Carl Blomqvist

Uppsala University, Uppsala, Uppsala, Sweden

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Publications (344)2398.2 Total impact

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    ABSTRACT: Majority of the known breast cancer susceptibility genes have a role in DNA repair and the most important high-risk genes BRCA1 and BRCA2 are specifically involved in the homologous recombination repair (HRR) of DNA double-strand breaks. A central player in HRR is RAD51 that binds DNA at the damage site. The RAD51 paralogs RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3 facilitate the binding of RAD51 to DNA. While germline mutations in RAD51C and RAD51D are associated with high ovarian cancer risk and RAD51B polymorphisms with breast cancer, the contribution of RAD51, XRCC3, and XRCC2 is more unclear. To investigate the role of RAD51, XRCC3, and XRCC2 in breast cancer predisposition and to identify putative recurrent founder mutations in the Finnish population where such mutations have been observed in most of the currently known susceptibility genes, we screened 182 familial Finnish breast or ovarian cancer patients for germline variation in the RAD51and XRCC3 genes and 342 patients for variation in XRCC2, with a subset of the patients selected on the basis of decreased RAD51 protein expression on tumors. We also performed haplotype analyses for 1516 breast cancer cases and 1234 controls to assess the common variation in these genes. No pathogenic mutations were detected in any of the genes and the distribution of haplotypes was similar between cases and controls. Our results suggest that RAD51, XRCC3, and XRCC2 do not substantially contribute to breast cancer predisposition in the Finnish population.
    SpringerPlus 12/2015; 4(1):92. DOI:10.1186/s40064-015-0880-3
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    ABSTRACT: HER2 is a well-established prognostic and predictive factor in invasive breast cancer. The role of HER2 in ductal breast carcinoma in situ (DCIS) is debated and recent data have suggested that HER2 is mainly related to in situ recurrences. Our aim was to study HER2 as a prognostic factor in a large population based cohort of DCIS with long-term follow-up. All 458 patients diagnosed with a primary DCIS 1986-2004 in two Swedish counties were included. Silver-enhanced in situ hybridisation (SISH) was used for detection of HER2 gene amplification and protein expression was assessed by immunohistochemistry (IHC) in tissue microarrays. HER2 positivity was defined as amplified HER2 gene and/or HER2 3+ by IHC. HER2 status in relation to new ipsilateral events (IBE) and Invasive Breast Cancer Recurrences, local or distant (IBCR) was assessed by Kaplan-Meier survival analyses and Cox proportional hazards regression models. Primary DCIS was screening-detected in 75.5 % of cases. Breast conserving surgery (BCS) was performed in 78.6 % of whom 44.0 % received postoperative radiotherapy. No patients received adjuvant endocrine- or chemotherapy. The majority of DCIS could be HER2 classified (N = 420 (91.7 %)); 132 HER2 positive (31 %) and 288 HER2 negative (69 %)). HER2 positivity was related to large tumor size (P = 0.002), high grade (P < 0.001) and ER- and PR negativity (P < 0.001 for both). During follow-up (mean 184 months), 106 IBCRs and 105 IBEs were identified among all 458 cases corresponding to 54 in situ and 51 invasive recurrences. Eighteen women died from breast cancer and another 114 had died from other causes. The risk of IBCR was statistically significantly lower subsequent to a HER2 positive DCIS compared to a HER2 negative DCIS, (Log-Rank P = 0.03, (HR) 0.60 (95 % CI 0.38-0.94)). Remarkably, the curves did not separate until after 10 years. In ER-stratified analyses, HER2 positive DCIS was associated with lower risk of IBCR among women with ER negative DCIS (Log-Rank P = 0.003), but not for women with ER positive DCIS. Improved prognostic tools for DCIS patients are warranted to tailor adjuvant therapy. Here, we demonstrate that HER2 positive disease in the primary DCIS is associated with lower risk of recurrent invasive breast cancer.
    BMC Cancer 06/2015; 15(1):468. DOI:10.1186/s12885-015-1479-3 · 3.32 Impact Factor
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    ABSTRACT: Although most estrogen receptor (ER)-positive breast cancer patients benefit from endocrine therapies, a significant proportion do not. Our aim was to identify inherited genetic variations that might predict survival among patients receiving adjuvant endocrine therapies. We performed a meta-analysis of two genome-wide studies; Helsinki Breast Cancer Study, 805 patients, with 240 receiving endocrine therapy and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer, 536 patients, with 155 endocrine therapy-patients, evaluating 486,478 single nucleotide polymorphisms (SNPs). The top four associations from the endocrine treatment subgroup were further investigated in two independent datasets totalling 5011 patients, with 3485 receiving endocrine therapy. A meta-analysis identified a common SNP rs8113308, mapped to 19q13.41, associating with reduced survival among endocrine treated patients (hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.37-2.07, P = 6.34 ×10-7) and improved survival among ER-negative patients, with a similar trend in ER-positive cases not receiving endocrine therapy. In a multivariate analysis adjusted for conventional prognostic factors, we found a significant interaction between the rs8113308 and endocrine treatment indicating a predictive, treatment-specific effect of the SNP rs8113308 on breast cancer survival, with the per-allele HR for interaction 2.16 (95% CI 1.30 - 3.60, Pinteraction = 0.003) and HR=7.77 (95% CI 0.93 - 64.71) for the homozygous genotype carriers. A biological rationale is suggested by in silico functional analyses. Our findings suggest carrying the rs8113308 rare allele may identify patients who will not benefit from adjuvant endocrine treatment. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 05/2015; DOI:10.1158/1078-0432.CCR-15-0296 · 8.19 Impact Factor
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    ABSTRACT: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.
    Gynecologic Oncology 05/2015; DOI:10.1016/j.ygyno.2015.04.034 · 3.69 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):P6-13-03-P6-13-03. DOI:10.1158/1538-7445.SABCS14-P6-13-03 · 9.28 Impact Factor
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    Ailith Pirie, Qi Guo, Peter Kraft, Sander Canisius, Diana M Eccles, Nazneen Rahman, Heli Nevanlinna, Constance Chen, Sofia Khan, Jonathan Tyrer, [...], Arto Mannermaa, Irene L Andrulis, Per Hall, Jenny Chang-Claude, Douglas F Easton, Stig E Bojesen, Angela Cox, Peter A Fasching, Paul DP Pharoah, Marjanka K Schmidt
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    ABSTRACT: Introduction Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. Methods A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect. Results Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease. Conclusions Although no variants reached genome-wide significance (P <5 x 10−8), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels. Electronic supplementary material The online version of this article (doi:10.1186/s13058-015-0570-7) contains supplementary material, which is available to authorized users.
    Breast Cancer Research 04/2015; 17(1). DOI:10.1186/s13058-015-0570-7 · 5.33 Impact Factor
  • JNCI Journal of the National Cancer Institute 04/2015; 107:5. DOI:10.1093/jnci/djv036 · 15.16 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: Introduction: Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy). Methods: We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test. Results: Three independent SNPs in TGFBR2 and IL12B were associated with OS (P < 10(-3)) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 x 10(-4)) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction < 10-3). Two SNPs in IL12B (r(2) = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 x 10(-4)), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 x 10(-4)). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 x 10(-5)) without study heterogeneity. Conclusions: TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.
    Breast cancer research: BCR 02/2015; 17. DOI:10.1186/s13058-015-0522-2 · 5.88 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: Background:Although Osteopontin has been known as a marker for cancer progression, the elevated production of this cytokine is not specific for cancer. We have identified the splice variant Osteopontin-c as being absent from healthy tissue but associated with about 75% of breast cancer cases. However, in previous studies of Osteopontin-c, follow-up information was not available.Methods:Here we have analysed 671 patients, comprising a cohort of 291 paraffin blocks plus a population-based case-control study of 380 arrayed breast tumor tissues.Results:We find that high staining intensity of nuclear Osteopontin-c is strongly associated with mortality in patients with early breast cancer. Cytosolic staining for exon 4, reflective of Osteopontin-a and -b also predicts poor outcome. By contrast, total Osteopontin does not correlate with prognosis. These diverse assessments of Osteopontin also do not correlate with each other, suggesting distinct expression patterns for the variant forms. Consistent with its role in tumor progression, not tumor initiation, Osteopontin-c is not correlated with proliferation markers (Ki-67, cyclin A, cyclin B, cyclin E and cyclin D), neither is it correlated with ER, PR or HER2.Conclusions:The addition of Osteopontin-c immunohistochemistry to standard pathology work-ups may have prognostic benefit in early breast cancer diagnosis.British Journal of Cancer advance online publication, 27 January 2015; doi:10.1038/bjc.2014.664 www.bjcancer.com.
    British Journal of Cancer 01/2015; 112(4). DOI:10.1038/bjc.2014.664 · 4.82 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; 36(2). DOI:10.1093/carcin/bgu326 · 5.27 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: Genes sharing similar genomic landscape have the potential to interactively orchestrate certain clinicopathological features of a disease. Deletion of the RAD50 gene is a common event particularly in basal-like breast cancer, and often occurs together with deletions of BRCA1, RB1, TP53, PTEN, and INPP4B. In this study, we investigate whether these co-deleted genes have interactive effects on survival in breast cancer. Using publicly available TCGA data, we employed Cox’s proportional hazards models to test whether genomic deletions of these genes, or reduced protein or transcript levels associate with breast cancer patient survival in an interactive manner. Further validation was obtained at the transcriptional level by including 1,596 additional cases from 13 publicly available gene expression data sets from the KM-plotter database. Our results indicate that RAD50 and INPP4B associate interactively with breast cancer survival at the transcriptional, translational, and genomic levels in the TCGA data set (p (interaction) RAD50 abundance associated with increased hazard, both at the mRNA (HR 2.39, 95 % CI 1.20–4.76) and protein (HR 2.92, 95 % CI 1.42–6.00) levels, whereas concomitant deletion or low expression of both genes associated with unexpectedly improved survival. A similar pattern was observed in the KM-plotter data set (p (interaction) = 0.0067). We find that RAD50 and INPP4B expression levels have a synergistic influence on breast cancer survival, possibly through their effects on treatment response.
    Breast Cancer Research and Treatment 12/2014; 149(2). DOI:10.1007/s10549-014-3241-y · 4.20 Impact Factor
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    ABSTRACT: Genome wide association studies (GWAs) of breast cancer mortality have identified few potential associations. The concordance between these studies is unclear. In this study, we used a meta-analysis of two prognostic GWAs and a replication cohort to identify the strongest associations and to evaluate the loci suggested in previous studies. We attempt to identify those SNPs which could impact overall survival irrespective of the age of onset. To facilitate the meta-analysis and to refine the association signals, SNPs were imputed using data from the 1000 genomes project. Cox-proportional hazard models were used to estimate hazard ratios (HR) in 536 patients from the POSH cohort (Prospective study of Outcomes in Sporadic versus Hereditary breast cancer) and 805 patients from the HEBCS cohort (Helsinki Breast Cancer Study). These hazard ratios were combined using a Mantel-Haenszel fixed effects meta-analysis and a p-value threshold of 5×10-8 was used to determine significance. Replication was performed in 1523 additional patients from the POSH study. Although no SNPs achieved genome wide significance, three SNPs have significant association in the replication cohort and combined p-values less than 5.6×10-6. These SNPs are; rs421379 which is 556 kb upstream of ARRDC3 (HR = 1.49, 95% confidence interval (CI) = 1.27-1.75, P = 1.1×10-6), rs12358475 which is between ECHDC3 and PROSER2 (HR = 0.75, CI = 0.67-0.85, P = 1.8×10-6), and rs1728400 which is between LINC00917 and FOXF1. In a genome wide meta-analysis of two independent cohorts from UK and Finland, we identified potential associations at three distinct loci. Phenotypic heterogeneity and relatively small sample sizes may explain the lack of genome wide significant findings. However, the replication at three SNPs in the validation cohort shows promise for future studies in larger cohorts. We did not find strong evidence for concordance between the few associations highlighted by previous GWAs of breast cancer survival and this study.
    PLoS ONE 12/2014; 9(12):e101488. DOI:10.1371/journal.pone.0101488 · 3.53 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: Breast cancer risk factors and clinical outcomes vary by tumour marker expression. However, individual studies often lack the power required to assess these relationships, and large-scale analyses are limited by the need for high throughput, standardized scoring methods. To address these limitations, we assessed whether automated image analysis of immunohistochemically stained tissue microarrays can permit rapid, standardized scoring of tumour markers from multiple studies. Tissue microarray sections prepared in nine studies containing 20 263 cores from 8267 breast cancers stained for two nuclear (oestrogen receptor, progesterone receptor), two membranous (human epidermal growth factor receptor 2 and epidermal growth factor receptor) and one cytoplasmic (cytokeratin 5/6) marker were scanned as digital images. Automated algorithms were used to score markers in tumour cells using the Ariol system. We compared automated scores against visual reads, and their associations with breast cancer survival. Approximately 65–70% of tissue microarray cores were satisfactory for scoring. Among satisfactory cores, agreement between dichotomous automated and visual scores was highest for oestrogen receptor (Kappa50.76), followed by human epidermal growth factor receptor 2 (Kappa50.69) and progesterone receptor (Kappa50.67). Automated quantitative scores for these markers were associated with hazard ratios for breast cancer mortality in a dose-response manner. Considering visual scores of epidermal growth factor receptor or cytokeratin 5/6 as the reference, automated scoring achieved excellent negative predictive value (96–98%), but yielded many false positives (positive predictive value530–32%). For all markers, we observed substantial heterogeneity in automated scoring performance across tissue microarrays. Automated analysis is a potentially useful tool for large-scale, quantitative scoring of immunohistochemically stained tissue microarrays available in consortia. However, continued optimization, rigorous marker-specific quality control measures and standardization of tissue microarray designs, staining and scoring protocols is needed to enhance results.
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    ABSTRACT: Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
    PLoS ONE 11/2014; 9(11-11):e109973. DOI:10.1371/journal.pone.0109973 · 3.53 Impact Factor
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    ABSTRACT: Background. A large proportion of women with lymph node negative breast cancer treated with systemic adjuvant treatment do not benefit from such therapy since the patient is already cured by local treatment. Several studies have suggested that proliferation markers are strong prognostic factors in early breast cancer. Cyclins are probably the most specific markers of cell proliferation. Previously high expression of cyclin E has been associated with breast cancer recurrence. Materials and methods. In this study we investigate the prognostic value of cyclin E1 in node negative breast cancer patients. In a population-based cohort 186 women who died from breast cancer were defined as cases and 186 women alive at the corresponding time as controls. Inclusion criteria were tumour size ≤ 50 mm, no lymph node metastases and no adjuvant chemotherapy. The study was designed to detect an odds ratio of 2.5 with a power of 90% and significance level of 0.05. Cyclin E1 was determined with immunohistochemistry (IHC) on tissue microarray (TMA). Results. High expression of cyclin E1 was significantly associated with breast cancer death, in both uni- and multivariate analyses with odds ratios (OR) 2.3 [univariate, 95% confidence interval (CI) 1.5–3.6] and 2.1 (multivariate, 95% CI 1.2–3.5). Discussion. Cyclin E1 is a strong prognostic factor for breast cancer death in a population-based and node negative patient cohort and can identify high-risk patients in this group.
    Acta Oncologica 10/2014; 54(4). DOI:10.3109/0284186X.2014.965274 · 3.71 Impact Factor
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    ABSTRACT: Introduction. Breast cancer with mammographic casting type calcifications, high grade DCIS with an abnormal number of ducts, periductal desmoplastic reaction, lymphocyte infiltration, and tenascin-C (TN-C) overexpression has been proposed to represent a more aggressive form of breast cancer and has been denominated as breast cancer with neoductgenesis. We developed histopathological criteria for neoductgenesis in order to study reproducibility and correlation with other tumour markers. Methods. 74 cases of grades 2 and 3 DCIS, with or without an invasive component, were selected. A combined score of the degree(s) of concentration of ducts, lymphocyte infiltration, and periductal fibrosis was used to classify cases as showing neoductgenesis, or not. Diagnostic reproducibility, correlation with tumour markers, and mammographic features were studied. Results. Twenty-three of 74 cases were diagnosed with neoductgenesis. The kappa value between pathologists showed moderate reproducibility (0.50) (95% CI; 0.41-0.60). Neoductgenesis correlated significantly with malignant type microcalcifications and TN-C expression (P = 0.008 and 0.04) and with ER, PR, and HER2 status (P < 0.00001 for all three markers). Conclusions. We developed histological criteria for breast cancer with neoductgenesis. Neoductgenesis, by our applied histopathological definition was related to more aggressive tumour biology and malignant mammographic calcifications.
    10/2014; 2014:581706. DOI:10.1155/2014/581706

Publication Stats

12k Citations
2,398.20 Total Impact Points

Institutions

  • 2001–2015
    • Uppsala University
      • Department of Radiology, Oncology and Radiation Science
      Uppsala, Uppsala, Sweden
  • 1983–2015
    • Helsinki University Central Hospital
      • • Department of Oncology
      • • Department of Obstetrics and Gynaecology
      • • Division of Plastic Surgery
      • • Department of Clinical Chemistry
      Helsinki, Uusimaa, Finland
    • University of Helsinki
      • • Department of Pathology
      • • Department of Oncology
      • • Department of Psychology
      • • Department of Obstetrics and Gynaecology
      • • Department of Dental Public Health
      • • Department of Radiotherapy and Oncology
      Helsinki, Uusimaa, Finland
  • 2013
    • Herlev Hospital
      Herlev, Capital Region, Denmark
  • 2011–2013
    • Mayo Clinic - Rochester
      • Department of Health Science Research
      Rochester, Minnesota, United States
  • 2009–2013
    • University of Cambridge
      • • Department of Public Health and Primary Care
      • • Department of Oncology
      Cambridge, England, United Kingdom
  • 2012
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • Department of Obstetrics and Gynaecology, School of Midwifery
      Erlangen, Bavaria, Germany
  • 1999–2009
    • Uppsala University Hospital
      • Department of Oncology
      Uppsala, Uppsala, Sweden
  • 1989–1999
    • Lund University
      • Department of Oncology
      Lund, Skåne, Sweden
  • 1993
    • University of Tampere
      Tammerfors, Pirkanmaa, Finland
  • 1992
    • University of Oulu
      Uleoborg, Northern Ostrobothnia, Finland