Hannu Haapasalo

Tampere University | UTA · Department of Pathology

As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with...

Background: The purpose of our study was to analyze the impact of time interval from referral to surgery and from surgery to adjuvant treatment on survival of adult IDH-wildtype glioblastomas. Methods: Data on 392 IDH-wildtype glioblastomas diagnosed at the Tampere University Hospital in 2004-2016 were obtained from the electronic patient record...

Background Central nervous system (CNS) tumors are a heterogeneous group of tumors that include several aggressive malignancies with a high mortality rate. This study aimed to evaluate the familial relative risk of CNS tumors in family members of early-onset index cases (probands) in and between diffuse glioma, non-diffuse glioma, meningioma, and o...

IDH-mutant low-grade diffuse astrocytomas frequently progress to grade IV astrocytomas with implications for patient prognosis. To better understand this process, we applied whole-genome and transcriptome sequencing to matched tumor samples collected before and after progression to grade IV astrocytomas from five patients. All tumors carried an IDH...

Understanding oncogenic epigenetic mechanisms in brain tumors is crucial for improved diagnosis and treatment. Recently DNA methylation has proven to be powerful for brain tumor characterization and diagnostic classification. To evaluate tumor type specific features, we compared atypical teratoid/rhabdoid tumors (AT/RTs), medulloblastomas (MBs), an...

Oligodendrogliomas are typically associated with the most favorable prognosis among diffuse gliomas. However, many of the tumors progress, eventually leading to patient death. To characterize the changes associated with oligodendroglioma recurrence and progression, we analyzed two recurrent oligodendroglioma tumors upon diagnosis and after tumor re...

BACKGROUND: Liquid biopsies (LBs) hold great promise as a non-invasive method for tumor detection and disease monitoring. Their application in pediatric neuro-oncology patients has been challenging due to the blood-brain barrier limiting the amount of circulating tumor DNA (ctDNA) and low volumes of cerebrospinal fluid (CSF) and serum samples. Here...

Isocitrate dehydrogenase (IDH) mutation status is an important factor for surgical decision-making: patients with IDH-mutated tumors are more likely to have a good long-term prognosis, and thus favor aggressive resection with more survival benefit to gain. Patients with IDH wild-type tumors have generally poorer prognosis and, therefore, conservati...

Understanding oncogenic epigenetic mechanisms in brain tumors is crucial for improved diagnosis and treatment. To evaluate tumor type-specific features, we compared atypical teratoid/rhabdoid tumors (AT/RTs), medulloblastomas, and choroid plexus tumors with each other by integrating DNA methylation (507 samples), gene expression (120 samples), and...

Glioma stem cells (GSCs) drive propagation and therapeutic resistance of glioblastomas, the most aggressive diffuse brain tumors. However, the molecular mechanisms that maintain the stemness and promote therapy resistance remain poorly understood. Here we report CD109/STAT3 axis as crucial for the maintenance of stemness and tumorigenicity of GSCs...

p>DNA methylation has proven to be powerful for brain tumor characterization and diagnostic classification. To obtain information about the oncogenic role of DNA methylation, we analyzed medulloblastoma, choroid plexus, and atypical teratoid/rhabdoid tumors (AT/RTs) with public data from 450K-methylation arrays (N=584) and gene-expression arrays (N...

Carbonic anhydrases (CAs) are zinc-containing metalloenzymes that participate in the regulation of pH homeostasis in addition to many other important physiological functions. Importantly, CAs have been associated with neoplastic processes and cancer. Brain tumors represent a heterogeneous group of diseases with a frequently dismal prognosis, and ne...

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 microarra...

MAPK-activated protein kinase 2 (MK2) has diverse roles in cancer. In response to chemotherapy, MK2 inhibition is synthetically lethal to p53-deficiency. While TP53 deletion is rare in glioblastomas, these tumors often carry TP53 mutations. Here, we show that MK2 inhibition strongly attenuated glioblastoma cell proliferation through p53wt stabiliza...

Malignant tumors of the central nervous system in adults comprise a heterogeneous group of malignancies, the largest subgroups comprising astrocytomas, ependymomas, and oligodendrogliomas. Glioblastomas are the most common tumor type, and they have dismal prognosis. Due to differences in cell type of origin, as well as pathogenesis, it is plausible...

Glioblastomas and brain metastases (BM) of solid tumors are the most common central nervous system neoplasms associated with very unfavorable prognosis. In this study, we report the association of Prostate Specific Membrane Antigen with various clinical parameters in a large cohort of primary and secondary brain tumors. A tissue micro array contain...

Introduction: 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...

OBJECTIVE There is a need for real-time, intraoperative tissue identification technology in neurosurgery. Several solutions are under development for that purpose, but their adaptability for standard clinical use has been hindered by high cost and impracticality issues. The authors tested and preliminarily validated a method for brain tumor identif...

Background: Several studies have reported increased incidence trends of malignant gliomas in the late 1900s with a plateau in the 2000s, but also some recent increases have been reported. The purpose of our study was to analyze incidence trends of malignant gliomas in Finland by morphology and tumor location. Material and methods: Data on 4730 mali...

Background One of the biggest caveats in diffuse glioma therapy is anti-tumor immune response suppression. By using cell-cell interactions like secreting cytokines and grow factors that modulate recruited macrophages and resident microglia, neoplastic cells do manage to promote favorable immediate milieus within healthy brain tissue. The aim of thi...

Background Fibroblast growth factor receptor 3 (FGFR3) gene fusion with transforming acidic coiled coil 3 (TACC3) has been detected in a subset of diffuse gliomas and other malignancies. Tumors with FGFR3:TACC3 fusion are typically aggressive isocitrate dehydrogenase (IDH) wild-type tumors and are more commonly observed in female patients. Strong F...

p><Glioblastoma (GBM) is the most common and lethal form of brain cancer in humans. Median survival is 15 months with best available treatment. Most GBMs arise de novo (primary GBM), but 5 - 10% progress from lower grade gliomas (secondary GBM). As progression of low grade glioma into secondary GBM significantly impacts prognosis, a better understa...

Background: Diffusely infiltrating astrocytomas originate from astrocytic glial cells or their precursor cells and are the most common type of brain tumors in adults. In this retrospective study, we investigated the content of hyaluronan, its cell surface receptor, CD44 and the expression of hyaluronan metabolizing enzymes, in these aggressive tum...

Background: Carbonic anhydrase related proteins (CARPs) VIII, X and XI functionally differ from the other carbonic anhydrase (CA) enzymes. Structurally, they lack the zinc binding residues, which are important for enzyme activity of classical CAs. The distribution pattern of the CARPs in fetal brain implies their role in brain development. In the...

Brain tumors typically arise sporadically and do not affect several family members simultaneously. In the present study, we describe clinical and genetic data from two patients, a mother and her daughter, with familial brain tumors. Exome sequencing revealed a germline missense mutation in the TP53 and ATRX genes in both cases, and a somatic copy-n...

Nuclear factor erythroid 2-related factor 2 (NRF2), DJ1 and sulfiredoxin 1 (SRXN1) are transcription factors which protect cells from the oxidative damage caused by reactive oxygen species and, on the other hand, are associated with resistance to cancer treatments. The immunohistochemical expression of NRF2, DJ1 and SRNX1 was assessed in human grad...

Background Fibroblast growth factor receptors (FGFRs) are well-known proto-oncogenes in several human malignancies and are currently therapeutically targeted in clinical trials. Among glioma subtypes, activating FGFR1 alterations have been observed in a subpopulation of pilocytic astrocytomas while FGFR3 fusions occur in IDH wild-type diffuse gliom...

Background.: Inhibitors of fibroblast growth factor receptors (FGFRs) have recently arisen as a promising treatment option for patients with FGFR alterations. Gene fusions involving FGFR3 and transforming acidic coiled-coil protein 3 (TACC3) have been detected in diffuse gliomas and other malignancies, and fusion-positive cases have responded well...

Glioblastoma multiforme lacks effective therapy options. Although deregulated kinase pathways are drivers of malignant progression in glioblastoma multiforme, glioma cells exhibit intrinsic resistance toward many kinase inhibitors, and the molecular basis of this resistance remains poorly understood. Here, we show that overexpression of the protein...

Diffusely infiltrating astrocytomas are central nervous system tumors originating from astrocytic glial cells or their precursor cells. In this retrospective study we investigated the content of hyaluronan and the expression of hyaluronan metabolizing enzymes and its cell surface receptor, CD44, in these aggressive tumors. Hyaluronan is a large ext...

Inhibitors of fibroblast growth factor receptors (FGFRs) have recently arisen as a promising treatment option for patients with FGFR alterations. Gene fusions involving FGFR3 and transforming acidic coiled coil 3 (TACC3) have been detected in diffuse gliomas and other malignancies, and fusion-positive cases have responded well to FGFR inhibitors. A...

Objectives: Carbonic anhydrase IX (CA IX) expression is induced by local hypoxia. We studied whether CA IX deposits associate with ascending aortic dilatation. Design: Aortic wall histology, CA IX expression, presence of leukocytes, plasma cells, macrophages, endothelial cells, smooth muscle cells, cell proliferation, elastin and collagen were s...

Limb girdle muscular dystrophies are a large group of both dominantly and recessively inherited muscle diseases. LGMD1D is caused by mutated DNAJB6 and the molecular pathogenesis is mediated by defective chaperonal function leading to impaired handling of misfolded proteins which normally would be degraded. Here we aim to clarify muscle pathology o...

Epithelial-mesenchymal transition (EMT) has previously been linked to glioma invasion and progression. To determine whether EMT regulators, Twist and Zeb1, had clinical significance in astrocytic gliomas, the association of Twist and Zeb1 with clinicopathological and molecular factors was studied in 269 astrocytoma samples. Twist and Zeb1 were wide...

Expression of novel stem cell-associated marker human embryonic stem cell 77 (HES77) was studied in rectal neuroendocrine tumors (NETs), which comprise 10 to 15% of gastroenteropancreatic NETs, some with metastatic potential. WHO 2010 classification was applied, and immunohistochemical positivity for HES77 was assessed in 72 primary tumors and 6 me...

PROX1 is a homeobox transcription factor involved in the development of the lens, liver and heart and found upregulated in colorectal cancers. We studied PROX1 expression by immunohistochemistry in rectal neuroendocrine tumors (NETs). Approximately 10 to 15 % of gastroenteropancreatic NETs occur in the rectum, and some may metastasize. Yet little i...

Objective: To elaborate the diagnostic methods used as "gold standard" in one of the most common glycogen storage diseases (GSDs), Tarui disease (GSDVII). Methods: Two siblings with disease suggestive of GSD underwent thorough clinical analysis, including muscle biopsy, muscle MRI, exercise tests, laboratory examinations, and whole-exome sequenc...

Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogenic protein that has both extracellular and intracellular functions. Despite a clear causal role in cancer development, the tumor-promoting mechanisms of IGFBP2 are poorly understood. The contributions of intracellular IGFBP2 to tumor development and progression are also u...

Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. Several phase II studies with high-dose methotrexate-based regimens have shown promising early results, but in all hospital-based data published so far, the disease outcome is poor. We performed a hospital-based retrospective analysis to evaluate the lon...

Aberrant activation of fibroblast growth factor receptor 3 (FGFR3) has been reported to be tumorigenic in various cancer types. When FGFR3 is fused with another gene, most commonly with transforming acidic coiled coil 3 (TACC3), it can escape miRNA-mediated regulation and remain constitutively active most likely due to the dimerization via the doma...

Background The aim of the study was to assess the localization of Polysialic acid (polySia) and Neural cell adhesion molecule (NCAM) in grade I–IV astrocytomas by confocal microscopy, and also to clarify and compare their relationship to conventional clinicopathological features in these tumors. Methods Study material was stained immunohistochemic...

The microenvironment of glioblastoma (GBM) contains high levels of inflammatory cytokine interleukin 6 (IL-6), which contributes to promote tumour progression and invasion. The common epidermal growth factor receptor variant III (EGFRvIII) mutation in GBM is associated with significantly higher levels of IL-6. Furthermore, elevated IL-1β levels in...

Rectal neuroendocrine tumors (NETs) are rare tumors representing 10 to 15% of gastroenteropancreatic NETs. The grade of these tumors, according to the WHO 2010 classification and based on Ki-67 index and mitotic count, correlates with their metastatic potential. We studied the expression of a cell cycle-regulatory protein, cyclin A, in rectal NETs....

Gliomas are tumors of the support cells of the brain and the most common of the primary brain tumors. Treatment of diffuse gliomas is based on surgical excision of the tumor and on radiotherapy and chemotherapy. The diagnosis is made in histopathological examination of the tumor, which today can be complemented with examinations involving molecular...

MIR-491 is commonly co-deleted with its adjacent CDKN2A on chromosome 9p21.3 in glioblastoma multiforme (GBM). However, it is not known whether deletion of MIR-491 is only a passenger event or has an important role. Small-RNA sequencing of samples from GBM patients demonstrated that both mature products of MIR-491 (miR-491-5p and -3p) are downregul...

Aims: Heat shock protein 27 (Hsp27) is induced by cell stress conditions. In the presence of oxidative stress it functions as an antioxidant. To study the putative expression patterns and clinical significance of Hsp27, we assessed the associations between Hsp27, R132H mutation of Isocitrate dehydrogenase1 (IDH1-R132H), Hypoxia-inducible factor su...

Limb girdle muscular dystrophies are a large group of both dominantly and recessively inherited muscle diseases. Dominantly inherited LGMD1 diseases are usually milder and later onset forms than recessive LGMD2. We have followed six Finnish families with LGMD1D and reported clinical and MRI findings in these families. All families represent the sam...

Brain tumors are the second most common pediatric neoplastic disease after leukemias. As causes of mortality and morbidity they add up to the most significant group of tumors. Treatment is based on thorough surgical excision of the tumor. Additional treatment with cytotoxic agents and radiotherapy is applied to malignant tumors. Treatment results h...

The aim of our study was to assess the nature and importance of claudin expression in grade I-III ependymomas. The expression of claudins 2-5, 7, 10, TWIST, and ZEB1 were investigated in a series of 61 ependymomas using immunohistochemistry. All the claudins were expressed in ependymomas, except for CLDN4. CLDN5 positive tumours were associated wit...

Copy number changes or reduced expression of the Neuron navigator 3 (NAV3) gene occurs in neuroblastomas and malignancies of epithelial or lymphoid origin. To elucidate whether NAV3 has a role in the tumorigenesis of nervous system tumors in general, we studied central and peripheral nervous system tumors for NAV3 copy number changes. In search for...

Fusion genes are chromosomal aberrations that are found in many cancers and can be used as prognostic markers and drug targets in clinical practice. Fusions can lead to production of oncogenic fusion proteins or to enhanced expression of oncogenes. Several recent studies have reported that some fusion genes can escape microRNA regulation via 3'-unt...

Background C4d is a cleavage product of complement component C4 and is considered to serve as a marker for the site of complement activation. In this study C4d staining of grade I-IV astrocytic tumors was studied to explore if there is an association between complement activation and the grade of tumor, or patient survival. Methods Tissue micro-ar...

Objective: The objective of this study was to validate the immunohistochemical assay for the diagnosis of nondystrophic myotonia and to provide full clarification of clinical disease to patients in whom basic genetic testing has failed to do so. Methods: An immunohistochemical assay of sarcolemmal chloride channel abundance using 2 different ClC...