Torben A Kruse

Publications (95)365.46 Total impact

• Article: A novel permutation test for case-only analysis identifies epistatic effects on human longevity in the FOXO gene family.

  Qihua Tan, Mette Sørensen, Torben A Kruse, Kaare Christensen, Lene Christiansen
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  ABSTRACT: Genetic interactions or epistasis could make a substantial contribution to variation in human complex traits including longevity. However, detecting epistatic interactions in high dimensional datasets is difficult due to various reasons including multiple testing of correlated tests. We introduce a novel permutation strategy to the case-only analysis of gene by gene interaction using multiple SNPs. The method is applied to genes coding for Forkhead box O transcription factors which recently have been associated with human longevity across different populations hypothesizing that epistatic interaction in the regulation and expression of the FOXO gene family could contribute to the human longevity phenotype. Genotype data was collected from 1088 individuals from the Danish 1905 birth cohort aged over 92/93 years with 12 SNPs in the FOXO1a and 15 SNPs in the FOXO3a genes. Our analysis detected a joint effect between rs9486902 in FOXO3a and rs2701858 in FOXO1a that highly significantly contributes to human longevity (OR=3.23, 95% CI: 2.93-3.53) which is consistent in both males and females. Our results were compared with published studies and importance of our novel method and findings discussed. This article is protected by copyright. All rights reserved.
  Aging cell 04/2013; · 7.55 Impact Factor
• Source

  Available from: Robert A Vierkant

  Article: Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

  Stig E Bojesen, Karen A Pooley, Sharon E Johnatty, Jonathan Beesley, Kyriaki Michailidou, Jonathan P Tyrer, Stacey L Edwards, Hilda A Pickett, Howard C Shen, Chanel E Smart, [......], Simon A Gayther, Paul D P Pharoah, Roger R Reddel, Ellen L Goode, Mark H Greene, Douglas F Easton, Andrew Berchuck, Antonis C Antoniou, Georgia Chenevix-Trench, Alison M Dunning
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  ABSTRACT: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
  Nature Genetics 03/2013; 45(4):371-384. · 35.53 Impact Factor
• Article: Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk.

  Fergus J Couch, Xianshu Wang, Lesley McGuffog, Andrew Lee, Curtis Olswold, Karoline B Kuchenbaecker, Penny Soucy, Zachary Fredericksen, Daniel Barrowdale, Joe Dennis, [......], Chen Wang, Steven Hart, Kristen Stevens, Jacques Simard, Tomi Pastinen, Vernon S Pankratz, Kenneth Offit, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou
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  ABSTRACT: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
  PLoS Genetics 03/2013; 9(3):e1003212. · 8.69 Impact Factor
• Article: Whole Blood Transcriptional Profiling Reveals Significant Downregulation of HLA Class I and II Genes in Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis.

  Vibe Skov, Caroline Hasselbalch Riley, Mads Thomassen, Thomas Stauffer Larsen, Morten K Jensen, Ole Weis Bjerrum, Torben A Kruse, Hans Carl Hasselbalch
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  ABSTRACT: Abstract Gene expression profiling studies in the Philadelphia-negative chronic myeloproliferative neoplasms have unraveled significant deregulation of several immune and inflammation genes that might be of importance for clonal evolution due to defective tumor immune surveillance. Other mechanisms might be downregulation of major histocompatibility (MHC) class I and II genes, which are used by tumor cells to escape antitumor T-cell-mediated immune responses. We have performed whole blood transcriptional profiling of genes encoding human leukocyte antigen (HLA) class I and II molecules, beta2microglobulin and members of the antigen processing machinery of HLA class I molecules (LMP2, LMP7, TAP1, TAP2 and tapasin). The findings of significant downregulation of several of these genes may likely be of major importance for defective tumor immune surveillance. Since up-regulation of HLA-genes are recorded during treatment with epigenome modulating agents (DNA-hypometylators and DNA-hyperacetylators (histone deacetylase inhibitors)) and interferon-alpha2 our findings call for prospective transcriptional studies of HLA-genes during treatment with these agents.
  Leukemia & lymphoma 01/2013; · 2.40 Impact Factor
• Article: Analyzing age-specific genetic effects on human extreme age survival in cohort-based longitudinal studies.

  Qihua Tan, Rune Jacobsen, Mette Sørensen, Lene Christiansen, Torben A Kruse, Kaare Christensen
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  ABSTRACT: The analysis of age-specific genetic effects on human survival over extreme ages is confronted with a deceleration pattern in mortality that deviates from traditional survival models and sparse genetic data available. As human late life is a distinct phase of life history, exploring the genetic effects on extreme age survival can be of special interest to evolutionary biology and health science. We introduce a non-parametric survival analysis approach that combines population survival information with individual genotype data in assessing the genetic effects in cohort-based longitudinal studies. Our approach is characterized by non-parametric analysis of late age survival to capture the observed pattern of mortality deceleration and frailty modeling to account for individual heterogeneity in unobserved frailty. The method is applied to ApoE genotype data in the Danish 1905 birth cohort to estimate effect of the e4 allele. Our results revealed an age-specific relative risk of the allele that increases nonlinearly with age and non-proportional patterns in hazard of death for carriers and non-carriers of the allele, suggesting that the e4 mutation preserves its deleterious effect that progressively affect human survival even at extreme ages.European Journal of Human Genetics advance online publication, 15 August 2012; doi:10.1038/ejhg.2012.182.
  European journal of human genetics: EJHG 08/2012; · 3.56 Impact Factor
• Article: Molecular profiling of peripheral blood cells from patients with polycythemia vera and related neoplasms: Identification of deregulated genes of significance for inflammation and immune surveillance.

  Vibe Skov, Thomas Stauffer Larsen, Mads Thomassen, Caroline Hasselbalch Riley, Morten K Jensen, Ole Weis Bjerrum, Torben A Kruse, Hans Carl Hasselbalch
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  ABSTRACT: Essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) are hematopoietic stem cell neoplasms that may be associated with autoimmune or chronic inflammatory disorders. Earlier gene expression profiling studies have demonstrated aberrant expression of genes involved in inflammatory responses, mainly being performed on granulocytes or CD34+ cells. Using gene expression profiling of whole blood from patients with ET (n=16), PV (n=36), and PMF (n=9), several genes involved in inflammation and immune regulation were found to be significantly deregulated. Our findings may reflect chronic inflammation to be of pathogenetic importance for the progression of these neoplasms toward the myelofibrotic end-stage and may also account for the increased frequency of second cancer in these diseases.
  Leukemia research 08/2012; 36(11):1387-92. · 2.36 Impact Factor
• Article: Genome-wide linkage and association scans for pulse pressure in Chinese twins.

  Dongfeng Zhang, Zengchang Pang, Shuxia Li, Wenjie Jiang, Shaojie Wang, Mads Thomassen, Jacob V B Hjelmborg, Torben A Kruse, Kirsten Ohm Kyvik, Kaare Christensen, Gu Zhu, Qihua Tan
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  ABSTRACT: Elevated pulse pressure (PP) is associated with cardiovascular disorders and mortality in various populations. The genetic influence on PP has been confirmed by heritability estimates using related individuals. Recently, efforts have been made by mapping genes that are linked to the phenotype. We report the results of our gene mapping studies conducted in the Chinese population in mainland China. The genome-wide linkage and association scans were carried out on 63 middle-aged dizygotic twin pairs using high-density markers. The linkage analysis identified three significant linkage peaks (all with a single point P<1e(-05)) on chromosome 11 (LOD core 4.06 at 30.5 cM), chromosome 12 (LOD score 3.97 at 100.7 cM) and chromosome 18 (LOD score 4.01 at 70.7 cM), with the last two peaks closely overlapping with linkage peaks reported by two American studies. Multiple regions with suggestive linkages were identified, with many of the peaks overlapping with published linkage regions. The genome-wide association analysis detected a suggestive association on chromosome 4 (rs17031508, P<8.34e(-08)) located within a wide region of suggestive linkage. Our results provide some evidence for genetic linkages and associations with PP in the Chinese population. Further investigation is warranted to replicate the findings and to explore the susceptibility loci or genes for PP.Hypertension Research advance online publication, 5 July 2012; doi:10.1038/hr.2012.90.
  Hypertension Research 07/2012; · 2.58 Impact Factor
• Article: Twins for epigenetic studies of human aging and development.

  Qihua Tan, Lene Christiansen, Mads Thomassen, Torben A Kruse, Kaare Christensen
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  ABSTRACT: Most of the complex traits including aging phenotypes are caused by the interaction between genome and environmental conditions and the interface of epigenetics may be a central mechanism. Although modern technologies allow us high-throughput profiling of epigenetic patterns already at genome level, our understanding of genetic and environmental influences on the epigenetic processes remains limited. Twins are of special interest for genetic studies due to their genetic similarity and rearing-environment sharing. The classical twin design has made a great contribution in dissecting the genetic and environmental contributions to human diseases and complex traits. In the era of functional genomics, the valuable sample of twins is helping to bridge the gap between gene activity and the environments through epigenetic mechanisms unlimited by DNA sequence variations. We propose to extend the classical twin design to study the aging-related molecular epigenetic phenotypes and link them with environmental exposures especially early life events. Different study designs and application issues will be highlighted and novel approaches introduced with aim at making uses of twins in assessing the environmental impact on epigenetic changes during development and in the aging process.
  Ageing research reviews 06/2012; 12(1):182-187. · 5.62 Impact Factor
• Article: Gene expression profiling with principal component analysis depicts the biological continuum from essential thrombocythemia over polycythemia vera to myelofibrosis.

  Vibe Skov, Mads Thomassen, Caroline H Riley, Morten K Jensen, Ole Weis Bjerrum, Torben A Kruse, Hans Carl Hasselbalch, Thomas Stauffer Larsen
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  ABSTRACT: The recent discovery of the Janus activating kinase 2 V617F mutation in most patients with polycythemia vera (PV) and half of those with essential thrombocythemia (ET) and primary myelofibrosis (PMF) has favored the hypothesis of a biological continuum from ET over PV to PMF. We performed gene expression profiling of whole blood from control subjects (n = 21) and patients with ET (n = 19), PV (n = 41), and PMF (n = 9) using DNA microarrays. Applying an unsupervised method, principal component analysis, to search for patterns in the data, we demonstrated a separation of the four groups with biological relevant overlaps between the different entities. Moreover, the analysis separates Janus activating kinase 2-negative ET patients from Janus activating kinase 2-positive ET patients. Functional annotation analysis demonstrates that clusters of gene ontology terms related to inflammation, immune system, apoptosis, RNA metabolism, and secretory system were the most significantly deregulated terms in the three different disease groups. Our results yield further support for the hypothesis of a biological continuum originating from ET over PV to PMF. Functional analysis suggests an important implication of these gene ontology clusters in the pathogenesis of these neoplasms and in disease evolution from ET over PV to PMF.
  Experimental hematology 05/2012; 40(9):771-780.e19. · 3.11 Impact Factor
• Article: Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

  Fergus J Couch, Mia M Gaudet, Antonis C Antoniou, Susan J Ramus, Karoline B Kuchenbaecker, Penny Soucy, Jonathan Beesley, Xiaoqing Chen, Xianshu Wang, Tomas Kirchhoff, [......], Alessandra Viel, Giuseppe Giannini, Liliana Varesco, Paolo Radice, Mark H Greene, Phuong L Mai, Douglas F Easton, Georgia Chenevix-Trench, Kenneth Offit, Jacques Simard
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  ABSTRACT: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)). 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.
  Cancer Epidemiology Biomarkers &amp Prevention 02/2012; 21(4):645-57. · 4.12 Impact Factor
• Article: Reproducibility of mass spectrometry based protein profiles for diagnosis of ovarian cancer across clinical studies: A systematic review.

  Anne K Callesen, Ole Mogensen, Andreas K Jensen, Torben A Kruse, Torben Martinussen, Ole N Jensen, Jonna S Madsen
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  ABSTRACT: The focus of this systematic review is to give an overview of the current status of clinical protein profiling studies using MALDI and SELDI MS platforms in the search for ovarian cancer biomarkers. A total of 34 profiling studies were qualified for inclusion in the review. Comparative analysis of published discriminatory peaks to peaks found in an original MALDI MS protein profiling study was made to address the key question of reproducibility across studies. An overlap was found despite substantial heterogeneity between studies relating to study design, biological material, pre-analytical treatment, and data analysis. About 47% of the peaks reported to be associated to ovarian cancer were also represented in our experimental study, and 34% of these redetected peaks also showed a significant difference between cases and controls in our study. Thus, despite known problems related to reproducibility an overlap in peaks between clinical studies was demonstrated, which indicate convergence toward a set of common discriminating, reproducible peaks for ovarian cancer. The potential of the discriminating protein peaks for clinical use as ovarian cancer biomarkers will be discussed and evaluated. This article is part of a Special Issue entitled: Proteomics: The clinical link.
  Journal of proteomics 02/2012; 75(10):2758-72. · 5.07 Impact Factor
• Article: Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

  Susan J Ramus, Antonis C Antoniou, Karoline B Kuchenbaecker, Penny Soucy, Jonathan Beesley, Xiaoqing Chen, Lesley McGuffog, Olga M Sinilnikova, Sue Healey, Daniel Barrowdale, [......], Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, Paul D P Pharoah, Simon A Gayther, Jacques Simard, Douglas F Easton, Fergus J Couch, Georgia Chenevix-Trench, Hans Ehrencrona
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  ABSTRACT: Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.
  Human Mutation 01/2012; 33(4):690-702. · 5.69 Impact Factor
• Article: Prediction of breast cancer metastasis by gene expression profiles: a comparison of metagenes and single genes.

  Mark Burton, Mads Thomassen, Qihua Tan, Torben A Kruse
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  ABSTRACT: The popularity of a large number of microarray applications has in cancer research led to the development of predictive or prognostic gene expression profiles. However, the diversity of microarray platforms has made the full validation of such profiles and their related gene lists across studies difficult and, at the level of classification accuracies, rarely validated in multiple independent datasets. Frequently, while the individual genes between such lists may not match, genes with same function are included across such gene lists. Development of such lists does not take into account the fact that genes can be grouped together as metagenes (MGs) based on common characteristics such as pathways, regulation, or genomic location. Such MGs might be used as features in building a predictive model applicable for classifying independent data. It is, therefore, demanding to systematically compare independent validation of gene lists or classifiers based on metagene or individual gene (SG) features. In this study we compared the performance of either metagene-or single gene-based feature sets and classifiers using random forest and two support vector machines for classifier building. The performance within the same dataset, feature set validation performance, and validation performance of entire classifiers in strictly independent datasets were assessed by 10 times repeated 10-fold cross validation, leave-one-out cross validation, and one-fold validation, respectively. To test the significance of the performance difference between MG- and SG-features/classifiers, we used a repeated down-sampled binomial test approach. MG- and SG-feature sets are transferable and perform well for training and testing prediction of metastasis outcome in strictly independent data sets, both between different and within similar microarray platforms, while classifiers had a poorer performance when validated in strictly independent datasets. The study showed that MG- and SG-feature sets perform equally well in classifying independent data. Furthermore, SG-classifiers significantly outperformed MG-classifier when validation is conducted between datasets using similar platforms, while no significant performance difference was found when validation was performed between different platforms. Prediction of metastasis outcome in lymph node-negative patients by MG- and SG-classifiers showed that SG-classifiers performed significantly better than MG-classifiers when validated in independent data based on the same microarray platform as used for developing the classifier. However, the MG- and SG-classifiers had similar performance when conducting classifier validation in independent data based on a different microarray platform. The latter was also true when only validating sets of MG- and SG-features in independent datasets, both between and within similar and different platforms.
  Cancer informatics 01/2012; 11:193-217.
• Article: Gene expression profiles for predicting metastasis in breast cancer: a cross-study comparison of classification methods.

  Mark Burton, Mads Thomassen, Qihua Tan, Torben A Kruse
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  ABSTRACT: Machine learning has increasingly been used with microarray gene expression data and for the development of classifiers using a variety of methods. However, method comparisons in cross-study datasets are very scarce. This study compares the performance of seven classification methods and the effect of voting for predicting metastasis outcome in breast cancer patients, in three situations: within the same dataset or across datasets on similar or dissimilar microarray platforms. Combining classification results from seven classifiers into one voting decision performed significantly better during internal validation as well as external validation in similar microarray platforms than the underlying classification methods. When validating between different microarray platforms, random forest, another voting-based method, proved to be the best performing method. We conclude that voting based classifiers provided an advantage with respect to classifying metastasis outcome in breast cancer patients.
  TheScientificWorldJOURNAL 01/2012; 2012:380495. · 1.66 Impact Factor
• Article: Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

  Nasim Mavaddat, Daniel Barrowdale, Irene L Andrulis, Susan M Domchek, Diana Eccles, Heli Nevanlinna, Susan J Ramus, Amanda Spurdle, Mark Robson, Mark Sherman, [......], Kunle Odunsi, Lara Sucheston, Simon A Gayther, Kate Nathanson, Jenny Gross, Christine Walsh, Beth Karlan, Georgia Chenevix-Trench, Douglas F Easton, Antonis C Antoniou
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  ABSTRACT: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers. There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). CONCLUSIONS/IMPACT: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis.
  Cancer Epidemiology Biomarkers &amp Prevention 12/2011; 21(1):134-47. · 4.12 Impact Factor
• Source

  Available from: Hilmi Ozcelik

  Article: Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

  Anna Marie Mulligan, Fergus J Couch, Daniel Barrowdale, Susan M Domchek, Diana Eccles, Heli Nevanlinna, Susan J Ramus, Mark Robson, Mark Sherman, Amanda B Spurdle, [......], Melissa C Southey, John L Hopper, Mary Beth Terry, Wendy Chung, Alexander F Miron, David Goldgar, Georgia Chenevix-Trench, Douglas F Easton, Irene L Andrulis, Antonis C Antoniou
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  ABSTRACT: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.
  Breast cancer research: BCR 11/2011; 13(6):R110. · 5.24 Impact Factor
• Article: Fibulin-1 is a marker for arterial extracellular matrix alterations in type 2 diabetes.

  Claudia Cangemi, Vibe Skov, Michael Kjaer Poulsen, Jonas Funder, Waleed O Twal, Mari-Anne Gall, Vibeke Hjortdal, Marie Louise Jespersen, Torben A Kruse, Jan Aagard, Hans-Henrik Parving, Steen Knudsen, Poul-Flemming Høilund-Carlsen, Peter Rossing, Jan Erik Henriksen, William Scott Argraves, Lars Melholt Rasmussen
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  ABSTRACT: Extracellular matrix alterations are important elements in the arterial changes seen in diabetes, being associated with increased vascular stiffness and the development of cardiovascular diseases. However, no biomarkers for diabetes-related arterial changes have been defined. Mammary artery specimens from 17 men with type 2 diabetes and 18 nondiabetic individuals were used for microarray expression profiling, quantitative real-time PCR, immunoassay, and immunohistochemical analyses. A derived candidate marker, fibulin-1, which is an elastin-associated matrix molecule, was measured immunochemically in plasma from (a) 70 patients scheduled for vascular surgery, (b) 305 patients with type 2 diabetes examined with carotid ultrasonography and echocardiography, and (c) 308 patients with type 2 diabetes, followed for 15 years. The most upregulated transcript in nonatherosclerotic arterial tissue from patients with type 2 diabetes encoded the extracellular matrix protein, fibulin-1. Higher concentrations of fibulin-1-protein were present in artery extracts from patients with diabetes than extracts from individuals without diabetes, and increased fibulin-1 immunostaining was apparent around the external elastic lamina of diabetic arteries. Patients with diabetes displayed increased plasma concentrations of fibulin-1 (P = 0.006). Plasma fibulin-1 concentrations correlated with hemoglobin A(1c) (P < 0.001), arterial stiffness indices including pulse pressure (P < 0.001), and carotid compliance (P = 0.004), as well as plasma N-terminal pro-B-type natriuretic peptide concentrations (P < 0.001) and were predictive of 15-year mortality (P = 0.013). Fibulin-1 accumulates in the arterial wall and in plasma of patients with type 2 diabetes, and appears to be a factor associated with arterial extracellular matrix changes in type 2 diabetes.
  Clinical Chemistry 09/2011; 57(11):1556-65. · 7.91 Impact Factor
• Article: A cross-sectional analysis of age and sex patterns in grip strength, tooth loss, near vision and hearing levels in Chinese aged 50-74 years.

  Yili Wu, Zengchang Pang, Dongfeng Zhang, Wenjie Jiang, Shaojie Wang, Shuxia Li, Torben A Kruse, Kaare Christensen, Qihua Tan
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  ABSTRACT: By focusing on four health variables, handgrip strength, near visual acuity, tooth loss and hearing level, this study examined the different patterns of age-related changes in these variables in Chinese aged from 50 to 74 years, as well as explored the relationship among the variables in a cross-sectional sample of 2006 individuals. The data exhibited high quality with a low missing rate of under 5% in any age groups for each variable. Effects of age and sex on the changes in the four health variables were assessed using multiple regression models with age and sex interactions included. Upon the highly significant effects of age on all four measurements, we observed substantially higher grip strength for men who, however, exhibited a faster age-related decline than for women. No sex difference or age-sex interaction was found in the number of teeth lost. Near visual acuity displayed a faster age-related decline in women than in men but neither the overall sex difference nor age-sex interaction reached statistical significance. For hearing function, while no sex difference was found at middle frequency, women had better sensitivity at high frequency and men were more sensitive at low frequency. Multivariate analysis did not support an age-related common mechanism underlying the four health variables.
  Archives of gerontology and geriatrics 09/2011; 54(2):e213-20. · 1.36 Impact Factor
• Article: A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene.

  Noomi Gregersen, Hans A Dahl, Henriette N Buttenschøn, Mette Nyegaard, Anne Hedemand, Thomas D Als, August G Wang, Sofus Joensen, David Pd Woldbye, Pernille Koefoed, Ann S Kristensen, Torben A Kruse, Anders D Børglum, Ole Mors
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  ABSTRACT: Panic disorder (PD) is a mental disorder with recurrent panic attacks that occur spontaneously and are not associated to any particular object or situation. There is no consensus on what causes PD. However, it is recognized that PD is influenced by environmental factors, as well as genetic factors. Despite a significant hereditary component, genetic studies have only been modestly successful in identifying genes of importance for the development of PD. In this study, we conducted a genome-wide scan using microsatellite markers and PD patients and control individuals from the isolated population of the Faroe Islands. Subsequently, we conducted a fine mapping, which revealed the amiloride-sensitive cation channel 1 (ACCN1) located on chromosome 17q11.2-q12 as a potential candidate gene for PD. The further analyses of the ACCN1 gene using single-nucleotide polymorphisms (SNPs) revealed significant association with PD in an extended Faroese case-control sample. However, analyses of a larger independent Danish case-control sample yielded no substantial significant association. This suggests that the possible risk alleles associated in the isolated population are not those involved in the development of PD in a larger outbred population.
  European journal of human genetics: EJHG 08/2011; 20(1):84-90. · 3.56 Impact Factor
• Article: Increased gene expression of histone deacetylases in patients with Philadelphia-negative chronic myeloproliferative neoplasms.

  Vibe Skov, Thomas Stauffer Larsen, Mads Thomassen, Caroline Hasselbalch Riley, Morten K Jensen, Ole Weis Bjerrum, Torben A Kruse, Hans Carl Hasselbalch
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  ABSTRACT: Myeloproliferation, myeloaccumulation (decreased apoptosis), inflammation, bone marrow fibrosis and angiogenesis are cardinal features of the Philadelphia-negative chronic myeloproliferative neoplasms: essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Histone deacetylases (HDACs) have a critical role in modulating gene expression and, accordingly, in the control of cell pathobiology and cancer development. HDAC inhibition has been shown to inhibit tumor growth (impaired myeloproliferation), to modulate the balance between pro- and antiapoptotic proteins in favor of apoptosis (enhanced apoptosis) and also to inhibit angiogenesis. Recently, enhanced HDAC enzyme activity has been found in CD34+cells from patients with PMF, enzyme activity levels highly exceeding those recorded in other chronic myeloproliferative neoplasms (CMPNs). The raised levels correlated to the degree of splenomegaly, suggesting that HDAC might be recruited as ET or PV progresses into myelofibrosis or PMF progresses into a more advanced stage. Accordingly, HDAC inhibition is an obvious novel therapeutic approach in these neoplasms. Using global gene expression profiling of whole blood from patients with CMPNs, we have found a pronounced deregulation of HDAC genes, involving significant up-regulation of the HDAC genes 9 and 11, with the highest expression levels being found in patients with ET (HDAC9 and 11), PMF (HDAC9) and CMPNs (both HDAC9 and HDAC11). Furthermore, we have identified that the HDAC6 gene is progressively expressed in patients with ET, PV and PMF, reflecting a steady accumulation of abnormally expressed HDAC6 during disease evolution. Our results lend further support to HDACs as important epigenetic targets in the future treatment of patients with CMPNs. Since the highest expression levels of HDAC genes were recorded in ET, in PMF and in the entire CMPN group, their down-regulation by HDAC inhibitors might be associated with decreased disease activity, including reduction of splenomegaly.
  Leukemia & lymphoma 08/2011; 53(1):123-9. · 2.40 Impact Factor