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Sökning: L773:1078 0432 OR L773:1557 3265 > Borg Åke

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1.
  • Harbst, Katja, et al. (författare)
  • Molecular profiling reveals low- and high-grade forms of primary melanoma.
  • 2012
  • Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1557-3265. ; 18:15, s. 4026-4036
  • Tidskriftsartikel (refereegranskat)abstract
    • For primary melanomas, tumor thickness, mitotic rate, and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma, which predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome.We subjected 223 archival primary melanomas to a horizontally integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry, and survival data.Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Because these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between "high" and "low" grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared with low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P < 0.01), and poorer relapse-free (HR = 4.94; 95% CI, 2.84-8.59), and overall (HR = 3.66; 95% CI, 2.40-5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes, whereas low-grade lesions harbored higher expression of immune genes. Importantly, the molecular-grade signature was validated in two external gene expression data sets.We provide evidence for a molecular organization within melanomas, which is preserved across all stages of disease.
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2.
  • 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. - 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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3.
  • Gruvberger, Sofia, et al. (författare)
  • Estrogen receptor beta expression is associated with tamoxifen response in ER alpha-negative breast carcinoma
  • 2007
  • Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:7, s. 1987-1994
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Endocrine therapies, such as tamoxifen, are commonly given to most patients with estrogen receptor (ERalpha)-positive breast carcinoma but are not indicated for persons with ERalpha-negative cancer. The factors responsible for response to tamoxifen in 5% to 10% of patients with ERalpha-negative tumors are not clear. The aim of the present study was to elucidate the biology and prognostic role of the second ER, ERbeta, in patients treated with adjuvant tamoxifen.EXPERIMENTAL DESIGN: We investigated ERbeta by immunohistochemistry in 353 stage II primary breast tumors from patients treated with 2 years adjuvant tamoxifen, and generated gene expression profiles for a representative subset of 88 tumors.RESULTS: ERbeta was associated with increased survival (distant disease-free survival, P = 0.01; overall survival, P = 0.22), and in particular within ERalpha-negative patients (P = 0.003; P = 0.04), but not in the ERalpha-positive subgroup (P = 0.49; P = 0.88). Lack of ERbeta conferred early relapse (hazard ratio, 14; 95% confidence interval, 1.8-106; P = 0.01) within the ERalpha-negative subgroup even after adjustment for other markers. ERalpha was an independent marker only within the ERbeta-negative tumors (hazard ratio, 0.44; 95% confidence interval, 0.21-0.89; P = 0.02). An ERbeta gene expression profile was identified and was markedly different from the ERalpha signature.CONCLUSION: Expression of ERbeta is an independent marker for favorable prognosis after adjuvant tamoxifen treatment in ERalpha-negative breast cancer patients and involves a gene expression program distinct from ERalpha. These results may be highly clinically significant, because in the United States alone, approximately 10,000 women are diagnosed annually with ERalpha-negative/ERbeta-positive breast carcinoma and may benefit from adjuvant tamoxifen.
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4.
  • Jönsson, Göran B, et al. (författare)
  • Gene Expression Profiling-Based Identification of Molecular Subtypes in Stage IV Melanomas with Different Clinical Outcome.
  • 2010
  • Ingår i: Clinical Cancer Research. - 1078-0432. ; 16:13, s. 3356-3367
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. While spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers selecting patients for immune therapy. Experimental design: We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the CDKN2A locus and NRAS/BRAF mutation screening. RESULTS: The analysis revealed four distinct subtypes with gene signatures characterized by expression of immune response, pigmentation differentiation, proliferation or stromal composition genes. Even though all subtypes harbored NRAS and BRAF mutations, there was a significant difference between subtypes (p<0.01), with no BRAF/NRAS wild-type samples in the proliferative subtype. Additionally, the proliferative subtype was characterized by high frequency of CDKN2A homozygous deletions (p<0.01). We observed different prognosis between the subtypes (p=0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared to the others (p = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III/IV melanomas. Moreover, low expression of an a priori-defined gene set associated to immune response signaling was significantly associated to poor outcome (p=0.001). CONCLUSIONS: Our data reveal a biologically-based taxonomy of malignant melanomas with prognostic impact and support an influence of the anti-tumoral immune response on outcome.
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5.
  • Karlsson, Anna K, et al. (författare)
  • Genome-wide DNA methylation analysis of lung carcinoma reveals one neuroendocrine and four adenocarcinoma epitypes associated with patient outcome.
  • 2014
  • Ingår i: Clinical Cancer Research. - 1078-0432. ; 20:23, s. 6127-6140
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer remains unclear. Experimental Design: Whole-genome DNA methylation analysis using 450K Illumina BeadArrays was performed on 12 normal lung tissues and 124 tumors including 83 adenocarcinomas, 23 squamous cell carcinomas (SqCC), one adenosquamous cancer, five large cell carcinomas, nine large cell neuroendocrine carcinomas (LCNEC), and three small cell carcinomas (SCLC). Unsupervised bootstrap clustering was performed to identify DNA methylation subgroups, which were validated in 695 adenocarcinomas and 122 SqCCs. Subgroups were characterized by clinicopathological factors, whole-exome sequencing data, and gene expression profiles. Results: Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, remaining four epitypes were associated with unsupervised and supervised gene expression phenotypes, and differences in molecular features including global hypomethylation, promoter hypermethylation, genomic instability, expression of proliferation-associated genes, and mutations in KRAS, TP53, KEAP1, SMARCA4, and STK11. Furthermore, these epitypes were associated with clinicopathological features such as smoking history, and patient outcome. Conclusions: Our findings highlight one neuroendocrine and four adenocarcinoma epitypes associated with molecular and clinicopathological characteristics, including patient outcome. This study highlights the possibility to further subgroup lung cancer, and more specifically adenocarcinomas, based on epigenetic/molecular classification that could lead to more accurate tumor classification, prognostication, and tailored patient therapy.
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