Publications by authors named "Matti Nykter"

121 Publications

Genetic and epigenetic characteristics of inflammatory bowel disease associated colorectal cancer.

Gastroenterology 2021 Apr 27. Epub 2021 Apr 27.

Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland. Electronic address:

Background And Aims: Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder associated with an elevated risk of colorectal cancer (CRC). IBD-associated CRC (IBD-CRC) may represent a distinct pathway of tumorigenesis compared to sporadic CRC (sCRC). Our aim was to comprehensively characterize IBD-associated tumorigenesis integrating multiple high-throughput approaches, and to compare the results with in-house data sets from sCRCs.

Methods: Whole-genome sequencing, single nucleotide polymorphism arrays, RNA sequencing, genome-wide methylation analysis, and immunohistochemistry were performed using fresh frozen and formalin-fixed tissue samples of tumor and corresponding normal tissues from 31 IBD-CRC patients.

Results: Transcriptome-based tumor subtyping revealed the complete absence of canonical epithelial tumor subtype associated with WNT signaling in IBD-CRCs, dominated instead by mesenchymal stroma-rich subtype. Negative WNT regulators AXIN2 and RNF43 were strongly downregulated in IBD-CRCs and chromosomal gains at HNF4A, a negative regulator of WNT-induced epithelial-mesenchymal transition (EMT), were less frequent compared to sCRCs. Enrichment of hypomethylation at HNF4α binding sites was detected solely in sCRC genomes. PIGR and OSMR involved in mucosal immunity were dysregulated via epigenetic modifications in IBD-CRCs. Genome-wide analysis showed significant enrichment of noncoding mutations to 5'UTR of TP53 in IBD-CRCs. As previously reported, somatic mutations in APC and KRAS were less frequent in IBD-CRCs compared to sCRCs.

Conclusions: Distinct mechanisms of WNT pathway dysregulation skew IBD-CRCs towards mesenchymal tumor subtype, which may affect prognosis and treatment options. Increased OSMR signaling may favor the establishment of mesenchymal tumors in IBD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2021.04.042DOI Listing
April 2021

Gene Regulation Network Analysis on Human Prostate Orthografts Highlights a Potential Role for the Regulon in Clinical Prostate Cancer.

Cancers (Basel) 2021 Apr 26;13(9). Epub 2021 Apr 26.

GenomeScan B.V. Plesmanlaan 1D, 2333 BZ Leiden, The Netherlands.

Background: Prostate cancer (PCa) is the second most common tumour diagnosed in men. Tumoral heterogeneity in PCa creates a significant challenge to develop robust prognostic markers and novel targets for therapy. An analysis of gene regulatory networks (GRNs) in PCa may provide insight into progressive PCa. Herein, we exploited a graph-based enrichment score to integrate data from GRNs identified in preclinical prostate orthografts and differentially expressed genes in clinical resected PCa. We identified active regulons (transcriptional regulators and their targeted genes) associated with PCa recurrence following radical prostatectomy.

Methods: The expression of known transcription factors and co-factors was analysed in a panel of prostate orthografts ( = 18). We searched for genes (as part of individual GRNs) predicted to be regulated by the highest number of transcriptional factors. Using differentially expressed gene analysis (on a per sample basis) coupled with gene graph enrichment analysis, we identified candidate genes and associated GRNs in PCa within the UTA cohort, with the most enriched regulon being which was further validated in two additional cohorts, namely EMC and ICGC cohorts. Cox regression analysis was performed to evaluate the association of the regulon activity with disease-free survival time in the three clinical cohorts as well as compared to three published prognostic gene signatures (TMCC11, BROMO-10 and HYPOXIA-28).

Results: 1308 regulons were correlated to transcriptomic data from the three clinical prostatectomy cohorts. The regulon was identified as the top enriched regulon in the UTA cohort and again validated in the EMC cohort as the top-ranking regulon. In both UTA and EMC cohorts, the regulon was significantly associated with cancer recurrence. Active regulon also correlated with disease recurrence in the ICGC cohort. Furthermore, Kaplan-Meier analysis confirmed shorter time to recurrence in patients with active regulon for all three clinical cohorts (UTA, EMC and ICGC), which was not the case for three published prognostic gene signatures (TMCC11, BROMO-10 and HYPOXIA-28). In multivariate analysis, the regulon status significantly predicted disease recurrence in the UTA and EMC, but not ICGC datasets, while none of the three published signatures significantly prognosticate for cancer recurrence.

Conclusions: We have characterised gene regulatory networks from preclinical prostate orthografts and applied transcriptomic data from three clinical cohorts to evaluate the prognostic potential of the regulon.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13092094DOI Listing
April 2021

Independent and cumulative coeliac disease-susceptibility loci are associated with distinct disease phenotypes.

J Hum Genet 2021 Jan 15. Epub 2021 Jan 15.

Coeliac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

The phenotype of coeliac disease varies considerably for incompletely understood reasons. We investigated whether established coeliac disease susceptibility variants (SNPs) are individually or cumulatively associated with distinct phenotypes. We also tested whether a polygenic risk score (PRS) based on genome-wide associated (GWA) data could explain the phenotypic variation. The phenotypic association of 39 non-HLA coeliac disease SNPs was tested in 625 thoroughly phenotyped coeliac disease patients and 1817 controls. To assess their cumulative effects a weighted genetic risk score (wGRS39) was built, and stratified by tertiles. In our PRS model in cases, we took the summary statistics from the largest GWA study in coeliac disease and tested their association at eight P value thresholds (P) with phenotypes. Altogether ten SNPs were associated with distinct phenotypes after correction for multiple testing (P ≤ 0.05). The TLR7/TLR8 locus was associated with disease onset before and the SH2B3/ATXN2, ITGA4/UBE2E3 and IL2/IL21 loci after 7 years of age. The latter three loci were associated with a more severe small bowel mucosal damage and SH2B3/ATXN2 with type 1 diabetes. Patients at the highest wGRS39 tertiles had OR > 1.62 for having coeliac disease-related symptoms during childhood, a more severe small bowel mucosal damage, malabsorption and anaemia. PRS was associated only with dermatitis herpetiformis (P = 0.2, P = 0.02). Independent coeliac disease-susceptibility loci are associated with distinct phenotypes, suggesting that genetic factors play a role in determining the disease presentation. Moreover, the increased number of coeliac disease susceptibility SNPs might predispose to a more severe disease course.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-020-00888-5DOI Listing
January 2021

Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer.

Nat Commun 2021 01 8;12(1):184. Epub 2021 Jan 8.

Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.

Molecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-20493-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794518PMC
January 2021

Immunogenomic Landscape of Hematological Malignancies.

Cancer Cell 2020 09 9;38(3):380-399.e13. Epub 2020 Jul 9.

Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center (HUH CCC), 00029 Helsinki, Finland; Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki (UH), 00029 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland. Electronic address:

Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. We integrated over 8,000 transcriptomes and 2,000 samples with multilevel genomics of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival, and validated key findings experimentally. Infiltration of cytotoxic lymphocytes was associated with TP53 and myelodysplasia-related changes in acute myeloid leukemia, and activated B cell-like phenotype and interferon-γ response in lymphoma. CIITA methylation regulating antigen presentation, cancer type-specific immune checkpoints, such as VISTA in myeloid malignancies, and variation in cancer antigen expression further contributed to immune heterogeneity and predicted survival. Our study provides a resource linking immunology with cancer subtypes and genomics in hematological malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2020.06.002DOI Listing
September 2020

AR and ERG drive the expression of prostate cancer specific long noncoding RNAs.

Oncogene 2020 07 17;39(30):5241-5251. Epub 2020 Jun 17.

Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland.

Long noncoding RNAs (lncRNAs) play pivotal roles in cancer development and progression, and some function in a highly cancer-specific manner. However, whether the cause of their expression is an outcome of a specific regulatory mechanism or nonspecific transcription induced by genome reorganization in cancer remains largely unknown. Here, we investigated a group of lncRNAs that we previously identified to be aberrantly expressed in prostate cancer (PC), called TPCATs. Our high-throughput real-time PCR experiments were integrated with publicly available RNA-seq and ChIP-seq data and revealed that the expression of a subset of TPCATs is driven by PC-specific transcription factors (TFs), especially androgen receptor (AR) and ETS-related gene (ERG). Our in vitro validations confirmed that AR and ERG regulated a subset of TPCATs, most notably for EPCART. Knockout of EPCART was found to reduce migration and proliferation of the PC cells in vitro. The high expression of EPCART and two other TPCATs (TPCAT-3-174133 and TPCAT-18-31849) were also associated with the biochemical recurrence of PC in prostatectomy patients and were independent prognostic markers. Our findings suggest that the expression of numerous PC-associated lncRNAs is driven by PC-specific mechanisms and not by random cellular events that occur during cancer development. Furthermore, we report three prospective prognostic markers for the early detection of advanced PC and show EPCART to be a functionally relevant lncRNA in PC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-020-1365-6DOI Listing
July 2020

Activating AKT1 and PIK3CA Mutations in Metastatic Castration-Resistant Prostate Cancer.

Eur Urol 2020 12 22;78(6):834-844. Epub 2020 May 22.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Background: Activating mutations in AKT1 and PIK3CA are undercharacterised in metastatic castration-resistant prostate cancer (mCRPC), but are linked to activation of phosphatidylinositol 3-kinase (PI3K) signalling and sensitivity to pathway inhibitors in other cancers.

Objective: To determine the prevalence, genomic context, and clinical associations of AKT1/PIK3CA activating mutations in mCRPC.

Design, Setting, And Participants: We analysed targeted cell-free DNA (cfDNA) sequencing data from 599 metastatic prostate cancer patients with circulating tumour DNA (ctDNA) content above 2%.

Outcome Measurements And Statistical Analysis: In patients with AKT1/PIK3CA mutations, cfDNA was subjected to PTEN intron sequencing and matched diagnostic tumour tissue was analysed when possible.

Results And Limitations: Of the patients, 6.0% (36/599) harboured somatic clonal activating mutation(s) in AKT1 or PIK3CA. Mutant allele-specific imbalance was common. Clonal mutations in mCRPC ctDNA were typically detected in pretreatment primary tissue and were consistent across serial ctDNA collections. AKT1/PIK3CA-mutant mCRPC had fewer androgen receptor (AR) gene copies than AKT1/PIK3CA wild-type mCRPC (median 4.7 vs 10.3, p =  0.003). AKT1 mutations were mutually exclusive with PTEN alterations. Patients with and without AKT1/PIK3CA mutations showed similar clinical outcomes with standard of care treatments. A heavily pretreated mCRPC patient with an AKT1 mutation experienced a 50% decline in prostate-specific antigen with Akt inhibitor (ipatasertib) monotherapy. Ipatasertib also had a marked antitumour effect in a patient-derived xenograft harbouring an AKT1 mutation. Limitations include the inability to assess AKT1/PIK3CA correlatives in ctDNA-negative patients.

Conclusions: AKT1/PIK3CA activating mutations are relatively common and delineate a distinct mCRPC molecular subtype with low-level AR copy gain. Clonal prevalence and evidence of mutant allele selection propose PI3K pathway dependency in selected patients. The use of cfDNA screening enables prospective clinical trials to test PI3K pathway inhibitors in this population.

Patient Summary: Of advanced prostate cancer cases, 6% have activating mutations in the genes AKT1 or PIK3CA. These mutations can be identified using a blood test and may help select patients suitable for clinical trials of phosphatidylinositol 3-kinase inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2020.04.058DOI Listing
December 2020

Prostate-specific membrane antigen expression in the vasculature of primary lung carcinomas associates with faster metastatic dissemination to the brain.

J Cell Mol Med 2020 06 11;24(12):6916-6927. Epub 2020 May 11.

Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Glioblastomas and brain metastases (BM) of solid tumours are the most common central nervous system neoplasms associated with very unfavourable prognosis. In this study, we report the association of prostate-specific membrane antigen (PSMA) with various clinical parameters in a large cohort of primary and secondary brain tumours. A tissue microarray containing 371 cases of ascending grades of gliomas pertaining to astrocytic origin and samples of 52 cases of primary lung carcinomas with matching BM with follow-up time accounting to 10.4 years was evaluated for PSMA expression using immunohistochemistry. In addition, PSMA expression was studied in BM arising from melanomas and breast carcinomas. Neovascular expression of PSMA was evident alongside with high expression in the proliferating microvasculature of glioblastomas when compared to the tumour cell expression. This result correlated with the results obtained from the in silico (cancer genome databases) analyses. In gliomas, only the vascular expression of PSMA associated with poor overall survival but not the tumour cell expression. In the matched primary lung cancers and their BM (n = 52), vascular PSMA expression in primary tumours associated with significantly accelerated metastatic dissemination to the brain with a tendency towards poor overall survival. Taken together, we report that the vascular expression of PSMA in the primary and secondary brain tumours globally associates with the malignant progression and poor outcome of the patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcmm.15350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299712PMC
June 2020

Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer.

Genes (Basel) 2020 03 14;11(3). Epub 2020 Mar 14.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden.

Germline variants in DNA repair genes are associated with aggressive prostate cancer (PrCa). The aim of this study was to characterize germline variants in DNA repair genes associated with lethal PrCa in Finnish and Swedish populations. Whole-exome sequencing was performed for 122 lethal and 60 unselected PrCa cases. Among the lethal cases, a total of 16 potentially damaging protein-truncating variants in DNA repair genes were identified in 15 men (12.3%). Mutations were found in six genes with (4.1%) and (3.3%) being most frequently mutated. Overall, the carrier rate of truncating variants in DNA repair genes among men with lethal PrCa significantly exceeded the carrier rate of 0% in 60 unselected PrCa cases ( = 0.030), and the prevalence of 1.6% ( < 0.001) and 5.4% ( = 0.040) in Swedish and Finnish population controls from the Exome Aggregation Consortium. No significant difference in carrier rate of potentially damaging nonsynonymous single nucleotide variants between lethal and unselected PrCa cases was observed ( = 0.123). We confirm that DNA repair genes are strongly associated with lethal PrCa in Sweden and Finland and highlight the importance of population-specific assessment of variants contributing to PrCa aggressiveness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11030314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140841PMC
March 2020

Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: the TEDDY study.

Gut 2020 08 19;69(8):1416-1422. Epub 2019 Nov 19.

The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.

Objective: Higher gluten intake, frequent gastrointestinal infections and adenovirus, enterovirus, rotavirus and reovirus have been proposed as environmental triggers for coeliac disease. However, it is not known whether an interaction exists between the ingested gluten amount and viral exposures in the development of coeliac disease. This study investigated whether distinct viral exposures alone or together with gluten increase the risk of coeliac disease autoimmunity (CDA) in genetically predisposed children.

Design: The Environmental Determinants of Diabetes in the Young study prospectively followed children carrying the HLA risk haplotypes DQ2 and/or DQ8 and constructed a nested case-control design. From this design, 83 CDA case-control pairs were identified. Median age of CDA was 31 months. Stool samples collected monthly up to the age of 2 years were analysed for virome composition by Illumina next-generation sequencing followed by comprehensive computational virus profiling.

Results: The cumulative number of stool enteroviral exposures between 1 and 2 years of age was associated with an increased risk for CDA. In addition, there was a significant interaction between cumulative stool enteroviral exposures and gluten consumption. The risk conferred by stool enteroviruses was increased in cases reporting higher gluten intake.

Conclusions: Frequent exposure to enterovirus between 1 and 2 years of age was associated with increased risk of CDA. The increased risk conferred by the interaction between enteroviruses and higher gluten intake indicate a cumulative effect of these factors in the development of CDA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2019-319809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234892PMC
August 2020

Moderate-to-strong expression of FGFR3 and TP53 alterations in a subpopulation of choroid plexus tumors.

Histol Histopathol 2020 Jul 29;35(7):673-680. Epub 2019 Oct 29.

Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland.

Deregulation of fibroblast growth factor receptor (FGFR) signaling is tightly associated with numerous human malignancies, including cancer. Indeed, FGFR inhibitors are being tested as anti-tumor drugs in clinical trials. Among gliomas, FGFR3 fusions occur in IDH wild-type diffuse gliomas leading to high FGFR3 protein expression and both, FGFR3 and FGFR1, show elevated expression in aggressive ependymomas. The aim of this study was to uncover the expression of FGFR1 and FGFR3 proteins in choroid plexus tumors and to further characterize FGFR-related as well as other genetic alterations in FGFR3 expressing tumors. Expression levels of FGFR1 and FGFR3 were detected in 15 choroid plexus tumor tissues using immunohistochemistry of tissue microarrays and 6 samples were subjected to whole mount FGFR3 staining. Targeted sequencing was used for deeper molecular analysis of two FGFR3 positive cases. Moderate expression of FGFR1 or FGFR3 was evidenced in one third of the studied choroid plexus tumors. Targeted sequencing of a choroid plexus carcinoma and an atypical choroid plexus papilloma, both with moderate-to-strong FGFR3 expression, revealed lack of protein-altering mutations or fusions in FGFR1 or FGFR3, but TP53 was altered in both tumors. FGFR3 and FGFR1 proteins are expressed in a subpopulation of choroid plexus tumors. Further studies using larger cohorts of patients will allow identification of the clinicopathological implications of FGFR1 and FGFR3 expression in choroid plexus tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14670/HH-18-180DOI Listing
July 2020

Characterization of immune response against Mycobacterium marinum infection in the main hematopoietic organ of adult zebrafish (Danio rerio).

Dev Comp Immunol 2020 02 15;103:103523. Epub 2019 Oct 15.

Laboratory of Experimental Immunology, BioMediTech, Faculty of Medicine and Health Technology, FI-33014, Tampere University, Finland; Department of Pediatrics, Tampere University Hospital, P.O. Box 2000, FI-33521, Tampere, Finland; PEDEGO Research Unit, Medical Research Center Oulu, P.O. Box 8000, FI-90014, University of Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, P.O. Box 10, FI-90029, OYS, Finland. Electronic address:

Tuberculosis remains a major global health challenge. To gain information about genes important for defense against tuberculosis, we used a well-established tuberculosis model; Mycobacterium marinum infection in adult zebrafish. To characterize the immunological response to mycobacterial infection at 14 days post infection, we performed a whole-genome level transcriptome analysis using cells from kidney, the main hematopoietic organ of adult zebrafish. Among the upregulated genes, those associated with immune signaling and regulation formed the largest category, whereas the largest group of downregulated genes had a metabolic role. We also performed a forward genetic screen in adult zebrafish and identified a fish line with severely impaired survival during chronic mycobacterial infection. Based on transcriptome analysis, these fish have decreased expression of several immunological genes. Taken together, these results give new information about the genes involved in the defense against mycobacterial infection in zebrafish.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dci.2019.103523DOI Listing
February 2020

Supervised pathway analysis of blood gene expression profiles in Alzheimer's disease.

Neurobiol Aging 2019 12 16;84:98-108. Epub 2019 Jul 16.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Early identification and treatment of Alzheimer's disease (AD) is hampered by the lack of easily accessible biomarkers. Currently available fluid biomarkers of AD provide indications of the disease stage; however, these are measured in the cerebrospinal fluid, requiring invasive procedures, which are not applicable at the population level. Thus, gene expression profiling of blood provides a viable alternative as a way to screen individuals at risk of AD. Previous studies have shown that despite the limited permeability of the blood-brain barriers, expression profiles of blood genes can be used for the diagnosis and prognosis of several brain disorders. Here, we propose a new approach to pathway analysis of blood gene expression profiles to classify healthy (control [CTL]), mildly cognitively impaired (mild cognitive impairment [MCI]; preclinical stage of AD), and AD subjects. In the pathway analysis, gene expression data are mapped to pathway scores according to a predefined gene set instead of considering each gene separately. The robustness of the analysis enables detection of weak differences between groups owing to the inherent dimension reduction. Our proposed method for pathway analysis takes advantage of linear discriminant analysis for identifying a linear combination of features best separating groups of subjects within each gene set. The gene expression data were retrieved from Gene Expression Omnibus (batch 1: GSE63060; batch 2: GSE63061). Predefined gene sets for pathway analysis were obtained from the Broad Institute Collection of Curated Pathways. The method achieved a 10-fold cross-validated area under receiver operating characteristic curve of 0.84 for classification of AD versus CTL and 0.80 for classification of mild cognitive impairment versus CTL. These results reveal the good potential of blood-based biomarkers for assisting early diagnosis and disease monitoring of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2019.07.004DOI Listing
December 2019

Nrf2 and SQSTM1/p62 jointly contribute to mesenchymal transition and invasion in glioblastoma.

Oncogene 2019 12 23;38(50):7473-7490. Epub 2019 Aug 23.

Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FIN-70211, Kuopio, Finland.

Accumulating evidence suggests that constitutively active Nrf2 has a pivotal role in cancer as it induces pro-survival genes that promote cancer cell proliferation and chemoresistance. The mechanisms of Nrf2 dysregulation and functions in cancer have not been fully characterized. Here, we jointly analyzed the Broad-Novartis Cancer Cell Line Encyclopedia (CCLE) and the Cancer Genome Atlas (TCGA) multi-omics data in order to identify cancer types where Nrf2 activation is present. We found that Nrf2 is hyperactivated in a subset of glioblastoma (GBM) patients, whose tumors display a mesenchymal subtype, and uncover several different mechanisms contributing to increased Nrf2 activity. Importantly, we identified a positive feedback loop between SQSTM1/p62 and Nrf2 as a mechanism for activation of the Nrf2 pathway. We also show that autophagy and serine/threonine signaling regulates p62 mediated Keap1 degradation. Our results in glioma cell lines indicate that both Nrf2 and p62 promote proliferation, invasion and mesenchymal transition. Finally, Nrf2 activity was associated with decreased progression free survival in TCGA GBM patient samples, suggesting that treatments have limited efficacy if this transcription factor is overactivated. Overall, our findings place Nrf2 and p62 as the key components of the mesenchymal subtype network, with implications to tumorigenesis and treatment resistance. Thus, Nrf2 activation could be used as a surrogate prognostic marker in mesenchymal subtype GBMs. Furthermore, strategies aiming at either inhibiting Nrf2 or exploiting Nrf2 hyperactivity for targeted gene therapy may provide novel treatment options for this subset of GBM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-019-0956-6DOI Listing
December 2019

Cytokeratin-Supervised Deep Learning for Automatic Recognition of Epithelial Cells in Breast Cancers Stained for ER, PR, and Ki-67.

IEEE Trans Med Imaging 2020 02 7;39(2):534-542. Epub 2019 Aug 7.

Immunohistochemistry (IHC) of ER, PR, and Ki-67 are routinely used assays in breast cancer diagnostics. Determination of the proportion of stained cells (labeling index) should be restricted on malignant epithelial cells, carefully avoiding tumor infiltrating stroma and inflammatory cells. Here, we developed a deep learning based digital mask for automated epithelial cell detection using fluoro-chromogenic cytokeratin-Ki-67 double staining and sequential hematoxylin-IHC staining as training material. A partially pre-trained deep convolutional neural network was fine-tuned using image batches from 152 patient samples of invasive breast tumors. Validity of the trained digital epithelial cell masks was studied with 366 images captured from 98 unseen samples, by comparing the epithelial cell masks to cytokeratin images and by visual evaluation of the brightfield images performed by two pathologists. A good discrimination of epithelial cells was achieved (AUC of mean ROC = 0.93; defined as the area under mean receiver operating characteristics), and well in concordance with pathologists' visual assessment (4.01/5 and 4.67/5). The effect of epithelial cell masking on the Ki-67 labeling index was substantial. 52 tumor images initially classified as low proliferation (Ki-67 < 14%) without epithelial cell masking were re-classified as high proliferation (Ki-67 ≥ 14%) after applying the deep learning based epithelial cell mask. The digital epithelial cell masks were found applicable also to IHC of ER and PR. We conclude that deep learning can be applied to detect carcinoma cells in breast cancer samples stained with conventional brightfield IHC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TMI.2019.2933656DOI Listing
February 2020

Data-driven characterization of molecular phenotypes across heterogeneous sample collections.

Nucleic Acids Res 2019 07;47(13):e76

Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.

Existing large gene expression data repositories hold enormous potential to elucidate disease mechanisms, characterize changes in cellular pathways, and to stratify patients based on molecular profiles. To achieve this goal, integrative resources and tools are needed that allow comparison of results across datasets and data types. We propose an intuitive approach for data-driven stratifications of molecular profiles and benchmark our methodology using the dimensionality reduction algorithm t-distributed stochastic neighbor embedding (t-SNE) with multi-study and multi-platform data on hematological malignancies. Our approach enables assessing the contribution of biological versus technical variation to sample clustering, direct incorporation of additional datasets to the same low dimensional representation, comparison of molecular disease subtypes identified from separate t-SNE representations, and characterization of the obtained clusters based on pathway databases and additional data. In this manner, we performed an integrative analysis across multi-omics acute myeloid leukemia studies. Our approach indicated new molecular subtypes with differential survival and drug responsiveness among samples lacking fusion genes, including a novel myelodysplastic syndrome-like cluster and a cluster characterized with CEBPA mutations and differential activity of the S-adenosylmethionine-dependent DNA methylation pathway. In summary, integration across multiple studies can help to identify novel molecular disease subtypes and generate insight into disease biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkz281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648337PMC
July 2019

Evaluation of Commercial Circulating Tumor DNA Test in Metastatic Prostate Cancer.

JCO Precis Oncol 2019 12;3. Epub 2019 Jun 12.

University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: Circulating tumor DNA (ctDNA) sequencing provides a minimally invasive method for tumor molecular stratification. Commercial ctDNA sequencing is increasingly used in the clinic, but its accuracy in metastatic prostate cancer is untested. We compared the commercial Guardant360 ctDNA test against an academic sequencing approach for profiling metastatic prostate cancer.

Patients And Methods: Plasma cell-free DNA was collected between September 2016 and April 2018 from 24 patients with clinically progressive metastatic prostate cancer representing a range of clinical scenarios. Each sample was analyzed using Guardant360 and a research panel encompassing 73 prostate cancer genes. Concordance of somatic mutation and copy number calls was evaluated between the two approaches.

Results: Targeted sequencing independently confirmed 94% of somatic mutations identified by Guardant360 at an allele fraction greater than 1%. amplifications and mutations were detected with high concordance in 14 patients, with only three discordant subclonal mutations at an allele fraction lower than 0.5%. Many somatic mutations identified by Guardant360 at an allele fraction lower than 1% seemed to represent subclonal passenger events or non-prostate-derived clones. Most of the non- gene amplifications reported by Guardant360 represented single copy gains. The research approach detected several clinically relevant DNA repair gene alterations not reported by Guardant360, including four germline truncating / mutations, two somatic stop gain mutations, one biallelic deletion, 11 stop gain reversal mutations in a patient treated with olaparib, and a hypermutator phenotype in a patient sample with 42 mutations per megabase.

Conclusion: Guardant360 accurately identifies somatic ctDNA mutations in patients with metastatic prostate cancer, but low allele frequency mutations should be interpreted with caution. Test utility in metastatic prostate cancer is currently limited by the lack of reporting on actionable deletions, rearrangements, and germline mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.19.00014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446428PMC
June 2019

Hemap: An Interactive Online Resource for Characterizing Molecular Phenotypes across Hematologic Malignancies.

Cancer Res 2019 05 2;79(10):2466-2479. Epub 2019 Apr 2.

Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.

Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease context for new therapeutic approaches. We analyzed 9,544 transcriptomes from more than 30 hematologic malignancies, normal blood cell types, and cell lines, and showed that disease types could be stratified in a data-driven manner. We then identified cluster-specific pathway activity, new biomarkers, and drug target prioritization through interrogation of drug target databases. Using known vulnerabilities and available drug screens, we highlighted the importance of integrating molecular phenotype with drug target expression for prediction of drug responsiveness. Our analysis implicated expression level as an important indicator of venetoclax responsiveness and provided a rationale for its targeting in specific leukemia subtypes and multiple myeloma, linked several polycomb group proteins that could be targeted by small molecules (SFMBT1, CBX7, and EZH1) with chronic lymphocytic leukemia, and supported as a disease-specific target in acute myeloid leukemia. Through integration with proteomics data, we characterized target protein expression for pre-B leukemia immunotherapy candidates, including DPEP1. These molecular data can be explored using our publicly available interactive resource, Hemap, for expediting therapeutic innovations in hematologic malignancies. SIGNIFICANCE: This study describes a data resource for researching derailed cellular pathways and candidate drug targets across hematologic malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-18-2970DOI Listing
May 2019

Modes of immunosuppression in glioblastoma microenvironment.

Oncotarget 2019 Jan 29;10(9):920-921. Epub 2019 Jan 29.

Kirsi J. Granberg: Faculty of Medicine and Health Technologies, Tampere University, Tampere, Finland; Science Center, Tampere University Hospital, Tampere, Finland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.26643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398170PMC
January 2019

Extensive reprogramming of the nascent transcriptome during iPSC to hepatocyte differentiation.

Sci Rep 2019 03 5;9(1):3562. Epub 2019 Mar 5.

Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland.

Hepatocyte-like cells (HLCs) derived from induced pluripotent stem cells (iPSCs) provide a renewable source of cells for drug discovery, disease modelling and cell-based therapies. Here, by using GRO-Seq we provide the first genome-wide analysis of the nascent RNAs in iPSCs, HLCs and primary hepatocytes to extend our understanding of the transcriptional changes occurring during hepatic differentiation process. We demonstrate that a large fraction of hepatocyte-specific genes are regulated at transcriptional level and identify hundreds of differentially expressed non-coding RNAs (ncRNAs), including primary miRNAs (pri-miRNAs) and long non-coding RNAs (lncRNAs). Differentiation induced alternative transcription start site (TSS) usage between the cell types as evidenced for miR-221/222 and miR-3613/15a/16-1 clusters. We demonstrate that lncRNAs and coding genes are tightly co-expressed and could thus be co-regulated. Finally, we identified sets of transcriptional regulators that might drive transcriptional changes during hepatocyte differentiation. These included RARG, E2F1, SP1 and FOXH1, which were associated with the down-regulated transcripts, and hepatocyte-specific TFs such as FOXA1, FOXA2, HNF1B, HNF4A and CEBPA, as well as RXR, PPAR, AP-1, JUNB, JUND and BATF, which were associated with up-regulated transcripts. In summary, this study clarifies the role of regulatory ncRNAs and TFs in differentiation of HLCs from iPSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-39215-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401154PMC
March 2019

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer.

Eur Urol 2019 04 10;75(4):667-675. Epub 2019 Jan 10.

Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada. Electronic address:

Background: Several systemic therapeutic options exist for metastatic castrate-sensitive prostate cancer (mCSPC). Circulating tumor DNA (ctDNA) can molecularly profile metastatic castration-resistant prostate cancer and can influence decision-making, but remains untested in mCSPC.

Objective: To determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically relevant information to a prostate biopsy.

Design, Setting, And Participants: We collected plasma cell-free DNA (cfDNA) from 53 patients newly diagnosed with mCSPC and, where possible, during treatment. Targeted sequencing was performed on cfDNA and DNA from diagnostic prostate tissue.

Results And Limitations: The median ctDNA fraction was 11% (range 0-84%) among untreated patients but was lower (1.0%, range 0-51%) among patients after short-term (median 22d) androgen deprivation therapy (ADT). TP53 mutations and DNA repair defects were identified in 47% and 21% of the cohort, respectively. The concordance for mutation detection in matched samples was 80%. Combined ctDNA and tissue analysis identified potential driver alterations in 94% of patients, whereas ctDNA or prostate biopsy alone was insufficient in 19 cases (36%). Limitations include the use of a narrow gene panel and undersampling of primary disease by prostate biopsy.

Conclusions: ctDNA provides additional information to a prostate biopsy in men with de novo mCSPC, but ADT rapidly reduces ctDNA availability. Primary tissue and ctDNA share relevant somatic alterations, suggesting that either is suitable for molecular subtyping in de novo mCSPC. The optimal approach for biomarker development should utilize both a tissue and liquid biopsy at diagnosis, as neither captures clinically relevant somatic alterations in all patients.

Patient Summary: In men with advanced prostate cancer, tumor DNA shed into the bloodstream can be measured via a blood test. The information from this test provides complementary information to a prostate needle biopsy and could be used to guide management strategies. Sequencing data were deposited in the European Genome-phenome Archive (EGA) under study identifier EGAS00001003351.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2018.12.042DOI Listing
April 2019

Frequent mutation of the untranslated region in prostate cancer.

Commun Biol 2018 24;1:122. Epub 2018 Aug 24.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada.

Prostate cancer has a low somatic mutation rate but non-coding regions remain underexplored. We sequenced the untranslated regions (UTRs) of 72 established driver genes in 428 patients with metastatic prostate cancer and identified 3'-UTR mutations in 12% of patients. The mutations were predominantly insertions or deletions, covered the entire UTR without motif enrichment, and were not detected in other cancers. lies in head-on orientation with the androgen-regulated non-coding gene , resulting in strong prostate lineage-specific bidirectional transcription across the 3'-UTR. This suggests transcriptional activity as a cause for the localized hypermutation. The indel-dominant pattern of somatic mutation extends into the coding region, where it is shaped by clonal selection to yield a cluster of non-frameshift indels inside the forkhead domain. Somatic 3'-UTR mutations may prove useful for diagnostic and screening approaches, given their high frequency and lineage specificity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-018-0128-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123809PMC
August 2018

Proteomics of prostate cancer - revealing how cancer cells master their messy genomes.

Oncoscience 2018 Jul 31;5(7-8):216-217. Epub 2018 Jul 31.

Leena Latonen: Prostate Cancer Research Center, Faculty of Medicine and Life Sciences and BioMediTech Institute, University of Tampere, Tampere, Finland; FimLab laboratories, Tampere University Hospital, Tampere, Finland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncoscience.453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142899PMC
July 2018

Bioinformatics Assembling and Assessment of Novel Coxsackievirus B1 Genome.

Methods Mol Biol 2018 ;1838:261-272

Computational Biology, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.

The human microbiome project via application of metagenomic next-generation sequencing techniques has found surprising large and diverse amounts of microbial sequences across different body sites. There is a wave of investigators studying autoimmune related diseases designing from birth case and control studies to elucidate microbial associations and potential direct triggers. Sequencing analysis, considered big data as it typically includes millions of reads, is challenging but particularly demanding and complex is virome profiling due to its lack of pan-viral genomic signature. Impressively thousands of virus complete genomes have been deposited and these high-quality references are core components of virus profiling pipelines and databases. Still it is commonly known that most viral sequences do not map to known viruses. Moreover human viruses, particularly RNA groups, are notoriously heterogeneous due to high mutation rates. Here, we present the related assembling challenges and a series of bioinformatics steps that were applied in the construction of the complete consensus genome of a novel clinical isolate of Coxsackievirus B1. We further demonstrate our effort in calling mutations between prototype Coxsackievirus B1 sequence from GenBank and serial clinical isolate genome grown in cell culture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-8682-8_18DOI Listing
April 2019

Comparison of iTRAQ and SWATH in a clinical study with multiple time points.

Clin Proteomics 2018 30;15:24. Epub 2018 Jul 30.

1Department of Ophthalmology, SILK, The Centre for Proteomics and Personalized Medicine (PPM), Faculty of Medicine and Life Sciences, University of Tampere, Arvo Ylpön katu 34, ARVO, PL 100, 33014 Tampere, Finland.

Background: Advances in mass spectrometry have accelerated biomarker discovery in many areas of medicine. The purpose of this study was to compare two mass spectrometry (MS) methods, isobaric tags for relative and absolute quantitation (iTRAQ) and sequential window acquisition of all theoretical fragment ion spectra (SWATH), for analytical efficiency in biomarker discovery when there are multiple methodological constraints such as limited sample size and several time points for each patient to be analyzed.

Methods: A total of 140 tear samples were collected from 28 glaucoma patients at 5 time points in a glaucoma drug switch study. Samples were analyzed with iTRAQ and SWATH methods using NanoLC-MSTOF mass spectrometry.

Results: We discovered that even though iTRAQ is faster than SWATH with respect to analysis time per sample, it loses in sensitivity, reliability and robustness. While SWATH analysis yielded complete data of 456 proteins in all samples, with iTRAQ we were able to quantify 477 proteins in total but on average only 125 proteins were quantified in a sample. 283 proteins were common in the datasets produced by the two methods. Repeatability of the methods was assessed by calculating percent relative standard deviation (% RSD) between replicate MS analyses: SWATH was more repeatable (56% of proteins < 20% RSD), compared to iTRAQ (43% of proteins < 20% RSD). Despite the overall benefits of SWATH, both methods showed less than 1 log fold change difference in the expression of 74% common proteins. In addition, comparison to MS/MS peptide results using 8 isotopically labeled peptide standards, SWATH and iTRAQ showed similar results in terms of accuracy. Moreover, both methods detected similar trends in a longitudinal analysis of protein expression of two known tear biomarkers.

Conclusions: Overall, we conclude that SWATH should be preferred for biomarker discovery studies when analyzing limited volumes of clinical samples collected at multiple time points.

Trial Registeration: The study was approved by the Ethics Committee at Tampere University Hospital and was registered in EU clinical trials register (EudraCT Number: 2010-021039-14).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12014-018-9201-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065059PMC
July 2018

Constitutively active androgen receptor splice variants AR-V3, AR-V7 and AR-V9 are co-expressed in castration-resistant prostate cancer metastases.

Br J Cancer 2018 08 10;119(3):347-356. Epub 2018 Jul 10.

Prostate Cancer Research Center, Faculty of Medicine and Life Sciences and BioMediTech Institute, University of Tampere, Tampere, Finland.

Background: A significant subset of prostate cancer (PC) patients with a castration-resistant form of the disease (CRPC) show primary resistance to androgen receptor (AR)-targeting drugs developed against CRPC. As one explanation could be the expression of constitutively active androgen receptor splice variants (AR-Vs), our current objectives were to study AR-Vs and other AR aberrations to better understand the emergence of CRPC.

Methods: We analysed specimens from different stages of prostate cancer by next-generation sequencing and immunohistochemistry.

Results: AR mutations and copy number variations were detected only in CRPC specimens. Genomic structural rearrangements of AR were observed in 5/30 metastatic CRPC patients, but they were not associated with expression of previously known AR-Vs. The predominant AR-Vs detected were AR-V3, AR-V7 and AR-V9, with the expression levels being significantly higher in CRPC cases compared to prostatectomy samples. Out of 25 CRPC metastases that expressed any AR variant, 17 cases harboured expression of all three of these AR-Vs. AR-V7 protein expression was highly heterogeneous and higher in CRPC compared to hormone-naïve tumours.

Conclusions: AR-V3, AR-V7 and AR-V9 are co-expressed in CRPC metastases highlighting the fact that inhibiting AR function via regions common to all AR-Vs is likely to provide additional benefit to patients with CRPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-018-0172-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070921PMC
August 2018

Interleukin 10 mutant zebrafish have an enhanced interferon gamma response and improved survival against a Mycobacterium marinum infection.

Sci Rep 2018 07 9;8(1):10360. Epub 2018 Jul 9.

Laboratory of Experimental Immunology, BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.

Tuberculosis ranks as one of the world's deadliest infectious diseases causing more than a million casualties annually. IL10 inhibits the function of Th1 type cells, and IL10 deficiency has been associated with an improved resistance against Mycobacterium tuberculosis infection in a mouse model. Here, we utilized M. marinum infection in the zebrafish (Danio rerio) as a model for studying Il10 in the host response against mycobacteria. Unchallenged, nonsense il10 mutant zebrafish were fertile and phenotypically normal. Following a chronic mycobacterial infection, il10 mutants showed enhanced survival compared to the controls. This was associated with an increased expression of the Th cell marker cd4-1 and a shift towards a Th1 type immune response, which was demonstrated by the upregulated expression of tbx21 and ifng1, as well as the down-regulation of gata3. In addition, at 8 weeks post infection il10 mutant zebrafish had reduced expression levels of proinflammatory cytokines tnfb and il1b, presumably indicating slower progress of the infection. Altogether, our data show that Il10 can weaken the immune defense against M. marinum infection in zebrafish by restricting ifng1 response. Importantly, our findings support the relevance of M. marinum infection in zebrafish as a model for tuberculosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-28511-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037744PMC
July 2018