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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. |
- 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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| 6. |
- 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. |
- Nilsson, Helén, et al.
(författare)
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Features of increased malignancy in eosinophilic clear cell renal cell carcinoma
- 2020
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 252:4, s. 384-397
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Tidskriftsartikel (refereegranskat)abstract
- Clear cell renal cell carcinoma (ccRCC) is the most common form of renal cancer. Due to inactivation of the von Hippel-Lindau tumour suppressor, the hypoxia-inducible transcription factors (HIFs) are constitutively activated in these tumours, resulting in a pseudo-hypoxic phenotype. The HIFs induce the expression of genes involved in angiogenesis and cell survival, but they also reset the cellular metabolism to protect cells from oxygen and nutrient deprivation. ccRCC tumours are highly vascularized and the cytoplasm of the cancer cells is filled with lipid droplets and glycogen, resulting in the histologically distinctive pale (clear) cytoplasm. Intratumoural heterogeneity may occur, and in some tumours, areas with granular, eosinophilic cytoplasm are found. Little is known regarding these traits and how they relate to the coexistent clear cell component, yet eosinophilic ccRCC is associated with higher grade and clinically more aggressive tumours. In this study, we have for the first time performed RNA sequencing comparing histologically verified clear cell and eosinophilic areas from ccRCC tissue, aiming to analyse the characteristics of these cell types. Findings from RNA sequencing were confirmed by immunohistochemical staining of biphasic ccRCC. We found that the eosinophilic phenotype displayed a higher proliferative drive and lower differentiation, and we confirmed a correlation to tumours of higher stage. We further identified mutations of the tumour suppressor p53 (TP53) exclusively in the eosinophilic ccRCC component, where mTORC1 activity was also elevated. Also, eosinophilic areas were less vascularized, yet harboured more abundant infiltrating immune cells. The cytoplasm of clear cell ccRCC cells was filled with lipids but had very low mitochondrial content, while the reverse was found in eosinophilic tissue. We herein suggest possible transcriptional mechanisms behind these phenomena. (c) 2020 The Authors.The Journal of Pathologypublished by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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| 9. |
- Pettersson, Louise, et al.
(författare)
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Subclonal patterns in follow-up of acute myeloid leukemia combining whole exome sequencing and ultrasensitive IBSAFE digital droplet analysis
- 2020
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 61:9, s. 2168-2179
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Tidskriftsartikel (refereegranskat)abstract
- We studied mutation kinetics in ten relapsing and four non-relapsing patients with acute myeloid leukemia by whole exome sequencing at diagnosis to identify leukemia-specific mutations and monitored selected mutations at multiple time-points using IBSAFE droplet digital PCR. Five to nine selected mutations could identify and track leukemic clones prior to clinical relapse in 10/10 patients at the time-points where measurable residual disease was negative by multicolor flow cytometry. In the non-relapsing patients, the load of mutations gradually declined in response to different therapeutic strategies. Three distinct patterns of relapse were observed: (1) one or more different clones with all monitored mutations reappearing at relapse; (2) one or more separate clones of which one prevailed at relapse; and (3) persistent clonal hematopoiesis with high variant allele frequency and most mutations present at relapse. These pilot results demonstrate that IBSAFE analyses detect leukemic clones missed by flow cytometry with possible clinical implications.Highlights The IBSAFE ddPCR MRD method seems applicable on virtually all newly diagnosed AML patients and was more sensitive than flow cytometry. Monitoring a few mutations captured the kinetics of the evolving recurrent leukemia. NPM1-mutation alone may not be a reliable MRD-marker.
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