing
June 2020

Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Nat Genet 2020 01 7;52(1):56-73. Epub 2020 Jan 7.

Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
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http://dx.doi.org/10.1038/s41588-019-0537-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974400PMC
January 2020

The :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

NPJ Breast Cancer 2019 1;5:38. Epub 2019 Nov 1.

25University of Texas MD Anderson Cancer Center, Department of Breast Medical Oncology, Houston, TX USA.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes , , , , and are associated with breast cancer risk. , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of or . These three variants were also studied functionally by measuring survival and chromosome fragility in patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44,  = 0.034 and OR = 3.79;  = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for :p.Arg658* and found that also :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96;  = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat -associated tumors.
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http://dx.doi.org/10.1038/s41523-019-0127-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825205PMC
November 2019

SMS behaviour change communication and eVoucher interventions to increase uptake of cervical cancer screening in the Kilimanjaro and Arusha regions of Tanzania: a randomised, double-blind, controlled trial of effectiveness.

BMJ Innov 2019 Jan 22;5(1):28-34. Epub 2019 Feb 22.

Department of Medicine, Queen's University, Kingston, Ontario, Canada.

Background: Cervical cancer, although almost entirely preventable through cervical cancer screening (CCS) and human papillomavirus vaccination, is the leading cause of cancer deaths among women in Tanzania. Barriers to attending CCS include lack of awareness of CCS, affordability concerns regarding screening and travel cost. We aimed to compare the effectiveness of SMS (short message service) behaviour change communication (BCC) messages and of SMS BCC messages delivered with a transportation electronic voucher (eVoucher) on increasing uptake of CCS versus the control group.

Methods: Door-to-door recruitment was conducted between 1 February and 13 March 2016 in randomly selected enumeration areas in the catchment areas of two hospitals, one urban and one rural, in Northern Tanzania. Women aged 25-49 able to access a mobile phone were randomised using a computer-generated 1:1:1 sequence stratified by urban/rural to receive either (1) 15 SMS, (2) an eVoucher for return transportation to CCS plus the same SMS, or (3) one SMS informing about the nearest CCS clinic. Fieldworkers and participants were masked to allocation. All areas received standard sensitisation including posters, community announcements and sensitisation similar to community health worker (CHW) sensitisation. The primary outcome was attendance at CCS within 60 days of randomisation.

Findings: Participants (n866) were randomly allocated to the BCC SMS group (n272), SMS + eVoucher group (n313), or control group (n281), with 851 included in the analysis (BCC SMS n272, SMS + eVoucher n298, control group n281). By day 60 of follow-up, 101 women (11.9%) attended CCS. Intervention group participants were more likely to attend than control group participants (SMS + eVoucher OR: 4.7, 95% CI 2.9 to 7.4; SMS OR: 3.0, 95% CI 1.5 to 6.2).

Trial Registration Number: NCT02680613.
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http://dx.doi.org/10.1136/bmjinnov-2018-000276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792319PMC
January 2019

Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestry.

EBioMedicine 2019 Oct 16;48:203-211. Epub 2019 Oct 16.

Department of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA; Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.

Background: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets.

Methods: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets.

Findings: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P < 2·19 × 10. The associations for four variants reached P < 5 × 10 and have been reported by previous GWAS, including rs6435074 and rs6723097 (CASP8), rs17879961 (CHEK2) and rs2853669 (TERT). The remaining eight variants were rs676387 (HSD17B1), rs762551 (CYP1A2), rs1045485 (CASP8), rs9340799 (ESR1), rs7931342 (CHR11), rs1050450 (GPX1), rs13010627 (CASP10) and rs9344 (CCND1). Further investigating these 10 genes identified associations for two additional variants at P < 5 × 10, including rs4793090 (near HSD17B1), and rs9210 (near CYP1A2), which have not been identified by previous GWAS.

Interpretation: Though most candidate gene variants were not associated with breast cancer risk, we found 14 variants showing an association. Our findings warrant further functional investigation of these variants. FUND: National Institutes of Health.
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http://dx.doi.org/10.1016/j.ebiom.2019.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838373PMC
October 2019

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

Breast Cancer (Dove Med Press) 2019 16;11:261-271. Epub 2019 Aug 16.

School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.

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 (-heterogeneity=0.04). Risk did not differ across the other assessed tumor characteristics (-heterogeneity values >0.05).

Conclusion: These findings do not provide strong evidence that mammographic density parameters differentially affect specific breast cancer tumor characteristics.
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http://dx.doi.org/10.2147/BCTT.S192766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702445PMC
August 2019

Two truncating variants in FANCC and breast cancer risk.

Sci Rep 2019 08 29;9(1):12524. Epub 2019 Aug 29.

Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
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http://dx.doi.org/10.1038/s41598-019-48804-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715680PMC
August 2019

Shift Work, Chronotype, and Cancer Risk-Response.

Cancer Epidemiol Biomarkers Prev 2019 08 12;28(8):1405. Epub 2019 Jul 12.

Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canada.

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http://dx.doi.org/10.1158/1055-9965.EPI-19-0524DOI Listing
August 2019

The functional ALDH2 polymorphism is associated with breast cancer risk: A pooled analysis from the Breast Cancer Association Consortium.

Mol Genet Genomic Med 2019 06 7;7(6):e707. Epub 2019 May 7.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Background: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium.

Methods: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models.

Results: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537).

Conclusion: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.
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http://dx.doi.org/10.1002/mgg3.707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565553PMC
June 2019

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

Nat Commun 2019 04 15;10(1):1741. Epub 2019 Apr 15.

Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), 28040, Madrid, Spain.

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
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http://dx.doi.org/10.1038/s41467-018-08053-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465407PMC
April 2019

Shift Work Patterns, Chronotype, and Epithelial Ovarian Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2019 05 6;28(5):987-995. Epub 2019 Mar 6.

Université de Montréal Hospital Research Centre (CRCHUM), Montreal, Quebec, Canada.

Background: Shift work causing circadian disruption is classified as a "probable carcinogen" and may contribute to the pathogenesis of hormone-sensitive cancers. This study investigated shift work exposure in relation to epithelial ovarian cancer (EOC) risk.

Methods: In a population-based case-control study with 496 EOC cases and 906 controls, lifetime occupational histories were collected and used to calculate cumulative years of shift work exposure, average number of night shifts per month, and average number of consecutive night shifts per month. ORs and 95% confidence intervals (CI) for associations with EOC risk were estimated using logistic regression. Associations were also examined according to chronotype and menopausal status.

Results: More than half of the cases (53.4%) and controls (51.7%) worked evening and/or night shifts. There was no clear pattern of increasing EOC risk with increasing years of shift work; the adjusted OR of EOC comparing the highest shift work category versus never working shift work was 1.20 (95% CI, 0.89-1.63). This association was more pronounced among those self-identified as having a "morning" chronotype (OR, 1.64; 95% CI, 1.01-2.65). Associations did not greatly differ by menopausal status.

Conclusions: These results do not strongly demonstrate a relationship between shift work and EOC risk.

Impact: This study collected detailed shift work information and examined shift work patterns according to shift times and schedules. The findings highlight that chronotype should be considered in studies of shift work as an exposure.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1112DOI Listing
May 2019

The relationship between night work, chronotype, and cardiometabolic risk factors in female hospital employees.

Chronobiol Int 2019 05 7;36(5):616-628. Epub 2019 Feb 7.

a Department of Public Health Sciences , Queen's University , Kingston , Ontario , Canada.

Night work has emerged as a risk factor for many chronic diseases, including obesity, diabetes, and cardiovascular disease. While night work is linked to a number of cardiometabolic indices, few studies have explored how different parameters, such as cumulative night work and intensity of night work, may influence cardiometabolic risk. Fewer studies have also explored the relationship while considering chronotype, a potential modifier between shift-induced circadian disruption and cardiometabolic outcomes. The main objective is to determine the association between night work parameters and cardiometabolic risk factors. The secondary objective is to assess how the association between night work parameters and cardiometabolic risk factors differs by chronotype. A cross-sectional study was conducted with 325 full- and part-time female hospital employees (168 rotating night workers, 157 day workers). Night work status, cumulative night work duration, and night work intensity were determined through self-report, and cardiometabolic risk factors were assessed through clinical exams. Chronotype was determined using the Munich Chronotype Questionniare (MCTQ). Multiple linear regression was used to examine the association between night work parameters and cardiometabolic risk factors. Current night work, cumulative night work, and night work intensity are associated with a number of cardiometabolic indices, including higher waist circumference, body mass index, fasting glucose, blood pressure, and cardiometabolic risk score. When stratified by chronotype, night work parameters are associated with a number of cardiometabolic risk factors in the evening-oriented chronotype subgroup. There is no difference in cardiometabolic risk factors in morning-oriented chronotypes when comparing night work parameters, with the exception of LDL cholesterol. These results suggest that night work parameters are associated with cardiometabolic risk, and night workers with an evening-oriented chronotype may be more susceptible to the adverse cardiometabolic impacts of night work. Future studies should consider chronotype when examining the relationship between night work and cardiometabolic risk.
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http://dx.doi.org/10.1080/07420528.2019.1570247DOI Listing
May 2019

Working Time Society consensus statements: Individual differences in shift work tolerance and recommendations for research and practice.

Ind Health 2019 Apr 31;57(2):201-212. Epub 2019 Jan 31.

University of Applied Sciences for Economics and Management (FOM), Germany.

There is no standard definition of shift work universally, and no validated report of complete biological adjustment to shift work in workers. Similarly, the evidence for shift work tolerance is limited due to a small number of studies and a narrow range of outcome measures. This paper discusses evidence to date regarding individual differences in shift work tolerance and highlights areas for future research and recommendations for workplace practice. The few factors that are consistently associated with perceived or actual shift work tolerance are young age, low scores of morningness or being a late chronotype, low scores of languidity and neuroticism, high scores on extraversion, internal locus of control and flexibility and male sex. An important first step is to differentiate between factors that are potentially modifiable, such as those that are determined by lifestyle choices, and those factors specific to the working time arrangement. Identifying determinants of shift work tolerance and the ability to adjust to shift work, whether they are innate and/or acquired mechanisms, is important so workers who are less likely to tolerate shift work well can be self-identified and supported with appropriate harm/risk minimization strategies. This paper also identifies important areas for future research with the goal of increasing the evidence base on which we can develop evidence-based harm mitigation strategies for shift workers.
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http://dx.doi.org/10.2486/indhealth.SW-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449641PMC
April 2019
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