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Search Results: 1 - 10 of 4736 matches for " Oskar Th Johannsson "
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Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression
Olafur A Stefansson, Jon G Jonasson, Kristrun Olafsdottir, Hordur Bjarnason, Oskar Th Johannsson, Sigridur K Bodvarsdottir, Sigridur Valgeirsdottir, Jorunn E Eyfjord
Breast Cancer Research , 2011, DOI: 10.1186/bcr3020
Abstract: Breast tumors (n = 33) derived from BRCA2 999del5 mutation carriers were examined in terms of copy-number changes with high-resolution aCGH (array comparative genomic hybridization) containing 385 thousand probes (about one for each 7 kbp) and expression of phenotypic markers on TMAs (tissue microarrays). The data were examined with respect to clinical parameters including TNM staging, histologic grade, S phase, and ploidy.Tumors from BRCA2 carriers of luminal and basal/triple-negative phenotypes (TNPs) differ with respect to patterns of DNA copy-number changes. The basal/TNP subtype was characterized by lack of pRb (RB1) coupled with high/intense expression of p16 (CDKN2A) gene products. We found increased proportions of Ki-67-positive cells to be significantly associated with loss of the wild-type (wt) BRCA2 allele in luminal types, whereas BRCA2wt loss was less frequent in BRCA2 tumors displaying basal/TNP phenotypes. Furthermore, we show that deletions at 13q13.1, involving the BRCA2wt allele, represents a part of a larger network of co-occurring genetic changes, including deletions at 6q22.32-q22.33, 11q14.2-q24.1, and gains at 17q24.1. Importantly, copy-number changes at these BRCA2-linked networking regions coincide with those associated with advanced progression, involving the capacity to metastasize to the nodes or more-distant sites at diagnosis.The results presented here demonstrate divergent paths of tumor evolution in BRCA2 carriers and that deletion of the wild-type BRCA2 allele, together with co-occurring changes at 6 q, 11 q, and 17 q, are important events in progression toward advanced disease.Germline mutations in one allele of the BRCA2 tumor-suppressor gene confer greatly increased risk of developing breast cancer [1]. The BRCA2 gene is known to be involved in error-free DNA repair of double-strand breaks (DSBs) through homologous recombination (HR) [2]. Defects in this mechanism lead to repair of DSBs by error-prone nonhomologous end joining (NH
Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families
Adalgeir Arason, Haukur Gunnarsson, Gudrun Johannesdottir, Kristjan Jonasson, P?r-Ola Bendahl, Elizabeth M Gillanders, Bjarni A Agnarsson, G?ran J?nsson, Katri Pylk?s, Aki Mustonen, Tuomas Heikkinen, Kristiina Aittom?ki, Carl Blomqvist, Beatrice Melin, Oskar TH Johannsson, P?l M?ller, Robert Winqvist, Heli Nevanlinna, ?ke Borg, Rosa B Barkardottir
Breast Cancer Research , 2010, DOI: 10.1186/bcr2608
Abstract: GWS was performed using 811 microsatellite markers providing about five centiMorgan (cM) resolution. Multipoint logarithm of odds (LOD) scores were calculated using parametric and nonparametric methods. For selected markers and cases, tumour tissue was compared to normal tissue to look for allelic loss indicative of a tumour suppressor gene.The three highest signals were located at chromosomes 6q, 2p and 14q. One family contributed suggestive LOD scores (LOD 2.63 to 3.03, dominant model) at all these regions, without consistent evidence of a tumour suppressor gene. Haplotypes in nine affected family members mapped the loci to 2p23.2 to p21, 6q14.2 to q23.2 and 14q21.3 to q24.3. No evidence of a highly penetrant locus was found among the remaining families. The heterogeneity LOD (HLOD) at the 6q, 2p and 14q loci in all families was 3.27, 1.66 and 1.24, respectively. The subset of 13 Nordic families showed supportive HLODs at chromosome 6q (ranging from 0.34 to 1.37 by country subset). The 2p and 14q loci overlap with regions indicated by large families in previous GWS studies of breast cancer.Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.Increased susceptibility to breast cancer (BC) has been shown to be caused by germline segregation of three different classes of alleles: 1) high-penetrance genes with rare risk variants, 2) moderate-penetrance genes, also with rare variants and 3) low-penetrance alleles of common frequency [1]. Hereditary BC, defined by a significant familial aggregation of BC and explaining approximately 5 to 10% of cases diagnosed with BC, is as yet seen to arise from the first allele class whenever the causative gene is known. Genetic counselling c
Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics
G?ran J?nsson, Johan Staaf, Johan Vallon-Christersson, Markus Ringnér, Karolina Holm, Cecilia Hegardt, Haukur Gunnarsson, Rainer Fagerholm, Carina Strand, Bjarni A Agnarsson, Outi Kilpivaara, Lena Luts, P?ivi Heikkil?, Kristiina Aittom?ki, Carl Blomqvist, Niklas Loman, Per Malmstr?m, H?kan Olsson, Oskar Th Johannsson, Adalgeir Arason, Heli Nevanlinna, Rosa B Barkardottir, ?ke Borg
Breast Cancer Research , 2010, DOI: 10.1186/bcr2596
Abstract: We applied global DNA copy number and gene-expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene-expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy-number aberrations and genomic subgroups of breast cancer.We identified 31 genomic regions that were highly amplified in > 1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions revealed six genomic subtypes, termed 17q12, basal-complex, luminal-simple, luminal-complex, amplifier, and mixed subtypes. Four of them had striking similarity to intrinsic gene-expression subtypes and showed associations to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having a better prognosis, whereas the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene-expression subtypes, the former being enriched for 8p12-amplified cases, whereas the mixed subtype included many tumors with predominantly DNA copy-number losses and poor prognosis.Global DNA copy-number analysis integrated with gene-expression data can be used to dissect the complexity of breast cancer. This revealed six genomic subtypes with different clinical behavior and a striking concordance to the intrinsic subtypes. These genomic subtypes may pro
Correction: Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes
Olafur Stefansson, Jon Jonasson, Oskar Johannsson, Kristrun Olafsdottir, Margret Steinarsdottir, Sigridur Valgeirsdottir, Jorunn Eyfjord
Breast Cancer Research , 2009, DOI: 10.1186/bcr2355
Abstract: Due to a production error, the final two sentences of the legend to figure 2a are incomplete. These two sentences should appear as follows:The characters represent cluster memberships of each tumour with BRCA1 and BRCA2 abnormalities indicated, see bottom of the figure. It can be hypothesised here that component three reflects differences between BRCA1- and BRCA2-related tumours whereas component two reflects their similarities, see further in Additional data file 3.
Cancer incidence in relatives of a population-based set of cases of early-onset breast cancer with a known BRCA1 and BRCA2 mutation status
Niklas Loman, Anna Bladstr?m, Oskar Johannsson, ?ke Borg, H?kan Olsson
Breast Cancer Research , 2003, DOI: 10.1186/bcr632
Abstract: Standardized incidence ratios (SIRs) and cumulative cancer incidences were calculated for relatives of a population-based set of early-onset breast cancer index cases (younger than age 41 years) with a defined BRCA mutation status (n = 203).In first-degree relatives (FDRs) of mutation-negative cases, breast cancer incidences (SIR = 2.3), prostate cancer incidences (SIR = 1.7), cervix cancer incidences (SIR = 3.3) and nonmelanoma skin cancer incidences (SIR = 2.8) were increased. The risks of breast cancer, prostate cancer and nonmelanoma skin cancer were further increased in FDRs of breast cancer cases younger than 36 years of age. In high-risk individuals with at least one relative with breast cancer apart from the index case, but no BRCA mutation in the family, breast cancer incidence was increased (SIR = 5.3); again the prostate cancer incidence was elevated (SIR = 2.5). The cumulative incidence of breast cancer at ages 50 and 70 years for FDRs of index cases without a BRCA mutation was 3.6% and 12.8%, respectively. Similarly, the cumulative incidence of breast cancer for high-risk women was 6.3% and 21.1% at ages 50 and 70 years, and that for FDRs of BRCA mutation carriers was 17.2% and 27.7% at the same ages.The incidence of breast cancer is increased for FDRs of women with early-onset breast cancer irrespective of the BRCA status in the family. Risk increases with decreasing age and with increasing number of affected relatives. The incidences of prostate cancer, cervix cancer and nonmelanoma skin cancer are elevated for FDRs of early-onset breast cancer cases without a BRCA mutation, indicating a possible association between these cancers and early-onset breast cancer.The influence of hereditary factors over breast cancer risk in women is well established. In a review and meta-analysis of previously published case–control and cohort studies, Pharoah and colleagues concluded in 1997 that a woman with a relative with breast cancer has an approximately doubled br
Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes
Olafur Stefansson, Jon Jonasson, Oskar Johannsson, Kristrun Olafsdottir, Margret Steinarsdottir, Sigridur Valgeirsdottir, Jorunn Eyfjord
Breast Cancer Research , 2009, DOI: 10.1186/bcr2334
Abstract: The study group consisted of 67 primary breast tumours with and without BRCA1 or BRCA2 abnormalities. Genomic alterations were profiled by high-resolution (~7 kbp) comparative genome hybridisation (CGH) microarrays. Tumour phenotypes were analysed by immunohistochemistry on tissue microarrays using selected biomarkers (ER, PR, HER-2, EGFR, CK5/6, CK8, CK18).Classification of genomic profiles through cluster analysis revealed four subgroups, three of which displayed high genomic instability indices (GII). Two of these GII-high subgroups were enriched with either BRCA1- or BRCA2-related tumours whereas the third was not BRCA-related. The BRCA1-related subgroup mostly displayed non-luminal phenotypes, of which basal-like were most prominent, whereas the other two genomic instability subgroups BRCA2- and GII-high-III (non-BRCA), were almost entirely of luminal phenotype. Analysis of genome architecture patterns revealed similarities between the BRCA1- and BRCA2 subgroups, with long deletions being prominent. This contrasts with the third instability subgroup, not BRCA-related, where small gains were more prominent.The results suggest that BRCA1- and BRCA2-related tumours develop largely through distinct genetic pathways in terms of the regions altered while also displaying distinct phenotypes. Importantly, we show that the development of a subset of sporadic tumours is similar to that of either familial BRCA1- or BRCA2 tumours. Despite their differences, we observed clear similarities between the BRCA1- and BRCA2-related subgroups reflected in the type of genomic alterations acquired with deletions of long DNA segments being prominent. This suggests similarities in the mechanisms promoting genomic instability for BRCA1- and BRCA2-associated tumours, possibly relating to deficiency in DNA repair through homologous recombination. Indeed, this feature characterized both familial and sporadic tumours displaying BRCA1- or BRCA2-like spectrums of genomic alterations. The impo
Broad phenotypic spectrum in familial adenomatous polyposis; from early onset and severe phenotypes to late onset of attenuated polyposis with the first manifestation at age 72
Mef Nilbert, Ulf Kristoffersson, Mats Ericsson, Oskar Johannsson, Eva Rambech, Peter Mangell
BMC Medical Genetics , 2008, DOI: 10.1186/1471-2350-9-101
Abstract: Full genomic sequencing combined with multiplex ligation-dependent probe amplification was used to identify APC gene mutations, which were correlated to the clinical presentations.10 novel APC gene mutations were identified in 11 families. A broad spectrum of extracolonic manifestations was identified in most of these individuals. Two sisters with an insertion in codon 528 (c.1582_1583insGC) both showed severe phenotypes with classical polyposis, upper gastrointestinal polyps and thyroid cancer. A woman with a 3'APC mutation (c.5030_5031insAA) developed colon cancer at age 72 as the first manifestation of attenuated FAP.With an increasing number of FAP families diagnosed, a broad and variable tumor spectrum and a high frequency of extracolonic manifestations are gradually recognized. We report novel APC mutations and present two FAP cases that suggest familial aggregation of thyroid cancer and demonstrate the need to consider attenuated FAP also among elderly patients with colon cancer.Familial adenomatous polyposis (FAP) affects about 1/13–18000 individuals, is characterized by development of multiple colonic polyps and causes less than 1% of colorectal cancer [1,2]. APC encodes for a 2843 amino acid protein that contains a variety of functional domains involved in transcription, cell cycle control, migration, differentiation, and apoptosis. Mutations in APC were demonstrated in 1991 and to date some 800 mutations have been identified [3,4]. Frameshift mutations predominate and nonsense mutations are found in one third of the cases, whereas large deletions and missense mutations represent rare causes of FAP [5]. A mutation cluster region in the 5'end of exon 15 of the APC gene has been identified and the two most frequent mutations, which account for 11–17% of the germline alterations, affect codons 1061 and 1309 [5].The severity of colonic polyposis has been linked to the genotype. Mutations between APC codons 1250 and 1464 cause profuse polyposis, generally with
Evidence against PALB2 involvement in Icelandic breast cancer susceptibility
Haukur Gunnarsson, Adalgeir Arason, Elizabeth M Gillanders, Bjarni A Agnarsson, Gudrun Johannesdottir, Oskar Johannsson, Rosa B Barkardottir
Journal of Negative Results in BioMedicine , 2008, DOI: 10.1186/1477-5751-7-5
Abstract: Breast cancer is among the most frequent human cancers and the most common carcinoma in women in the Western world, where one out of every ten women is affected. A dominant pattern of inheritance is evident in approximately 5–10% of all breast cancers. To date, two main breast cancer susceptibility genes have been identified; BRCA1 and BRCA2 accounting for nearly half of high-incidence breast cancer families and an increased relative risk of breast cancer by 10- to 20- fold [1,2]. Other known breast cancer susceptibility genes such as CHEK2 and ATM have a more moderate penetrance with an increased lifetime risk of about 2- to 3- fold [2].The PALB2 gene is a BRCA2 binding factor that ensures BRCA2 function as a tumor suppressor and has been shown to cause Fanconi anemia subtype FA-N when biallelic germ-line mutations occur in the gene [3-5]. Recent studies have reported several mutations in PALB2 to be associated with an increased risk of breast cancer [6-9]. One is the founder mutation 1592delT which has been found to be present at a significantly elevated frequency in breast cancer families in Finland, resulting in a 4-fold increased risk to mutation carriers [6]. Although predisposing PALB2 mutations generally appear to cause moderate risk of breast cancer [8], mutations have also been found in strong hereditary breast cancer families [7,9] and might thus be worthwhile searching for by linkage analysis in e.g. geographically confined populations.Only two BRCA1 and BRCA2 mutations have been found in the Icelandic population, BRCA2 999del5 and BRCA1 G5193A, both being founder mutations explaining a large proportion of familial breast cancer in Iceland [10]. The BRCA2 999del5 mutation is much more frequent, accounting for around 40% of the hereditary cases and found in about 8% of unselected breast cancer cases and 0,4% of population based control [11]. A BRCA2 999del5 mutation is also the most frequently occurring BRCA1/2 mutation in Finland [12], and haplotype anal
White Collar Crime and Informal Social Control: The Case of “Crisis Responders” in the Swedish Banking and Finance Sector  [PDF]
Oskar Engdahl
Sociology Mind (SM) , 2011, DOI: 10.4236/sm.2011.12010
Abstract: Drawing upon case studies on the type of white-collar offenders frequently called “crisis responders”, this article critically examines Sampson and Laubs general theory on informal social control. In the article, this theory is for the first time confronted with data not used in its development and prior testing. Based on the evidence, the theory retains its validity for the white-collar offenders considered, insofar as their crime was closely connected to a perceived threat of identity loss, distrust in social support obtainable from others, and lack of supervision and monitoring at workplace. At the same time, the argument is made that the notion of interdependence relied upon in this theory needs to be developed more fully if it is to take into account the kind of dependency relations tying these particular offenders to their environment.
Voluntary Contribution to Public Goods: Preferences and Wealth  [PDF]
Oskar Nupia
Theoretical Economics Letters (TEL) , 2016, DOI: 10.4236/tel.2016.63049
Abstract: This paper analyzes the role of wealth and its distribution in a model of voluntary-contribution to public goods where individuals’ preferences for these goods depend on the level of individual’s wealth. We find that under such circumstances a small redistribution of wealth among contributors is not necessary neutral. We then discuss the conditions under which a redistribution of wealth might improve efficiency in the aggregate provision of public goods. Unlikely what common sense might suggest, we show that a redistribution of wealth can increase the private provision of public goods regardless of whether individuals’ valuations for these goods increase or decrease as their level of wealth increases. Furthermore, we show that under some circumstances, a regressive redistribution of wealth can increase the provision of public goods.
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