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1.
  • Elliott, Kerryn, et al. (författare)
  • Elevated pyrimidine dimer formation at distinct genomic bases underlies promoter mutation hotspots in UV-exposed cancers.
  • 2018
  • Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 14:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Sequencing of whole cancer genomes has revealed an abundance of recurrent mutations in gene-regulatory promoter regions, in particular in melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these mutations are commonly believed to be due to locally inhibited DNA repair. Here, we first show that low-dose UV light induces mutations preferably at a known ETS promoter hotspot in cultured cells even in the absence of global or transcription-coupled nucleotide excision repair (NER). Further, by genome-wide mapping of cyclobutane pyrimidine dimers (CPDs) shortly after UV exposure and thus before DNA repair, we find that ETS-related mutation hotspots exhibit strong increases in CPD formation efficacy in a manner consistent with tumor mutation data at the single-base level. Analysis of a large whole genome cohort illustrates the widespread contribution of this effect to recurrent mutations in melanoma. While inhibited NER underlies a general increase in somatic mutation burden in regulatory elements including ETS sites, our data supports that elevated DNA damage formation at specific genomic bases is at the core of the prominent promoter mutation hotspots seen in skin cancers, thus explaining a key phenomenon in whole-genome cancer analyses.
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2.
  • Andersson, Daniel, 1979, et al. (författare)
  • Circulating cell-free tumor DNA analysis in pediatric cancers
  • 2020
  • Ingår i: Molecular Aspects of Medicine. - : Elsevier BV. - 0098-2997. ; 72:April
  • Tidskriftsartikel (refereegranskat)abstract
    • Analysis of circulating cell-free tumor DNA (ctDNA) has shown promising results within several clinical applications, including cancer detection, mutation profiling, treatment monitoring and early detection of relapse. Here, we discuss the potential and limitations of ctDNA analysis in pediatric cancer detection, therapy decision making and research. Biological properties associated to ctDNA are highlighted and related to technical constraints in downstream analyses. The effects of ctDNA release and clearance dynamics are illustrated and we argue that reporting ctDNA as a fraction of mutated compared to normal wild-type DNA may be problematic from a biological point of view. We have summarized experimental details, data and conclusions from 50 pediatric ctDNA studies. We discuss the genomic landscape of several pediatric entities and how their specific mutation profiles affects ctDNA analysis, often requiring custom-made technical solutions. Finally, we outline future aspects of ctDNA analysis and what is needed to fully implement it into clinical routine in pediatric oncology. © 2019 The Authors
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3.
  • Bar, Tzachi, 1970, et al. (författare)
  • Kinetic Outlier Detection (KOD) in real-time PCR.
  • 2003
  • Ingår i: Nucleic acids research. - 1362-4962 .- 0305-1048. ; 31:17
  • Tidskriftsartikel (refereegranskat)abstract
    • Real-time PCR is becoming the method of choice for precise quantification of minute amounts of nucleic acids. For proper comparison of samples, almost all quantification methods assume similar PCR efficiencies in the exponential phase of the reaction. However, inhibition of PCR is common when working with biological samples and may invalidate the assumed similarity of PCR efficiencies. Here we present a statistical method, Kinetic Outlier Detection (KOD), to detect samples with dissimilar efficiencies. KOD is based on a comparison of PCR efficiency, estimated from the amplification curve of a test sample, with the mean PCR efficiency of samples in a training set. KOD is demonstrated and validated on samples with the same initial number of template molecules, where PCR is inhibited to various degrees by elevated concentrations of dNTP; and in detection of cDNA samples with an aberrant ratio of two genes. Translating the dissimilarity in efficiency to quantity, KOD identifies outliers that differ by 1.3-1.9-fold in their quantity from normal samples with a P-value of 0.05. This precision is higher than the minimal 2-fold difference in number of DNA molecules that real-time PCR usually aims to detect. Thus, KOD may be a useful tool for outlier detection in real-time PCR.
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4.
  • Bjursten, Sara, et al. (författare)
  • Response to BRAF/MEK Inhibition in A598_T599insV BRAF Mutated Melanoma
  • 2019
  • Ingår i: Case Reports in Oncology. - : S. Karger AG. - 1662-6575. ; 12:3, s. 872-879
  • Tidskriftsartikel (refereegranskat)abstract
    • Approximately 50% of patients with metastatic melanoma harbor an activating BRAF mutation. Tumors with activating mutation BRAF gene proliferate excessively and can be treated with targeted BRAF-inhibitors in combination with MEK inhibitors. The most common BRAF mutation occurs at amino acid position 600. Other BRAF mutations are rare and their predictive value for treatment response to BRAF/MEK inhibition is low. Here, we report on a patient with a BRAF A598_T599insV mutated melanoma, a mutation that has only been described in one previous melanoma patient in which the treatment response to BRAF/MEK inhibition was transient. Our patient had a large ulcerated metastasis that showed a durable complete response implying that BRAF/MEK inhibition should be considered a treatment option for this mutation. We analyzed circulating cell-free tumor DNA (ctDNA) carrying the BRAF A598_T599insV mutation throughout treatment. The allele frequency of BRAF A598_T599insV decreased during regression of the tumors, indicating that this method has potential to monitor treatment response. Our case demonstrates durable response to BRAF/MEK inhibition in a melanoma patient carrying a BRAF A598_T599insV mutation. In addition, we show that allele frequency analysis of A598_T599insV mutation in blood using ultrasensitive sequencing can be used to monitor treatment response.
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5.
  • Dolatabadi, Soheila, et al. (författare)
  • JAK–STAT signalling controls cancer stem cell properties including chemotherapy resistance in myxoid liposarcoma
  • 2019
  • Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 145:2, s. 435-449
  • Tidskriftsartikel (refereegranskat)abstract
    • Myxoid liposarcoma (MLS) shows extensive intratumoural heterogeneity with distinct subpopulations of tumour cells. Despite improved survival of MLS patients, existing therapies have shortcomings as they fail to target all tumour cells. The nature of chemotherapy-resistant cells in MLS remains unknown. Here, we show that MLS cell lines contained subpopulations of cells that can form spheres, efflux Hoechst dye and resist doxorubicin, all properties attributed to cancer stem cells (CSCs). By single-cell gene expression, western blot, phospho-kinase array, immunoprecipitation, immunohistochemistry, flow cytometry and microarray analysis we showed that a subset of MLS cells expressed JAK–STAT genes with active signalling. JAK1/2 inhibition via ruxolitinib decreased, while stimulation with LIF increased, phosphorylation of STAT3 and the number of cells with CSC properties indicating that JAK–STAT signalling controlled the number of cells with CSC features. We also show that phosphorylated STAT3 interacted with the SWI/SNF complex. We conclude that MLS contains JAK–STAT-regulated subpopulations of cells with CSC features. Combined doxorubicin and ruxolitinib treatment targeted both proliferating cells as well as cells with CSC features, providing new means to circumvent chemotherapy resistance in treatment of MLS patients. © 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC
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6.
  • Fredriksson, Nils Johan, 1979-, et al. (författare)
  • Recurrent promoter mutations in melanoma are defined by an extended context-specific mutational signature
  • 2017
  • Ingår i: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Sequencing of whole tumor genomes holds the promise of revealing functional somatic regulatory mutations, such as those described in the TERT promoter. Recurrent promoter mutations have been identified in many additional genes and appear to be particularly common in melanoma, but convincing functional data such as influence on gene expression has been more elusive. Here, we show that frequently recurring promoter mutations in melanoma occur almost exclusively at cytosines flanked by a distinct sequence signature, TTCCG, with TERT as a notable exception. In active, but not inactive, promoters, mutation frequencies for cytosines at the 5' end of this ETS-like motif were considerably higher than expected based on a UV trinucleotide mutational signature. Additional analyses solidify this pattern as an extended context-specific mutational signature that mediates an exceptional position-specific vulnerability to UV mutagenesis, arguing against positive selection. We further use ultra-sensitive amplicon sequencing to demonstrate that cell cultures exposed to UV light quickly develop subclonal mutations specifically in affected positions. Our findings have implications for the interpretation of somatic mutations in regulatory regions, and underscore the importance of genomic context and extended sequence patterns to accurately describe mutational signatures in cancer.
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7.
  • Garre, Elena, 1978, et al. (författare)
  • Breast Cancer Patient-Derived Scaffolds Can Expose Unique Individual Cancer Progressing Properties of the Cancer Microenvironment Associated with Clinical Characteristics
  • 2022
  • Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Simple Summary Despite huge progress in cancer diagnostics and medicine we still lack optimal cancer treatments for patients with aggressive diseases. This problem can be influenced by the biological heterogeneity of cancer cells as well as poorly understood cancer promoting effects of the cancer microenvironment being an important part of the cancer niche. In this study we have specifically monitored the activity of the cancer microenvironment in breast cancer patients using cell-free scaffolds repopulated with reporter cancer cells sensing the activity of the patient environment. The data show that scaffold induced changes in epithelial-mesenchymal transition and pluripotency markers were linked to clinical and prognostic properties of the original cancer and the information was even more precise when matching estrogen receptor status in our system. The findings highlight that patient-derived scaffolds uncover important information about varying malignant promoting properties in the cancer niche and can be used as a complementary diagnostic tool. Breast cancer is a heterogeneous disease in terms of cellular and structural composition, and besides acquired aggressive properties in the cancer cell population, the surrounding tumor microenvironment can affect disease progression and clinical behaviours. To specifically decode the clinical relevance of the cancer promoting effects of individual tumor microenvironments, we performed a comprehensive test of 110 breast cancer samples using a recently established in vivo-like 3D cell culture platform based on patient-derived scaffolds (PDSs). Cell-free PDSs were recellularized with three breast cancer cell lines and adaptation to the different patient-based microenvironments was monitored by quantitative PCR. Substantial variability in gene expression between individual PDS cultures from different patients was observed, as well as between different cell lines. Interestingly, specific gene expression changes in the PDS cultures were significantly linked to prognostic features and clinical information from the original cancer. This link was even more pronounced when ER alpha-status of cell lines and PDSs matched. The results support that PDSs cultures, including a cancer cell line of relevant origin, can monitor the activity of the tumor microenvironment and reveal unique information about the malignancy-inducing properties of the individual cancer niche and serve as a future complementary diagnostic tool for breast cancer.
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8.
  • Håkansson, Joakim, 1975, et al. (författare)
  • N-CAM exhibits a regulatory function in pathological angiogenesis in oxygen induced retinopathy.
  • 2011
  • Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 6:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Diabetic retinopathy and retinopathy of prematurity are diseases caused by pathological angiogenesis in the retina as a consequence of local hypoxia. The underlying mechanism for epiretinal neovascularization (tuft formation), which contributes to blindness, has yet to be identified. Neural cell adhesion molecule (N-CAM) is expressed by Müller cells and astrocytes, which are in close contact with the retinal vasculature, during normal developmental angiogenesis.
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9.
  • Håkansson, Joakim, 1975, et al. (författare)
  • Neural cell adhesion molecule-deficient beta-cell tumorigenesis results in diminished extracellular matrix molecule expression and tumour cell-matrix adhesion
  • 2005
  • Ingår i: Tumour Biology. - : Springer Science and Business Media LLC. - 1010-4283 .- 1423-0380. ; 26:2, s. 103-112
  • Tidskriftsartikel (refereegranskat)abstract
    • To understand by which mechanism neural cell adhesion molecule (N-CAM) limits beta tumour cell disaggregation and dissemination, we searched for potential downstream genes of N-CAM during beta tumour cell progression by gene expression profiling. Here, we show that N-CAM-deficient beta-cell tumorigenesis is associated with changes in the expression of genes involved in cell-matrix adhesion and cytoskeletal dynamics, biological processes known to affect the invasive and metastatic behaviour of tumour cells. The extracellular matrix (ECM) molecules emerged as the primary target, i.e. N-CAM deficiency resulted in down-regulated mRNA expression of a broad range of ECM molecules. Consistent with this result, deficient deposition of major ECM stromal components, such as fibronectin, laminin 1 and collagen IV, was observed. Moreover, N-CAM-deficient tumour cells displayed defective matrix adhesion. These results offer a potential mechanism for tumour cell disaggregation during N-CAM-deficient beta tumour cell progression. Prospective consequences of these findings for the role of N-CAM in beta tumour cell dissemination are discussed.
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10.
  • Johansson, Gustav, et al. (författare)
  • Monitoring circulating tumor DNA during surgical treatment in patients with gastrointestinal stromal tumors
  • 2021
  • Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 20:12, s. 2568-2576
  • Tidskriftsartikel (refereegranskat)abstract
    • The majority of patients diagnosed with advanced gastrointestinal stromal tumors (GISTs) are successfully treated with a combination of surgery and tyrosine kinase inhibitors (TKIs). However, it remains challenging to monitor treatment efficacy and identify relapse early. Here, we utilized a sequencing strategy based on molecular barcodes and developed a GIST-specific panel to monitor tumor-specific and TKI resistance mutations in cell-free DNA and applied the approach to patients undergoing surgical treatment. Thirty-two patients with GISTs were included, and 161 blood plasma samples were collected and analyzed at routine visits before and after surgery and at the beginning, during, and after surgery. Patients were included regardless of their risk category. Our GIST-specific sequencing approach allowed detection of tumor-specific mutations and TKI resistance mutations with mutant allele frequency < 0.1%. Circulating tumor DNA (ctDNA) was detected in at least one timepoint in nine of 32 patients, ranging from 0.04% to 93% in mutant allele frequency. High-risk patients were more often ctDNA positive than other risk groups (P < 0.05). Patients with detectable ctDNA also displayed higher tumor cell proliferation rates (P < 0.01) and larger tumor sizes (P < 0.01). All patients who were ctDNA positive during surgery became negative after surgery. Finally, in two patients who progressed on TKI treatment, we detected multiple resistance mutations. Our data show that ctDNA may become a clinically useful biomarker in monitoring treatment efficacy in patients with high-risk GISTs and can assist in treatment decision making.
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