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1.
  • Ferreira, Manuel A., et al. (författare)
  • Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer
  • 2019
  • Ingår i: Nature communications. - 2041-1723. ; 10:1, s. 1741
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer. © 2019, The Author(s).
2.
  • Kharaziha, Pedram, et al. (författare)
  • Functional characterization of novel germline TP53 variants in Swedish families
  • 2019
  • Ingår i: Clinical Genetics. - Wiley-Blackwell. - 0009-9163. ; 96:3, s. 216-225
  • Tidskriftsartikel (refereegranskat)abstract
    • Pathogenic germline TP53 variants predispose to a wide range of early onset cancers, often recognized as the Li-Fraumeni syndrome (LFS). They are also identified in 1% of families with hereditary breast cancer (HrBC) that do not fulfill the criteria for LFS. In this study, we present a total of 24 different TP53 variants identified in 31 Swedish families with LFS or HrBC. Ten of these variants, nine exonic and one splice, have previously not been described as germline pathogenic variants. The nine exonic variants were functionally characterized and demonstrated partial transactivation activity compared to wild-type p53. Some show nuclear localization similar to wild-type p53 while others possess cytoplasmic or perinuclear localization. The four frameshift variants (W91Gfs*32, L111 Wfs*12, S227 Lfs*20 and S240Kfs*25) had negligible, while F134 L and T231del had low level of p53 activity. The L111 Wfs*12 and T231del variants are also deficient for induction of apoptosis. The missense variant R110C retain p53 effects and the nonsense E349* shows at least partial transcription factor activity but has reduced ability to trigger apoptosis. This is the first functional characterization of novel germline TP53 pathogenic or likely pathogenic variants in the Swedish cohort as an attempt to understand its association with LFS and HrBC, respectively.
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3.
  • Li, Jingmei, et al. (författare)
  • Prevalence of BRCA1 and BRCA2 pathogenic variants in a large, unselected breast cancer cohort
  • 2019
  • Ingår i: International Journal of Cancer. - John Wiley & Sons. - 0020-7136. ; 144:5, s. 1195-1204
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast cancer patients with BRCA1/2-driven tumors may benefit from targeted therapy. It is not clear whether current BRCA screening guidelines are effective at identifying these patients. The purpose of our study was to evaluate the prevalence of inherited BRCA1/2 pathogenic variants in a large, clinically representative breast cancer cohort and to estimate the proportion of BRCA1/2 carriers not detected by selectively screening individuals with the highest probability of being carriers according to current clinical guidelines. The study included 5,122 unselected Swedish breast cancer patients diagnosed from 2001 to 2008. Target sequence enrichment (48.48 Fluidigm Access Arrays) and sequencing were performed (Illumina Hi-Seq 2,500 instrument, v4 chemistry). Differences in patient and tumor characteristics of BRCA1/2 carriers who were already identified as part of clinical BRCA1/2 testing routines and additional BRCA1/2 carriers found by sequencing the entire study population were compared using logistic regression models. Ninety-two of 5,099 patients with valid variant calls were identified as BRCA1/2 carriers by screening all study participants (1.8%). Only 416 study participants (8.2%) were screened as part of clinical practice, but this identified 35 out of 92 carriers (38.0%). Clinically identified carriers were younger, less likely postmenopausal and more likely to be associated with familiar ovarian cancer compared to the additional carriers identified by screening all patients. More BRCA2 (34/42, 81.0%) than BRCA1 carriers (23/50, 46%) were missed by clinical screening. In conclusion, BRCA1/2 mutation prevalence in unselected breast cancer patients was 1.8%. Six in ten BRCA carriers were not detected by selective clinical screening of individuals.
4.
  • Lundgren, Christine, et al. (författare)
  • Agreement between molecular subtyping and surrogate subtype classification: a contemporary population-based study of ER-positive/HER2-negative primary breast cancer
  • 2019
  • Ingår i: Breast Cancer Research and Treatment. - Springer. - 1573-7217. ; s. 1-9
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose Oestrogen receptor-positive (ER+) and human epidermal receptor 2-negative (HER2-) breast cancers are classified as Luminal A or B based on gene expression, but immunohistochemical markers are used for surrogate subtyping. The aims of this study were to examine the agreement between molecular subtyping (MS) and surrogate subtyping and to identify subgroups consisting mainly of Luminal A or B tumours. Methods The cohort consisted of 2063 patients diagnosed between 2013-2017, with primary ER+/HER2- breast cancer, analysed by RNA sequencing. Surrogate subtyping was performed according to three algorithms (St. Gallen 2013, Maisonneuve and our proposed Grade-based classification). Agreement (%) and kappa statistics (kappa) were used as concordance measures and ROC analysis for luminal distinction. Ki67, progesterone receptor (PR) and histological grade (HG) were further investigated as surrogate markers. Results The agreement rates between the MS and St. Gallen 2013, Maisonneuve and Grade-based classifications were 62% (kappa = 0.30), 66% (kappa = 0.35) and 70% (kappa = 0.41), respectively. PR did not contribute to distinguishing Luminal A from B tumours (auROC = 0.56). By classifying HG1-2 tumours as Luminal A-like and HG3 as Luminal B-like, agreement with MS was 80% (kappa = 0.46). Moreover, by combining HG and Ki67 status, a large subgroup of patients (51% of the cohort) having amp;gt; 90% Luminal A tumours could be identified. Conclusions Agreement between MS and surrogate classifications was generally poor. However, a post hoc analysis showed that a combination of HG and Ki67 could identify patients very likely to have Luminal A tumours according to MS.
5.
  • Nilsson, Martin P., et al. (författare)
  • High patient satisfaction with a simplified BRCA1/2 testing procedure : : long-term results of a prospective study
  • 2019
  • Ingår i: Breast Cancer Research and Treatment. - Springer. - 0167-6806. ; 173:2, s. 313-318
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: In the BRCAsearch study, unselected breast cancer patients were prospectively offered germline BRCA1/2 mutation testing through a simplified testing procedure. The purpose of the present study was to evaluate satisfaction with the BRCAsearch testing procedure and, furthermore, to report on uptake rates of prophylactic surgeries among mutation carriers. Methods: Pre-test information was provided by a standardized invitation letter instead of in-person genetic counseling. The patients were offered contact with a genetic counselor for telephone genetic counseling if they felt a need for that. Mutation carriers were telephoned and given a time for a face-to-face post-test genetic counseling appointment. Non-carriers were informed about the test result through a letter. One year after the test results were delivered, a study-specific questionnaire was mailed to the study participants who had consented to testing. The response rate was 83.1% (448 of 539). Results: A great majority (96.0%) of the responders were content with the method used for providing information within the study, and 98.7% were content with having pursued genetic testing. 11.1% answered that they would have liked to receive more oral information. In an adjusted logistic regression model, patients with somatic comorbidity (OR 2.56; P = 0.02) and patients born outside of Sweden (OR 3.54; P = 0.01) were more likely, and patients with occupations requiring at least 3 years of university or college education (OR 0.37; P = 0.06) were less likely to wanting to receive more oral information. All 11 mutation carriers attended post-test genetic counseling. At a median follow-up of 2 years, the uptake of prophylactic salpingo-oophorectomy was 100%, and the uptake of prophylactic mastectomy was 55%. Conclusions: Satisfaction with a simplified BRCA1/2 testing procedure was very high. Written pre-test information has now replaced in-person pre-test counseling for breast cancer patients in our health care region.
6.
  • Vickovic, Sanja, et al. (författare)
  • High-definition spatial transcriptomics for in situ tissue profiling
  • 2019
  • Ingår i: Nature Methods. - NATURE PUBLISHING GROUP. - 1548-7091. ; 16:10, s. 987-
  • Tidskriftsartikel (refereegranskat)abstract
    • Spatial and molecular characteristics determine tissue function, yet high-resolution methods to capture both concurrently are lacking. Here, we developed high-definition spatial transcriptomics, which captures RNA from histological tissue sections on a dense, spatially barcoded bead array. Each experiment recovers several hundred thousand transcriptcoupled spatial barcodes at 2-mu m resolution, as demonstrated in mouse brain and primary breast cancer. This opens the way to high-resolution spatial analysis of cells and tissues.
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7.
  • Dihge, Looket, et al. (författare)
  • Prediction of lymph node metastasis in breast cancer by gene expression and clinicopathological models: Development and validation within a population based cohort.
  • 2019
  • Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - American Association for Cancer Research. - 1078-0432. ; 25:21, s. 6368-6381
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: More than 70% of patients with breast cancer present with node-negative disease, yet all undergo surgical axillary staging. We aimed to define predictors of nodal metastasis using clinicopathological characteristics (CLINICAL), gene expression data (GEX), and mixed features (MIXED) and to identify patients at low risk of metastasis who might be spared sentinel lymph node biopsy (SLNB).Experimental Design: Breast tumors (n = 3,023) from the population-based Sweden Cancerome Analysis Network–Breast initiative were profiled by RNA sequencing and linked to clinicopathologic characteristics. Seven machine-learning models present the discriminative ability of N0/N+ in development (n = 2,278) and independent validation cohorts (n = 745) stratified as ER+HER2−, HER2+, and TNBC. Possible SLNB reduction rates are proposed by applying CLINICAL and MIXED predictors.Results: In the validation cohort, the MIXED predictor showed the highest area under ROC curves to assess nodal metastasis; AUC = 0.72. For the subgroups, the AUCs for MIXED, CLINICAL, and GEX predictors ranged from 0.66 to 0.72, 0.65 to 0.73, and 0.58 to 0.67, respectively. Enriched proliferation metagene and luminal B features were noticed in node-positive ER+HER2− and HER2+ tumors, while upregulated basal-like features were observed in node-negative TNBC tumors. The SLNB reduction rates in patients with ER+HER2− tumors were 6% to 7% higher for the MIXED predictor compared with the CLINICAL predictor accepting false negative rates of 5% to 10%.Conclusions: Although CLINICAL and MIXED predictors of nodal metastasis had comparable accuracy, the MIXED predictor identified more node-negative patients. This translational approach holds promise for development of classifiers to reduce the rates of SLNB for patients at low risk of nodal involvement.
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8.
  • Nilsson, Martin P., et al. (författare)
  • Written pretest information and germline BRCA1/2 pathogenic variant testing in unselected breast cancer patients : predictors of testing uptake
  • 2019
  • Ingår i: Genetics in Medicine. - Lippincott Williams & Wilkins. - 1098-3600. ; 21:1, s. 89-96
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: This study aimed to evaluate predictors of testing uptake among unselected breast cancer patients who were offered germline BRCA1/2 testing in a prospective study. Methods: Pretest information was provided by a standardized invitation letter instead of in-person counseling. Data was abstracted from medical records. Using multivariate logistic regressions, predictors of testing uptake were analyzed. Results: The overall uptake of testing was 67% (539 of 805 patients). Low uptake rates were found for patients aged ≥80 years (33%), and patients born outside of Europe (37%). In adjusted analysis, age ≥80 years (odds ratio [OR] 0.10; P = 0.002), psychiatric disorders (OR 0.46; P = 0.006), occupation requiring at least 3 years of university or college education (OR 2.03; P = 0.003), and breast cancer or ovarian cancer in first-degree or second-degree relatives (OR 1.66; P = 0.02) were independently associated with uptake of BRCA1/2 testing. Somatic comorbidity in patients aged <70 years was associated with lower testing uptake. Conclusion: Testing uptake varies across different subgroups according to patient-related factors that are readily available in the medical records. Knowledge about these factors enables health care professionals to identify patients who are less likely to pursue genetic testing.
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9.
  • Parsons, Michael T, et al. (författare)
  • Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants : An ENIGMA resource to support clinical variant classification
  • 2019
  • Ingår i: Human Mutation. - John Wiley & Sons. - 1059-7794. ; s. 1557-1578
  • Tidskriftsartikel (refereegranskat)abstract
    • The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.
10.
  • Qian, Frank, et al. (författare)
  • Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers
  • 2019
  • Ingår i: British Journal of Cancer. - Nature Publishing Group. - 1532-1827.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94–1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85–1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06–1.48) and HR = 1.59 (95% CI: 1.08–2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population. © 2019, Cancer Research UK.
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