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| 2. |
- Brueffer, Christian, et al.
(författare)
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The Mutational Landscape of the SCAN-B Real-World Primary Breast Cancer Transcriptome
- 2020
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is a disease of genomic alterations, of which the complete panorama of somatic mutations and how these relate to molecular subtypes and therapy response is incompletely understood. Within the Sweden Cancerome Analysis Network–Breast project (SCAN-B; ClinicalTrials.govNCT02306096), an ongoing study elucidating the tumor transcriptomic profiles for thousands of breast cancers prospectively, we developed an optimized pipeline for detection of single nucleotide variants and small insertions and deletions from RNA sequencing (RNA-seq) data, and profiled a large real-world population-based cohort of 3,217 breast tumors. We use it to describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population-based cohort of patients, and relate it to patient overall survival. We demonstrate that RNA-seq can be used to call mutations in important breast cancer genes such asPIK3CA,TP53, andERBB2, as well as the status of key molecular pathways and tumor mutational burden, and identify potentially druggable genes in 86.8% percent of tumors. To make this rich and growing mutational portraiture of breast cancer available for the wider research community, we developed an open source web-based application, the SCAN-B MutationExplorer, accessible athttp://oncogenomics.bmc.lu.se/MutationExplorer. These results add another dimension to the use of RNA-seq as a potential clinical tool, where both gene expression-based and gene mutation-based biomarkers can be interrogated simultaneously and in real-time within one week of tumor sampling.
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| 3. |
- Brueffer, Christian, et al.
(författare)
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The mutational landscape of the SCAN‐B real‐world primary breast cancer transcriptome
- 2020
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a disease of genomic alterations, of which the panorama of somatic mutations and how these relate to subtypes and therapy response is incompletely understood. Within SCAN‐B (ClinicalTrials.gov: NCT02306096), a prospective study elucidating the transcriptomic profiles for thousands of breast cancers, we developed a RNA‐seq pipeline for detection of SNVs/indels and profiled a real‐world cohort of 3,217 breast tumors. We describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population‐based cohort and relate it to patient survival. We demonstrate that RNA‐seq can be used to call mutations in genes such as PIK3CA, TP53, and ERBB2, as well as the status of molecular pathways and mutational burden, and identify potentially druggable mutations in 86.8% of tumors. To make this rich dataset available for the research community, we developed an open source web application, the SCAN‐B MutationExplorer (http://oncogenomics.bmc.lu.se/MutationExplorer). These results add another dimension to the use of RNA‐seq as a clinical tool, where both gene expression‐ and mutation‐based biomarkers can be interrogated in real‐time within 1 week of tumor sampling.
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| 4. |
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| 5. |
- Dahlgren, Malin, et al.
(författare)
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Preexisting Somatic Mutations of Estrogen Receptor Alpha (ESR1) in Early-Stage Primary Breast Cancer
- 2021
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Ingår i: JNCI Cancer Spectrum. - : Oxford University Press (OUP). - 2515-5091. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ESR1), the most important factor for directing anti-estrogenic endocrine therapy (ET). Recently, mutations in ESR1 were identified as acquired mechanisms of resistance to ET, found in 12% to 55% of metastatic breast cancers treated previously with ET. We analyzed 3217 population-based invasive primary (nonmetastatic) breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096), sampled from initial diagnosis prior to any treatment, for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by droplet digital polymerase chain reaction on tumor and normal DNA. Patient outcomes were analyzed using Kaplan-Meier estimation and a series of 2-factor Cox regression multivariable analyses. We identified ESR1 resistance mutations in 30 tumors (0.9%), of which 29 were ER positive (1.1%). In ET-treated disease, presence of ESR1 mutation was associated with poor relapse-free survival and overall survival (2-sided log-rank test P < .001 and P = .008, respectively), with hazard ratios of 3.00 (95% confidence interval = 1.56 to 5.88) and 2.51 (95% confidence interval = 1.24 to 5.07), respectively, which remained statistically significant when adjusted for other prognostic factors. These population-based results indicate that ESR1 mutations at diagnosis of primary breast cancer occur in about 1% of women and identify for the first time in the adjuvant setting that such preexisting mutations are associated to eventual resistance to standard hormone therapy. If replicated, tumor ESR1 screening should be considered in ER-positive primary breast cancer, and for patients with mutated disease, ER degraders such as fulvestrant or other therapeutic options may be considered as more appropriate.
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| 6. |
- Glodzik, Dominik, et al.
(författare)
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Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.
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| 7. |
- Larsson, Christer, et al.
(författare)
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Prognostic implications of the expression levels of different immunoglobulin heavy chain-encoding RNAs in early breast cancer
- 2020
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Ingår i: npj Breast Cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- The extent and composition of the immune response in a breast cancer is one important prognostic factor for the disease. The aim of the current work was to refine the analysis of the humoral component of an immune response in breast tumors by quantifying mRNA expression of different immunoglobulin classes and study their association with prognosis. We used RNA-Seq data from two local population-based breast cancer cohorts to determine the expression of IGJ and immunoglobulin heavy (IGH) chain-encoding RNAs. The association with prognosis was investigated and public data sets were used to corroborate the findings. Except for IGHE and IGHD, mRNAs encoding heavy chains were generally detected at substantial levels and correlated with other immune-related genes. High IGHG1 mRNA was associated with factors related to poor prognosis such as estrogen receptor negativity, HER2 amplification, and high grade, whereas high IGHA2 mRNA levels were primarily associated with lower age at diagnosis. High IGHA2 and IGJ mRNA levels were associated with a more favorable prognosis both in univariable and multivariable Cox models. When adjusting for other prognostic factors, high IGHG1 mRNA levels were positively associated with improved prognosis. To our knowledge, these results are the first to demonstrate that expression of individual Ig class types has prognostic implications in breast cancer.
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| 8. |
- Malakpour Permlid, Atena, et al.
(författare)
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Identification of Extracellular Matrix Proteins Secreted by Human Dermal Fibroblasts Cultured in 3D Electrospun Scaffolds
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- The appreciation that cell interactions in tissues is dependent on their three dimensional (3D) distribution has stimulated the development of 3D cell culture models. We constructed an artificial 3D tumour by culturing human breast cancer JIMT-1 cells and human dermal fibroblasts (HDFs) in a 3D network of electrospun polycaprolactone fibres. Here, we investigate ECM components produced by the cells in the artificial 3D tumour, which is an important step in validating the model. Immunostaining and confocal fluorescence microscopy show that the ECM proteins fibronectin, collagen I, and laminin are deposited throughout the entire 3D structure. Secreted soluble factors including matrix metalloproteinases (MMPs) and interleukine-6 (IL-6) were analysed in collected medium and were found to be mainly derived from the HDFs. Treatment with transforming growth factor-β1 (TGF-β1), a major cytokine found in a tumour, significantly alters the MMP activity and IL-6 concentration. In addition, TGF-β1 treatment, changes the morphology of the HDFs to become more elongated and with increased linearized actin filaments compared to non-treated HDFs. Collectively, these novel findings suggest that the artificial 3D tumour displays a clear cell distribution and ECM deposition that resembles a tumour environment in vivo, suggesting an innovative biological model to study a human tumour.
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| 9. |
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| 10. |
- Mohlin, Åsa, et al.
(författare)
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Psychological resilience and health-related quality of life in Swedish women with newly diagnosed breast cancer
- 2020
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Ingår i: Cancer Management and Research. - 1179-1322. ; 12, s. 12041-12051
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Psychological resilience appears to be an important influencing factor in various aspects of health-related quality of life (HRQoL) in a context of adversity, eg, being informed of a cancer diagnosis. The purpose was to investigate psychological resilience and HRQoL in Swedish women with newly diagnosed breast cancer in relation to demographic and clinicopathological characteristics. Methods: A population-based cross-sectional study was conducted including 517 women with breast cancer in the South Swedish Health Care Region. Participants were enrolled at the time of consultation for the diagnosis. Psychological resilience was assessed with the Connor-Davidson Resilience Scale 25 (CD-RISC25), and HRQoL was assessed with the Short Form Health Survey. The participants responded to questions regarding demographic variables. Clinicopathological data were collected from the Swedish National Quality Register for Breast Cancer. Results: The mean score for psychological resilience was 70.6, identifying 15% of included patients with a score lower than 58 (−1 standard deviation). The study cohort had significantly lower mean scores for several aspects of HRQoL compared with Swedish normative data. Regression analyses demonstrated that psychological resilience was significantly associated with all domains of HRQoL after adjustment for demographic and clinicopathological factors. Conclusion: Higher levels of psychological resilience were significantly related to higher levels of HRQoL in Swedish women with newly diagnosed breast cancer and no modifying factor was identified. The assessment of psychological resilience at the time of breast cancer diagnosis might allow for early identification of women in need of more intense psychosocial support. Future studies are needed to identify a clinically relevant threshold of the CD-RISC25.
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