Irene L Andrulis

University of Toronto, Toronto, Ontario, Canada

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Publications (227)1761.44 Total impact

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    ABSTRACT: Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 × 10−8). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p = 0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63 ± 12 and 23 ± 10 % for ALT positive and negative tumors, respectively (p = 0.03), while for children with TP53 mutant choroid plexus carcinomas, 5 years overall survival was 67 ± 19 and 27 ± 13 % for ALT positive and negative tumors, respectively (p = 0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children.
    Acta Neuropathologica 10/2015; DOI:10.1007/s00401-014-1348-1 · 9.78 Impact Factor
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    ABSTRACT: The etiologic contribution of germline genetic variation to sporadic osteosarcoma is not well understood. Osteosarcoma is a sentinel cancer of Li-Fraumeni syndrome (LFS), in which approximately 70% of families meeting the classic criteria have germline TP53 mutations. We sequenced TP53 exons in 765 osteosarcoma cases. Data were analyzed with χ(2) tests, logistic regression, and Cox proportional hazards regression models. We observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated mutation (3.8%) or rare exonic variant (5.7%) with an overall frequency of 9.5%, compared with none in case patients age 30 years and older (P < .001). This high TP53 mutation prevalence in young osteosarcoma cases is statistically significantly greater than the previously reported prevalence of 3% (P = .0024). We identified a novel association between a TP53 rare variant and metastasis at diagnosis of osteosarcoma (rs1800372, odds ratio = 4.27, 95% confidence interval = 1.2 to 15.5, P = .026). Genetic susceptibility to young onset osteosarcoma is distinct from older adult onset osteosarcoma, with a high frequency of LFS-associated and rare exonic TP53 variants. Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
    CancerSpectrum Knowledge Environment 07/2015; 107(7). DOI:10.1093/jnci/djv101 · 15.16 Impact Factor
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    ABSTRACT: Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute non-dense area adjusted for study, age and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210 (ESR1) and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all p <10-5). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679 (EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and non-dense areas, and between rs17356907 (NTN4) and adjusted absolute non-dense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiological pathways implicated in how mammographic density predicts breast cancer risk. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 04/2015; DOI:10.1158/0008-5472.CAN-14-2012 · 9.28 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
    Nature Genetics 03/2015; DOI:10.1038/ng.3242 · 29.65 Impact Factor
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    ABSTRACT: We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43,160 cases and 42,600 controls of European ancestry ascertained from 52 studies and a further 5,795 cases and 6,624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (OR=0.90 [0.88-0.92]; P-value=1.58 x 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans approximately 14.5 Kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR=1.12 [1.08-1.17]; P-value=7.89 x 10(-09)) and rs13294895 (OR=1.09 [1.06-1.12]; P-value=2.97 x 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR=1.12 [1.06-1.18]; P-value=2.77 x 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 02/2015; DOI:10.1093/hmg/ddv035 · 6.68 Impact Factor
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    ABSTRACT: The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP AURKB BIRC5 and CDCA8) were genotyped in 88,911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk (per A allele OR 0.95 95% CI 1.02-1.10, p=0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, p=0.002). The data suggest that INCENP in the CPC pathway contributes to ER negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions please email: journals.permissions@oup.com.
    Carcinogenesis 01/2015; DOI:10.1093/carcin/bgu326 · 5.27 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
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    Karoline B Kuchenbaecker, Susan L Neuhausen, Mark Robson, Daniel Barrowdale, Lesley McGuffog, Anna Marie Mulligan, Irene L Andrulis, Amanda B Spurdle, Marjanka K Schmidt, Rita K Schmutzler, [......], Niklas Loman, Ake Borg, Hans Ehrencrona, Olufunmilayo I Olopade, Jacques Simard, Douglas F Easton, Georgia Chenevix-Trench, Kenneth Offit, Fergus J Couch, Antonis C Antoniou
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    ABSTRACT: Introduction More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10−6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Conclusions Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction. Electronic supplementary material The online version of this article (doi:10.1186/s13058-014-0492-9) contains supplementary material, which is available to authorized users.
    Breast Cancer Research 12/2014; 16(6). DOI:10.1186/s13058-014-0492-9 · 5.33 Impact Factor
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    ABSTRACT: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
    Breast cancer research: BCR 12/2014; 16(6):3419. DOI:10.1186/s13058-014-0474-y · 5.88 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 12/2014; DOI:10.1016/j.ajhg.2014.11.009 · 10.99 Impact Factor
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    ABSTRACT: Purpose:Chromosomal microarray analysis to assess copy-number variation has become a first-tier genetic diagnostic test for individuals with unexplained neurodevelopmental disorders or multiple congenital anomalies. More than 100 cytogenetic laboratories worldwide use the new ultra-high resolution Affymetrix CytoScan-HD array to genotype hundreds of thousands of samples per year. Our aim was to develop a copy-number variation resource from a new population sample that would enable more accurate interpretation of clinical genetics data on this microarray platform and others.Methods:Genotyping of 1,000 adult volunteers who are broadly representative of the Ontario population (as obtained from the Ontario Population Genomics Platform) was performed with the CytoScan-HD microarray system, which has 2.7 million probes. Four independent algorithms were applied to detect copy-number variations. Reproducibility and validation metrics were quantified using sample replicates and quantitative-polymerase chain reaction, respectively.Results:DNA from 873 individuals passed quality control and we identified 71,178 copy-number variations (81 copy-number variations/individual); 9.8% (6,984) of these copy-number variations were previously unreported. After applying three layers of filtering criteria, from our highest confidence copy-number variation data set we obtained >95% reproducibility and >90% validation rates (73% of these copy-number variations overlapped at least one gene).Conclusion:The genotype data and annotated copy-number variations for this largely Caucasian population will represent a valuable public resource enabling clinical genetics research and diagnostics.Genet Med advance online publication 11 December 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.178.
    Genetics in medicine: official journal of the American College of Medical Genetics 12/2014; DOI:10.1038/gim.2014.178 · 6.44 Impact Factor
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    ABSTRACT: Purpose:To analyse the effect of germline mutations in BRCA1 and BRCA2 on mortality in ovarian cancer patients up to ten years after diagnosis. Experimental Design:We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival-time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analysed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analysed using Fine and Gray model. Results: The combined 10-year overall survival was 30% (95% CI, 28%-31%) for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The hazard ratio for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the hazard ratio was 0.42 at time zero and increased over time (predicted to become greater than one at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors, and to ovarian cancer specific mortality. Conclusions: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and, in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.
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    ABSTRACT: Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
    Cancer Epidemiology Biomarkers & Prevention 10/2014; 24:308-16. DOI:10.1158/1055-9965.EPI-14-0532 · 4.32 Impact Factor
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    ABSTRACT: GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.
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    ABSTRACT: A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint ) <1.1×10(-3) . None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ≥170cm (OR=1.22, p=0.017), but inversely associated with ER-negative BC risk in women <160cm (OR=0.83, p=0.039, pint =1.9×10(-4) ). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR=0.85, p=2.0×10(-4) ), and absent in women who had had just one (OR=0.96, p=0.19, pint = 6.1×10(-4) ). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR=0.93, p=2.8×10(-5) ), but no association was observed in current smokers (OR=1.07, p=0.14, pint = 3.4×10(-4) ). In conclusion, recently identified breast cancer susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 09/2014; DOI:10.1002/ijc.29188 · 5.01 Impact Factor
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    ABSTRACT: Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single nucleotide polymorphisms (SNPs) spanning a 1Mb region around CASP8 were genotyped in 46,450 breast cancer cases and 42,600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1,232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10,052 case and 12,575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% CI)] for the minor allele of 1.05 (1.03-1.07), p=1x10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (p=3 x10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), p=1x10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
    Human Molecular Genetics 08/2014; DOI:10.1093/hmg/ddu431 · 6.68 Impact Factor
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    ABSTRACT: BACKGROUND Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown. METHODS We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation. RESULTS The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P < 0.001) and by other familial factors (P = 0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age. CONCLUSIONS Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.
    New England Journal of Medicine 08/2014; 371(6):497-506. DOI:10.1056/NEJMoa1400382 · 54.42 Impact Factor
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    ABSTRACT: Though the role of Estrogen Receptor (ER)α in breast cancer has been studied extensively, there is little consensus about the role of alternative ER isoform ERβ in breast cancer biology. ERβ has significant sequence homology to ERα but is located on a different chromosome and maintains both overlapping and unique functional attributes. Five variants exist, resulting from alternative splicing of the C-terminal region of ERβ. The relevance of ERβ variants in breast cancer outcomes and response to therapy is difficult to assess because of conflicting reports in the literature, likely due to variable methods used to assess ERβ in patient tumors. Here, we quantitatively assess expression of ERβ splice variants on over 2,000 breast cancer patient samples. Antibodies against ERβ variants were validated for staining specificity in cell lines by siRNA knockdown of ESR2 and staining reproducibility on formalin-fixed paraffin-embedded tissue by quantitative immunofluorescence (QIF) using AQUA technology. We found antibodies against splice variants ERβ1 and ERβ5, but not ERβ2/cx, which were sensitive, specific, and reproducible. QIF staining of validated antibodies showed both ERβ1 and ERβ5 QIF scores, which have a normal (bell shaped) distribution on most cohorts assessed, and their expression is significantly associated with each other. Extensive survival analyses show that ERβ1 is not a prognostic or predictive biomarker for breast cancer. ERβ5 appears to be a context-dependent marker of worse outcome in HER2-positive and triple-negative patients, suggesting an unknown biological function in the absence of ERα.
    Breast Cancer Research and Treatment 07/2014; 146(3). DOI:10.1007/s10549-014-3050-3 · 4.20 Impact Factor
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    ABSTRACT: Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46,450 cases and 42,600 controls) and analysed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 (rs1053338, per-allele OR=1.07, 95%CI=1.04-1.10, P=2.9x10(-6)), AKAP9-M463I at 7q21 (rs6964587, OR=1.05, 95%CI=1.03-1.07, P=1.7x10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR=1.10, 95%CI=1.07-1.12, P=5.1x10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine GWAS: for ATXN7-K264R, OR=1.07 (95%CI=1.05-1.10, P=1.0x10(-8)); for AKAP9-M463I, OR=1.05 (95%CI=1.04-1.07, P=2.0x10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known genome-wide association study (GWAS) hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
    Human Molecular Genetics 06/2014; DOI:10.1093/hmg/ddu311 · 6.68 Impact Factor

Publication Stats

7k Citations
1,761.44 Total Impact Points

Institutions

  • 1989–2015
    • University of Toronto
      • • Department of Molecular Genetics
      • • Department of Laboratory Medicine and Pathobiology
      • • Mount Sinai Hospital
      Toronto, Ontario, Canada
  • 2014
    • Sinai Hospital
      Mount Sinai, New York, United States
  • 2011–2014
    • Mount Sinai Hospital
      New York, New York, United States
    • National Institutes of Health
      • Division of Cancer Epidemiology and Genetics
      Maryland, United States
    • University College London
      Londinium, England, United Kingdom
  • 1993–2014
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 2013
    • University of Queensland 
      • School of Chemistry and Molecular Biosciences
      Brisbane, Queensland, Australia
    • Peter MacCallum Cancer Centre
      • Department of Cancer Medicine
      Melbourne, Victoria, Australia
    • German Cancer Research Center
      • Division of Cancer Epidemiology
      Heidelberg, Baden-Wuerttemberg, Germany
    • Herlev Hospital
      Herlev, Capital Region, Denmark
  • 2010–2013
    • Centro Nacional de Investigaciones Oncológicas
      • Human Cancer Genetics Programme
      Madrid, Madrid, Spain
    • Albert Einstein College of Medicine
      New York City, New York, United States
  • 1989–2013
    • Mount Sinai Hospital, Toronto
      • Department of Pathology and Laboratory Medicine
      Toronto, Ontario, Canada
  • 2012
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 2007–2012
    • University of Cambridge
      • • Department of Oncology
      • • Department of Public Health and Primary Care
      Cambridge, ENG, United Kingdom
    • Mayo Clinic - Rochester
      • Department of Laboratory Medicine & Pathology
      Rochester, MN, United States
  • 2005–2012
    • Cancer Care Ontario
      Toronto, Ontario, Canada
  • 2009
    • International Agency for Research on Cancer
      Lyons, Rhône-Alpes, France
    • Beijing University of Technology
      Peping, Beijing, China
  • 2006
    • Columbia University
      New York, New York, United States
  • 1984–1986
    • SickKids
      Toronto, Ontario, Canada