Publications by authors named "Olli Tynninen"

37 Publications

Sebaceous carcinoma of the eyelid: 21-year experience in a Nordic country.

Acta Ophthalmol 2021 Mar 4;99(2):181-186. Epub 2020 Aug 4.

Department of Ophthalmology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Purpose: To evaluate the clinical features, diagnostic challenges, management, and prognosis of sebaceous carcinoma (SC) of the eyelids and periocular region in a Nordic country.

Methods: Patients were identified from the Finnish Cancer Registry and the Helsinki University Hospital databases during the 21-year period 1998-2018. Age, sex, location, clinical and histopathologic diagnosis, treatment and outcome were registered.

Results: Sebaceous carcinoma (SC) was diagnosed in 32 patients. The incidence was 0.6 per million. Median age at the time of histopathologic diagnosis was 74 years, and 72% of patients were women. Diagnostic delay was often long, median 12 months. The most common cause for delay was misdiagnosis (72%): a chalazion in 34% and a benign tumour in 22%. The most common location was the upper eyelid (53%) and tumour type a solitary nodule (94%). The SC was not correctly diagnosed in 12 (40%) of 30 preoperative biopsies. The treatment for 31 (97%) patients was complete surgical removal with reconstruction. Conjunctival intraepithelial growth was found in 50%. The leading postoperative problem was ocular irritation (30%). During a median follow-up of 58 months, two patients (6%) experienced a local recurrence and one patient died from metastatic SC.

Conclusions: The estimated incidence of SC in Finland was somewhat higher than in other Western countries. The diagnosis was often markedly delayed. Especially differentiation from chalazion continues to be essential. To improve outcomes, it is essential to inform the pathologist about the possibility of SC in eyelid biopsies and specimens and ideally submit them to an ophthalmic pathology service.
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http://dx.doi.org/10.1111/aos.14552DOI Listing
March 2021

Medulloblastoma, macrocephaly, and a pathogenic germline PTEN variant: Cause or coincidence?

Mol Genet Genomic Med 2020 09 17;8(9):e1302. Epub 2020 May 17.

Department of Pediatrics, MRC Oulu, PEDEGO Research Unit, University of Oulu and Oulu University Hospital, Oulu, Finland.

Background: Medulloblastomas (MBs) are a heterogeneous group of childhood brain tumors with four consensus subgroups, namely MB , MB , MB , and MB , representing the second most common type of pediatric brain cancer after high-grade gliomas. They suffer from a high prevalence of genetic predisposition with up to 20% of MB caused by germline mutations in only six genes. However, the spectrum of germline mutations in MB remains incomplete.

Methods: Comprehensive Next-Generation Sequencing panels of both tumor and patient blood samples were performed as molecular genetic characterization. The panels cover genes that are known to predispose to cancer.

Results: Here, we report on a patient with a pathogenic germline PTEN variant resulting in an early stop codon p.(Glu7Argfs*4) (ClinVar ID: 480383). The patient developed macrocephaly and MB , but reached remission with current treatment protocols.

Conclusions: We propose that pathogenic PTEN variants may predispose to medulloblastoma, and show that remission was reached with current treatment protocols. The PTEN gene should be included in the genetic testing provided to patients who develop medulloblastoma at an early age. We recommend brain magnetic resonance imaging upon an unexpected acceleration of growth of head circumference for pediatric patients harboring pathogenic germline PTEN variants.
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http://dx.doi.org/10.1002/mgg3.1302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507464PMC
September 2020

IDH1 Expression via the R132H Mutation-Specific Antibody in Adrenocortical Neoplasias-Prognostic Impact in Carcinomas.

J Endocr Soc 2020 Apr 18;4(4):bvaa018. Epub 2020 Feb 18.

Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Context: Mutations to isocitrate dehydrogenase (IDH) appear to play a prognostic or predictive role in several neoplasias. Immunohistochemical staining designed to detect a specific R132H mutation to IDH1 showed expression in the normal adrenal cortex, raising interest to study the potential role of IDH1 in the pathogenesis of adrenocortical tumors.

Objective: The objective of this work is to study the role of IDH1 and its mutations in adrenocortical tumors.

Design And Patients: R132H immunohistological staining was performed on a cohort of 197 adrenocortical tumors. The exon of the gene was sequenced in 16 tumors.

Results: Positive IDH1 R132H immunohistochemical staining correlated with a better prognosis among patients with a malignant adrenocortical tumor. However, IDH1 R132H immunohistochemistry did not distinguish between local and metastasized tumors. We were unable to identify IDH1 mutations among our adrenocortical tumors using a targeted next-generation sequencing panel or via exon sequencing.

Conclusions: Among adrenocortical carcinomas, IDH1 R132H immunopositivity correlated with a better prognosis. Thus, IDH1 R132H immunohistochemical staining could serve as a prognostic or as a potential predictive marker in adrenocortical carcinomas. Further research is needed to identify the possible alterations in IDH1 that could explain our findings, because we identified no known mutations to the gene.
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http://dx.doi.org/10.1210/jendso/bvaa018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069839PMC
April 2020

The microsurgical management of benign pineal cysts: Helsinki experience in 60 cases.

Surg Neurol Int 2019 19;10:103. Epub 2019 Jun 19.

Departments of Neurosurgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

Background: Microsurgical resection represents a well-accepted management option for symptomatic benign pineal cysts. Symptoms such as a headache, hydrocephalus, and visual deficiency are typically associated with pineal cysts. However, more recent studies reported over the past years have characterized additional symptoms as a part of the clinical manifestation of this disease and represent additional indications for intervention.

Methods: We present a retrospective review of patients with histologically confirmed benign pineal cysts that were operated on in our department between 1997 and 2015. A demographic analysis, evaluation of preoperative status, surgical treatment, as well as immediate and long-term clinical and radiological outcomes were conducted.

Results: A total of 60 patients with benign pineal cysts underwent surgery between 1997 and 2015. Gross total resection was achieved in 58 cases. All patients except one improved in their clinical status or had made a full recovery at the time of the last follow-up. The key steps for surgical resection of pineal cysts are reported, based on an analysis of representative surgical videos.

Conclusions: We describe in this paper one of the largest series of microsurgically treated pineal cysts. In our opinion, judicious microsurgery remains the most suitable technique to effectively deal with this disease.
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http://dx.doi.org/10.25259/SNI-180-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744767PMC
June 2019

Extent of Resection and Long-Term Survival of Pineal Region Tumors in Helsinki Neurosurgery.

World Neurosurg 2019 Nov 30;131:e379-e391. Epub 2019 Jul 30.

"Juha Hernesniemi" International Center for Neurosurgery, Henan Provincial Peopleás Hospital, Zhengzhou, China.

Background: Pineal region tumors represent challenging surgical lesions with wide ranges of survival reported in different surgical series. In this article, we emphasize the role of complete microsurgical resection (CMR) to obtain a favorable long-term outcome of pineal region tumors.

Methods: We report a retrospective study of pineal region tumors operated on in Helsinki Neurosurgery between 1997 and 2015. Information was obtained from the hospital records, and an evaluation of the Finnish population register was conducted in July 2018 to determine the current status of the patients.

Results: A total of 76 pineal region tumors were operated on. The survival was 62% at a mean follow-up of 125 ± 105 months (range, 0-588 months), and the disease-related mortality was limited to 14 patients (18.4%). Up to July 2018, 29 patients had died. Two patients died 1 and 3 months after surgery of delayed thalamic infarctions, 12 patients of disease progression, and 15 had non-disease-related deaths. Only 1 patient was lost in the long-term follow-up. Ten of 14 disease-related deaths occurred during the first 5 years of follow-up: 5 diffuse gliomas, 3 germ cell tumors, 1 grade II-III pineal parenchymal tumor of intermediate differentiation, and 1 meningioma. CMR was linked to better tumor-free survival and long-term survival, with the exception of diffuse gliomas.

Conclusions: CMR, in the setting of a multidisciplinary management of pineal region tumors, correlates with favorable survival and with minimal mortality. Surgically treated grade II-IV gliomas constitute a particular group with high mortality within the first 5 years independently of the microsurgical resection.
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http://dx.doi.org/10.1016/j.wneu.2019.07.169DOI Listing
November 2019

Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization.

EMBO Mol Med 2019 06;11(6)

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

The current clinical care of glioblastomas leaves behind invasive, radio- and chemo-resistant cells. We recently identified mammary-derived growth inhibitor (MDGI/) as a biomarker for invasive gliomas. Here, we demonstrate a novel function for MDGI in the maintenance of lysosomal membrane integrity, thus rendering invasive glioma cells unexpectedly vulnerable to lysosomal membrane destabilization. MDGI silencing impaired trafficking of polyunsaturated fatty acids into cells resulting in significant alterations in the lipid composition of lysosomal membranes, and subsequent death of the patient-derived glioma cells via lysosomal membrane permeabilization (LMP). In a preclinical model, treatment of glioma-bearing mice with an antihistaminergic LMP-inducing drug efficiently eradicated invasive glioma cells and secondary tumours within the brain. This unexpected fragility of the aggressive infiltrating cells to LMP provides new opportunities for clinical interventions, such as re-positioning of an established antihistamine drug, to eradicate the inoperable, invasive, and chemo-resistant glioma cells from sustaining disease progression and recurrence.
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http://dx.doi.org/10.15252/emmm.201809034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554674PMC
June 2019

Anagrelide for Gastrointestinal Stromal Tumor.

Clin Cancer Res 2019 03 7;25(5):1676-1687. Epub 2018 Dec 7.

Laboratory of Molecular Oncology, Research Programs Unit, Translational Cancer Biology, Department of Oncology, University of Helsinki, Helsinki, Finland.

Purpose: Gastrointestinal stromal tumor (GIST) is a common type of soft-tissue sarcoma. Imatinib, an inhibitor of KIT, platelet-derived growth factor receptor alpha (PDGFRA), and a few other tyrosine kinases, is highly effective for GIST, but advanced GISTs frequently progress on imatinib and other approved tyrosine kinase inhibitors. We investigated phosphodiesterase 3 (PDE3) as a potential therapeutic target in GIST cell lines and xenograft models.

Experimental Design: The GIST gene expression profile was interrogated in the MediSapiens IST Online transcriptome database comprising human tissue and cancer samples, and PDE3A and PDE3B expression was studied using IHC on tissue microarrays (TMA) consisting of 630 formalin-fixed human tissue samples. GIST cell lines were screened for sensitivity to 217 anticancer compounds, and the efficacy of PDE inhibitors on GIST was further studied in GIST cell lines and patient-derived mouse xenograft models.

Results: GISTs expressed PDE3A and PDE3B frequently compared with other human normal or cancerous tissues both in the database and the TMAs. Anagrelide was identified as the most potent of the PDE3 modulators evaluated. It reduced cell viability, promoted cell death, and influenced cell signaling in GIST cell lines. Anagrelide inhibited tumor growth in GIST xenograft mouse models. Anagrelide was also effective in a GIST xenograft mouse model with exon 9 mutation that may pose a therapeutic challenge, as these GISTs require a high daily dose of imatinib.

Conclusions: PDE3A and PDE3B are frequently expressed in GIST. Anagrelide had anticancer efficacy in GIST xenograft models and warrants further testing in clinical trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0815DOI Listing
March 2019

Pineal Parenchymal Tumors of Intermediate Differentiation: A long-Term Follow-Up Study in Helsinki Neurosurgery.

World Neurosurg 2019 Feb 1;122:e729-e739. Epub 2018 Nov 1.

"Juha Hernesniemi" International Center for Neurosurgery, Henan Provincial Peoplés Hospital, Zhengzhou, People's Republic of China.

Background: Pineal parenchymal tumors of intermediate differentiation (PPTIDs) are rare lesions with particular features compared with other pineal parenchymal tumors.

Methods: We present a retrospective review of patients with histologically confirmed PPTIDs who were operated on in our department between 1997 and 2015. A demographic analysis and an evaluation of preoperative status, surgical treatment, as well as immediate and long-term clinical and radiologic outcomes were conducted.

Results: Fifteen patients with PPTIDs were operated on between 1997 and 2015. Gross total removal was achieved in 11 cases; 2 patients underwent near-total resection, 1 partial resection, and 1 received brachytherapy after an endoscopic biopsy. Nine patients required external radiation therapy (4 due to a pleomorphic histology of their lesion including pineoblastoma features in 3 of them; 3 after a subtotal resection; and 2 for tumor recurrence). No patient received chemotherapy. The survival rate of our patients was 57.1% at a mean follow-up of 137.2 ± 77.6 months (39-248 months).

Conclusions: A proper multidisciplinary management of PPTIDs based on a gross total removal of the lesion, and an adjuvant radiotherapy in selected cases, may improve the overall survival of these aggressive tumors.
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http://dx.doi.org/10.1016/j.wneu.2018.10.128DOI Listing
February 2019

Papillary Tumor of the Pineal Region in Children: Presentation of a Case and Comprehensive Literature Review.

World Neurosurg 2018 Sep 12;117:144-152. Epub 2018 Jun 12.

Department of Neurosurgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

Background: Papillary tumor of the pineal region (PTPR) is a rare grade II-III pineal lesion with peculiar histological and immunohistochemical features. These tumors mostly occur in adults, only rarely in children, with 19 cases reported up to now.

Case Description: We present a 3-year-old boy who underwent reoperation for a recurrent PTPR (grade II). Gross total resection of the lesion through an occipital interhemispheric approach with the patient in a sitting position was followed by adjuvant radiotherapy and chemotherapy. Histological examination revealed tumor progression (grade III) and an MIB-1 proliferation index >25%. The patient continues to do well with no evidence of recurrence more than 3 years following surgery. A comprehensive literature review regarding the PTPR, including the current management in children, is reported.

Conclusions: PTPRs are extremely rare in children, and immunohistochemistry is needed to differentiate them from other pineal tumors. These tumors show a high rate of recurrence, and a multidisciplinary management approach (microsurgical resection followed by radiotherapy and/or chemotherapy) can help achieve a favorable outcome.
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http://dx.doi.org/10.1016/j.wneu.2018.06.020DOI Listing
September 2018

Clinical relevance of integrin alpha 4 in gastrointestinal stromal tumours.

J Cell Mol Med 2018 04 29;22(4):2220-2230. Epub 2018 Jan 29.

Laboratory of Molecular Oncology, Translational Cancer Biology Program, Department of Oncology, University of Helsinki, Helsinki, Finland.

The molecular mechanisms for the dissemination and metastasis of gastrointestinal stromal tumours (GIST) are incompletely understood. The purpose of the study was to investigate the clinical relevance of integrin alpha 4 (ITGA4) expression in GIST. GIST transcriptomes were first compared with transcriptomes of other types of cancer and histologically normal gastrointestinal tract tissue in the MediSapiens in silico database. ITGA4 was identified as an unusually highly expressed gene in GIST. Therefore, the effects of ITGA4 knock-down and selective integrin alpha 4 beta 1 (VLA-4) inhibitors on tumour cell proliferation and invasion were investigated in three GIST cell lines. In addition, the prognostic role of ITGA4 expression in cancer cells was investigated in a series of 147 GIST patients with immunohistochemistry. Inhibition of ITGA4-related signalling decreased GIST cell invasion in all investigated GIST cell lines. ITGA4 protein was expressed in 62 (42.2%) of the 147 GISTs examined, and expression was significantly associated with distant metastases during the course of the disease and several adverse prognostic features. Patients whose GIST expressed strongly ITGA4 had unfavourable GIST-specific survival and overall survival compared to patients with low or no ITGA4 expression. Taken together, ITGA4 is an important integrin in the molecular pathogenesis of GIST and may influence their clinical behaviour.
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http://dx.doi.org/10.1111/jcmm.13502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867167PMC
April 2018

Molecular alterations in pediatric brainstem gliomas.

Pediatr Blood Cancer 2018 Jan 9;65(1). Epub 2017 Aug 9.

Department of Children and Adolescents, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Background: Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis. Previously, diagnosis was based on a typical clinical presentation and magnetic resonance imaging findings. After the start of the era of biopsies, DIPGs bearing H3 K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group.

Methods: We studied tumor samples obtained at diagnosis or upon autopsy from 23 children, including two long-term survivors. Based on clinical, radiological, and histological findings, all tumors were previously diagnosed as DIPGs. All samples were analyzed for genetic alterations by next-generation sequencing (NGS) and for protein expression by immunohistochemistry (IHC).

Results: H3 K27 was mutated in NGS or IHC in 20 patients, excluding both long-term survivors. One of these long-term survivors harbored a mutation in IDH1, formerly considered to be an alteration absent in pediatric diffuse brainstem gliomas. Other altered genes in NGS included TP53 (10 patients), MET and PDGFRA (3 patients each), VEGFR and SMARCA4 (2 patients each), and PPARγ, PTEN and EGFR in 1 patient, respectively. IHC revealed cMYC expression in 15 of 24 (63%) of all samples, exclusively in the biopsies.

Conclusions: Eighty-seven percent of the tumors formerly diagnosed as DIPGs could be reclassified as H3 K27-mutated diffuse midline gliomas. Both long-term survivors lacked this alteration. Contrary to former conceptions, IDH1 mutations may occur also in pediatric brainstem gliomas.
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http://dx.doi.org/10.1002/pbc.26751DOI Listing
January 2018

Upregulation of Early and Downregulation of Terminal Pathway Complement Genes in Subcutaneous Adipose Tissue and Adipocytes in Acquired Obesity.

Front Immunol 2017 16;8:545. Epub 2017 May 16.

Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.

Inflammation is an important mediator of obesity-related complications such as the metabolic syndrome but its causes and mechanisms are unknown. As the complement system is a key mediator of inflammation, we studied whether it is activated in acquired obesity in subcutaneous adipose tissue (AT) and isolated adipocytes. We used a special study design of genetically matched controls of lean and heavy groups, rare monozygotic twin pairs discordant for body mass index (BMI) [ = 26, within-pair difference (Δ) in body mass index, BMI >3 kg/m] with as much as 18 kg mean Δweight. Additionally, 14 BMI-concordant (BMI <3 kg/m) served as a reference group. The detailed measurements included body composition (DEXA), fat distribution (MRI), glucose, insulin, adipokines, C3a and SC5b-9 levels, and the expression of complement and insulin signaling pathway-related genes in AT and adipocytes. In both AT and isolated adipocytes, the classical and alternative pathway genes were upregulated, and the terminal pathway genes downregulated in the heavier co-twins of the BMI-discordant pairs. The upregulated genes included C1q, C1s, C2, ficolin-1, factor H, receptors for C3a and C5a (C5aR1), and the iC3b receptor (CR3). While the terminal pathway components C5 and C6 were downregulated, its inhibitor clusterin was upregulated. Complement gene upregulation in AT and adipocytes correlated positively with adiposity and hyperinsulinemia and negatively with the expression of insulin signaling-related genes. Plasma C3a, but not SC5b-9, levels were elevated in the heavier co-twins. There were no differences between the co-twins in BMI-concordant pairs. Obesity is associated with increased expression of the early, but not late, complement pathway components and of key receptors. The twins with acquired obesity have therefore an inflated inflammatory activity in the AT. The results suggest that complement is likely involved in orchestrating clearance of apoptotic debris and inflammation in the AT.
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http://dx.doi.org/10.3389/fimmu.2017.00545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432622PMC
May 2017

Motility of glioblastoma cells is driven by netrin-1 induced gain of stemness.

J Exp Clin Cancer Res 2017 01 9;36(1). Epub 2017 Jan 9.

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

Background: Glioblastoma is an untreatable brain cancer. The tumors contain a population of stem-like cells which are highly invasive and resistant to therapies. These cells are the main reason for the lethality of glioblastoma. Extracellular guidance molecule netrin-1 promotes the invasiveness and survival of various cancer cell types. We have previously found that netrin-1 activates Notch signaling, and Notch signaling associates with cell stemness. Therefore, we have here investigated the effects of netrin-1 on glioblastoma pathogenesis and glioblastoma cell stemness.

Methods: Glioma tissue microarrays were stained with immunohistochemistry and the results were used to evaluate the association between netrin-1 and survival of glioma patients. The localization of netrin-1 was analyzed utilizing fresh frozen glioblastoma tissues. The glioma cell invasion was investigated using ex vivo glioma tissue cultures and newly established primary cell cultures in 3D in vitro invasion assays. Intracranial mouse xenograft models were utilized to investigate the effects of netrin-1 on glioblastoma growth and invasion in vivo.

Results: Netrin-1 expression associated with poor patient prognosis in grade II-III gliomas. In addition, its expression correlated with the stem-like cell marker nestin. Netrin-1 overexpression in cultured cells led to increased formation of stem-like cell spheroids. In glioblastoma tumor biopsies netrin-1 localized to hypoxic tumor areas known to be rich in the stem-like cells. In xenograft mouse models netrin-1 expression altered the phenotype of non-invasive glioblastoma cells into diffusively invading and increased the expression of glioma stem-like cell markers. Furthermore, a distinct invasion pattern where netrin-1 positive cells were following the invasive stem-like cells was detected both in mouse models and ex vivo human glioblastoma tissue cultures. Inhibition of netrin-1 signaling targeted especially the stem-like cells and inhibited their infiltrative growth.

Conclusions: Our findings describe netrin-1 as an important regulator of glioblastoma cell stemness and motility. Netrin-1 activates Notch signaling in glioblastoma cells resulting in subsequent gain of stemness and enhanced invasiveness of these cells. Moreover, inhibition of netrin-1 signaling may offer a way to target stem-like cells.
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http://dx.doi.org/10.1186/s13046-016-0482-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223529PMC
January 2017

The expression of cancerous inhibitor protein phosphatase 2A in chronic rhinosinusitis with nasal polyps.

Acta Otolaryngol 2016 Nov 27;136(11):1173-1179. Epub 2016 Jun 27.

a Haartman Institute, University of Helsinki , Helsinki , Finland.

Conclusion: The study suggests that cancerous inhibitor of protein phosphatase 2A (CIP2A) expression and eosinophilia associate with chronic rhinosinusitis with nasal polyps with aspirin exacerbated respiratory disease (CRSwNP + AERD). Further studies with a larger sample size are needed to evaluate further the role of CIP2A and related pathways in CRSwNP + AERD.

Objectives: Low prostaglandin E2 levels putatively associate with CRSwNP + AERD and decreased c-Myc levels. The aim of this study was to evaluate the expression and revision-predictive role of oncoprotein CIP2A, another c-Myc modulator, in CRSwNP with/without AERD, and in antrochoanal polyps.

Method: Ninety retrospective archival objective glasses of nasal polyp tissue from CRSwNP or ACP patients were used for assessing mucosal eosinophilia. Of this population, 90 archival nasal polyp specimens were available for immunohistochemical staining with a polyclonal anti-CIP2A antibody, together with 19 control nasal mucosa specimens. CIP2A staining intensity and tissue eosinophilia were assessed by two blinded observers with a light microscope. Subject characteristics from 90 patients and 19 controls were obtained from patient records and additionally by a questionnaire from controls. The follow-up data was available from patient records of 84 patients and 16 controls.

Results: The expression of epithelial CIP2A was detected both in control inferior turbinate mucosa and nasal polyps. The expression was significantly lower in the CRSwNP + AERD group compared to controls and CRSwNP without AERD (p < 0.01). High mucosal eosinophilia associated with CRSwNP (p < 0.01). Neither CIP2A nor eosinophilia predicted the need for revision surgery (p > 0.05), whereas previous surgery, allergic rhinitis, and use of corticosteroids did predict the need for revision surgery (p < 0.05).
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http://dx.doi.org/10.1080/00016489.2016.1195918DOI Listing
November 2016

Human breast cancer cells educate macrophages toward the M2 activation status.

Breast Cancer Res 2015 Aug 5;17:101. Epub 2015 Aug 5.

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, P.O. Box 1627, FI-70211, Kuopio, Finland.

Introduction: The immune system plays a major role in cancer progression. In solid tumors, 5-40 % of the tumor mass consists of tumor-associated macrophages (TAMs) and there is usually a correlation between the number of TAMs and poor prognosis, depending on the tumor type. TAMs usually resemble M2 macrophages. Unlike M1-macrophages which have pro-inflammatory and anti-cancer functions, M2-macrophages are immunosuppressive, contribute to the matrix-remodeling, and hence favor tumor growth. The role of TAMs is not fully understood in breast cancer progression.

Methods: Macrophage infiltration (CD68) and activation status (HLA-DRIIα, CD163) were evaluated in a large cohort of human primary breast tumors (562 tissue microarray samples), by immunohistochemistry and scored by automated image analysis algorithms. Survival between groups was compared using the Kaplan-Meier life-table method and a Cox multivariate proportional hazards model. Macrophage education by breast cancer cells was assessed by ex vivo differentiation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of breast cancer cell conditioned media (MDA-MB231, MCF-7 or T47D cell lines) and M1 or M2 inducing cytokines (respectively IFN-γ, IL-4 and IL-10). Obtained macrophages were analyzed by flow cytometry (CD14, CD16, CD64, CD86, CD200R and CD163), ELISA (IL-6, IL-8, IL-10, monocyte colony stimulating factor M-CSF) and zymography (matrix metalloproteinase 9, MMP-9).

Results: Clinically, we found that high numbers of CD163(+) M2-macrophages were strongly associated with fast proliferation, poor differentiation, estrogen receptor negativity and histological ductal type (p<0.001) in the studied cohort of human primary breast tumors. We demonstrated ex vivo that breast cancer cell-secreted factors modulate macrophage differentiation toward the M2 phenotype. Furthermore, the more aggressive mesenchymal-like cell line MDA-MB231, which secretes high levels of M-CSF, skews macrophages toward the more immunosuppressive M2c subtype.

Conclusions: This study demonstrates that human breast cancer cells influence macrophage differentiation and that TAM differentiation status correlates with recurrence free survival, thus further emphasizing that TAMs can similarly affect therapy efficacy and patient outcome.
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http://dx.doi.org/10.1186/s13058-015-0621-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531540PMC
August 2015

A grey keratinous tarsal cyst with Gram+ cocci.

Acta Ophthalmol 2015 Nov 10;93(7):684-5. Epub 2015 Jun 10.

Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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http://dx.doi.org/10.1111/aos.12765DOI Listing
November 2015

IgG4-related disease mimicking chalazion in the upper eyelid with skin manifestations on the trunk.

Int Ophthalmol 2015 Aug 3;35(4):595-7. Epub 2015 Apr 3.

Helsinki University Eye Hospital, PL 220, 00029 HUS, Helsinki, Finland,

IgG4-related disease is a recently defined inflammatory process characterized by IgG4-bearing plasma cells in the involved tissues. The most common sites of involvement are the pancreas, hepatobiliary tract, salivary glands, lymph nodes, retroperitoneum and orbit, especially the lacrimal glands. Other ocular or ocular adnexal sites are rare. To our knowledge, there is one reported case of a conjunctival involvement. We describe a patient, who had an IgG4-RD mimicking chalazion in the upper eyelid, confined to the tarsus, with multiple skin lesions on the trunk. This is a case report of a 55-year-old female. A 55-year-old female presented with an upper eyelid lesion, which was clinically diagnosed as chalazion and drained three times. Histopathological diagnoses were chalazion and inflammation with mixed cells, respectively. Additionally, the patient had had skin nodules on the trunk for several years. Finally, after a third recurrence, the tarsal eyelid lesion was completely excised. The tarsal pathology specimen showed 85 IgG4 positive plasma cells per HPF and the IgG4/IgG ratio was 0.64, suggesting a probable IgG4-related disease. The re-examined skin lesions resembled histologically the eyelid lesion. It is essential to be aware of IgG4-related disease, including in recurrent chalazia.
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http://dx.doi.org/10.1007/s10792-015-0070-xDOI Listing
August 2015

Familial frontotemporal dementia associated with C9orf72 repeat expansion and dysplastic gangliocytoma.

Neurobiol Aging 2014 Feb 27;35(2):444.e11-4. Epub 2013 Sep 27.

Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Institute of Neurology, University College London, Queen Square, London, UK.

A hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 gene (C9orf72) was recently identified as the most common genetic cause of frontotemporal dementia/amyotrophic lateral sclerosis. Here we describe the clinical, pathologic, and genetic features of a Finnish C9orf72 expansion carrier, who developed a dysplastic gangliocytoma (Lhermitte-Duclos disease), a rare hamartoma/overgrowth syndrome of cerebellar granule cells associated with mutations in the phosphatase and tensin homolog gene. In addition to the dysplastic gangliocytoma, the patient showed typical transactive response DNA-binding protein with Mr 43 kD (TDP-43) pathology mainly in the cortex and the substantia nigra and numerous p62-positive/TDP-43-negative inclusions in the cerebellar granule cells. His sister carried the same gene defect and showed a similar type of TDP-43/p62 pathology in her brain. Our findings confirm that the clinical and pathologic picture of C9orf72 mutation carriers is more heterogeneous than originally thought and warrants further studies on the possible involvement of phosphatase and tensin homolog gene pathway in the specific cerebellar granule cell pathology associated with C9orf72 expansion.
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http://dx.doi.org/10.1016/j.neurobiolaging.2013.08.021DOI Listing
February 2014

The hypermethylation of the O6-methylguanine-DNA methyltransferase gene promoter in gliomas--correlation with array comparative genome hybridization results and IDH1 mutation.

Genes Chromosomes Cancer 2012 Jan 15;51(1):20-9. Epub 2011 Sep 15.

Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.

The use of molecular markers in the diagnostics of gliomas aids histopathological diagnosis and allows their further classification into clinically significant subgroups. The aim of this study was to characterize the methylation pattern of the O(6) -methylguanine-DNA methyltransferase (MGMT) promoter, gene copy number aberrations, and isocitrate dehydrogenase I (IDH1) mutation in gliomas. We studied 51 gliomas (15 oligodendrogliomas, 18 oligoastrocytomas, 3 astrocytomas, and 15 glioblastomas) by pyrosequencing, array comparative genome hybridization (CGH), and immunohistochemistry. MGMT hypermethylation was observed in 100% of oligoastrocytomas, 93% of oligodendrogliomas, and 47% of glioblastomas. The most frequently altered chromosomal regions were deletions of 1p31.1/21.1-22.2 and 19q13.3qter in oligodendroglial tumors, and losses of 9p21.3, 10q25.3qter, and 10q26.13-26.2 in glioblastomas. Deletions on 9p and 10q, and gain of 7p were associated with the unmethylated MGMT phenotype, whereas deletion of 19q and oligodendroglial morphology was associated with MGMT hypermethylation. IDH1 mutation showed positive correlation with MGMT hypermethylation and loss of 1p/19q. Our results suggest that MGMT promoter methylation, analyzed by pyrosequencing, is a frequent event in oligodendroglial tumors, and it correlates with IDH1 mutation and 19q loss in gliomas. Pyrosequencing proved a good method for assessing the degree of MGMT methylation in formalin-fixed paraffin-embedded glioma samples. However, further studies are needed to confirm a clinically relevant cut-off point for MGMT methylation in gliomas.
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http://dx.doi.org/10.1002/gcc.20927DOI Listing
January 2012

Tissue restoration after implantation of polyglycolide, polydioxanone, polylevolactide, and metallic pins in cortical bone: an experimental study in rabbits.

Calcif Tissue Int 2010 Jul 22;87(1):90-8. Epub 2010 May 22.

Research Department, Center for Military Medicine, Töölönkatu 44-48 D 65, 00250, Helsinki, Finland.

We performed qualitative and histoquantitative investigations of tissue restoration after implanting polyglycolide (PGA), polydioxanone (PDS), polylevolactide (PLLA), and stainless steel pins in the intramedullary canal of rabbit femurs. The effect of bioabsorbable devices on healing of a cortical bone defect was also assessed. The cortical bone defect was created in the right femur of 80 rabbits. Bioabsorbable and metallic pins in 60 and two metallic pins alone were implanted in 20 intramedullary canals; 80 left femurs served as intact controls. Follow-up times were 3, 6, 12, 24, and 52 weeks. At all time points, collagenous connective tissue, including bone trabeculae, surrounded the implant at the tissue-implant interface, replacing hematopoiesis and fat of the intramedullary canal. The groups did not differ in the area and trabecular bone area fraction of the resulting callus. Residual fragments of PGA and PDS were observed at 24 weeks, and complete degradation occurred within 52 weeks. PGA, PDS, PLLA, and metallic implants induced a bony and fibrous walling-off response in the intramedullary cavity. No inflammation was observed. Complete tissue restoration did not occur within the follow-up, even after complete degradation of PGA and PDS, which had shorter degradation times than PLLA. The cortical bone healing effect was not different between bioabsorbable pins and metallic wires. Thus, these polymers had no specific osteostimulatory or osteoinhibitory properties compared to stainless steel. Within the follow-up period, there were no significant differences in biocompatibility between the implants and no adverse inflammatory foreign-body reactions.
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http://dx.doi.org/10.1007/s00223-010-9374-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887933PMC
July 2010

Expression of KIT receptor tyrosine kinase in endothelial cells of juvenile brain tumors.

Brain Pathol 2010 Jul 30;20(4):763-70. Epub 2009 Nov 30.

Helsinki Biomedical Graduate School, Helsinki, Finland.

KIT receptor tyrosine kinase is expressed in tumor endothelial cells of adult glioblastomas, but its expression in pediatric brain tumor endothelial cells is unknown. We assessed expression of KIT, phosphorylated KIT, stem cell factor (SCF) and vascular endothelial growth factor receptor-2 (VEGFR-2) in 35 juvenile pilocytic astrocytomas and 49 other pediatric brain tumors using immunohistochemistry, and KIT messenger RNA (mRNA) using in situ hybridization. KIT and phospho-KIT were moderately or strongly expressed in tumor endothelia of 37% and 35% of pilocytic astrocytomas, respectively, whereas marked SCF and VEGFR-2 expression was uncommon. KIT mRNA was detected in tumor endothelial cells. Tumor endothelial cell KIT expression was strongly (P < 0.01) associated with endothelial cell phospho-KIT and SCF expression, and with tumor KIT (P = 0.0011) and VEGFR-2 expression (P = 0.022). KIT and phospho-KIT were present in endothelia of other pediatric brain tumors, notably ependymomas. Endothelial cell KIT expression was associated with a young age at diagnosis of pilocytic astrocytoma or ependymoma, and it was occasionally present in histologically normal tissue of the fetus and children. We conclude that KIT is commonly present in endothelial cells of juvenile brain tumors and thus may play a role in angiogenesis in these neoplasms.
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http://dx.doi.org/10.1111/j.1750-3639.2009.00357.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901521PMC
July 2010

Tumour microvessel endothelial cell KIT and stem cell factor expression in human solid tumours.

Histopathology 2009 Nov;55(5):544-53

Laboratory of Molecular Oncology, Biomedicum Helsinki, Helsinki, Finland.

Aims: To assess KIT receptor tyrosine kinase and stem cell factor (SCF, KIT ligand) expression in tumour microvessel endothelial cells.

Methods And Results: KIT and SCF expression were studied in 248 human tumours consisting of 15 different histological types using immunohistochemistry and in situ hybridization for KIT messenger RNA. Moderate to strong intratumoral endothelial cell KIT expression was present in 11 of the 15 tumour types, and was most common in glioblastoma (58%), mixed embryonal carcinoma with teratoma (33%) and renal clear cell carcinoma (29%). Results of in situ hybridization were in line with those obtained with immunohistochemistry in the cases studied (n = 9). Marked SCF expression was uncommon in tumour endothelial cells, but frequent in perinecrotic tumour cells. Patients with glioblastoma with moderate to strong endothelial cell KIT expression had more favourable survival than those whose tumour showed little or no expression (P = 0.024). Glioblastoma patients whose tumour expressed SCF had an unfavourable outcome compared with those with tumour with weak or no expression (P = 0.034).

Conclusions: Intratumoral microvessels of several types of human malignant tumours express KIT. Tumour cell SCF expression and absence of marked endothelial cell KIT expression are novel adverse prognostic features in glioblastoma.
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http://dx.doi.org/10.1111/j.1365-2559.2009.03418.xDOI Listing
November 2009

Amplification and overexpression of KIT, PDGFRA, and VEGFR2 in medulloblastomas and primitive neuroectodermal tumors.

J Neurooncol 2010 Apr 25;97(2):217-24. Epub 2009 Sep 25.

Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, 00014, University of Helsinki, Finland.

Medulloblastomas (MB) and primitive neuroectodermal tumors (PNET) are the most common malignant brain tumors in children. These two tumor types are histologically similar, but have different genetic backgrounds and clinical outcomes. Other brain tumors, such as gliomas, frequently have coamplification and overexpression of receptor tyrosine kinases KIT, platelet-derived growth factor receptor alpha (PDGFRA), and vascular endothelial growth factor receptor 2 (VEGFR2). We investigated protein expression and gene copy numbers of KIT, PDGFRA, and VEGFR2 in 41 MB and 11 PNET samples by immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH). KIT and PDGFRA expression was detected in both MBs and PNETs, whereas VEGFR2 expression was weak in these tumors. KIT, PDGFRA, and VEGFR2 amplifications were all present in 4% of MBs/PNETs, and KIT amplification was associated with concurrent PDGFRA and VEGFR2 amplifications (P
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http://dx.doi.org/10.1007/s11060-009-0014-2DOI Listing
April 2010

[Violent endocarditis in a previously healthy woman].

Duodecim 2009 ;125(3):289-96

HYKS, Meilahden sairaala, sydäntutkimusosasto, PL 340, 00290 HUS.

A previously healthy woman having recently retired to old-age pension contracted a mild respiratory infection. During a peroral course of antibiotics, the inflammatory values continued to elevate. Admission to hospital was followed by stroke, revealing an underlying endocarditis. The patient succumbed suddenly two days later. In this clinical-pathological meeting case report we review the cause of it all.
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April 2009

Copy number alterations of the polycomb gene BMI1 in gliomas.

Acta Neuropathol 2008 Jul 22;116(1):97-102. Epub 2008 Apr 22.

Developmental Biology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland.

Gliomas are heterogeneous tumours that grow in an uninhibited fashion, and these brain tumour cells share numerous characteristics with neural stem cells. The BMI1 gene encodes a component of the polycomb protein complex regulating epigenetically gene activity via histone modification. It functions for instance during the development of the central nervous system and maturation of neural cells. BMI-1 protein expression is deregulated in several forms of cancer and gene amplification has been identified in mantle cell lymphomas. Since BMI1 is located at chromosome 10p, a region implicated frequently in brain tumourigenesis, we investigated the genetic status and the corresponding expression patterns of BMI1 in a series of 100 low- and high-grade primary and recurrent gliomas. Chromogenic in situ hybridisation (CISH) with probes directed against BMI1 at 10p13 and the centromere of chromosome 10 was used in the analyses. Of all gliomas, 59% demonstrated aberrant copy numbers of BMI1. Deletions of the BMI1 locus were found in most types of tumours, and in a univariate survival analysis these cases had poor prognosis. Increased copy numbers of the BMI1 locus (3-5 copies) were found in all histological types, especially in high-grade astrocytomas. No difference in prognosis between cases with normal copy numbers and cases with increased copy numbers could be observed. This data suggests that BMI1 gene is aberrant at the chromosomal level in a subset of gliomas, and possibly contributes to brain tumour pathogenesis.
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http://dx.doi.org/10.1007/s00401-008-0376-0DOI Listing
July 2008

Enveloping bioabsorbable polyglycolide membrane and immobilization in Achilles tendon repair: A comparative experimental study on rabbits.

J Orthop Res 2008 Feb;26(2):264-70

Department of Orthopaedics and Traumatology, Helsinki University Hospital, P.O. Box 266, 00029 HUS, Helsinki, Finland.

Using qualitative and histoquantitative methods, we investigated the effect of immobilization versus nonimmobilization on the biodegradation process, implant-tissue interaction, and scar formation after enveloping a rejoined rabbit Achilles tendon with a self-reinforced polyglycolide (SR-PGA) membrane. The soleus and gastrocnemius tendons of the right hind legs of 40 rabbits were transected. After suturing the ends, the seam was enveloped with the bioabsorbable membrane. Twenty ankles were immobilized with cast, 20 remained nonimmobilized. All nonoperated left ankles served as intact controls. During the follow-up of 3, 6, 12, and 24 weeks, scar formation, tissue response, and membrane biodegradation were studied histologically and histomorphometrically. The amount of scar tissue, highest at 3 weeks, gradually approached intact controls. SR-PGA degradation in both cast and noncast specimens was near complete by 24 weeks. Signs of an inflammatory process were most prominent at 3 weeks and diminished gradually by 24 weeks. No significant difference between cast and noncast specimens was noted at any time point regarding the amount of scar tissue, degradation process of PGA, or intensity of inflammatory reaction. In the present experimental setting, cast immobilization influenced neither scar formation nor speed of degradation during reunion of transected Achilles tendon ends as compared with nonimmobilization. No differences in the reunion process of the tendon ends were seen between the immobilized and nonimmobilized groups. Moreover, inflammatory cells were similar in both groups and reflected a transient tissue reaction to the membrane. Within the follow-up, the seam area (cross-sectional) approached that of intact controls.
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http://dx.doi.org/10.1002/jor.20504DOI Listing
February 2008

The impact of polyglycolide membrane on a tendon after surgical rejoining. A histological and histomorphometric analysis in rabbits.

J Biomed Mater Res A 2007 Jun;81(4):987-93

Department of Orthopaedics and Traumatology, Helsinki University Hospital, P.O. Box 266, 00029 HUS, Helsinki, Finland.

Tissue response to self-reinforced polyglycolide (SR-PGA) membranes surrounding rejoined rabbit tendons was compared with tissue response to nonenveloped rejoined tendons, with special focus on scar formation and SR-PGA membrane biodegradation process. Both hind legs of 20 skeletally mature rabbits were operated on by transecting the plantaris longus tendons and rejoining the ends with sutures. The right side seams were enveloped with bioabsorbable SR-PGA membranes, while the left sides served as noncovered controls. The follow-up times were 3, 6, 12, and 24 weeks. Scar formation and tissue response to membranes were studied by histological and histomorphometric analysis. Tendon regeneration was most active at 3 weeks. Capillary formation was more prominent in specimens with shorter follow-up times. Membrane degradation induced an inflammatory reaction observed at all follow-up time points. Under polarizing microscopy, birefringent SR-PGA material was seen to vanish almost completely by 24 weeks. SR-PGA membranes had no specific effect on scar formation and there were no differences in the reunion process of the transected tendon ends between the SR-PGA membrane groups and the controls. Inflammatory cells in the SR-PGA membrane groups reflected a tissue reaction to the membrane. When placed in soft tissues, SR-PGA membranes degraded almost completely within 24 weeks.
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http://dx.doi.org/10.1002/jbm.a.31144DOI Listing
June 2007

Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas.

Mol Cancer Res 2006 Dec;4(12):927-34

Laboratory of Molecular Oncology, Biomedicum Helsinki, Helsinki, Finland.

Receptor tyrosine kinase aberrations are implicated in the genesis of gliomas. We investigated expression and amplification of KIT, PDGFRA, VEGFR2, and EGFR in 87 gliomas consisting of astrocytomas, anaplastic astrocytomas, oligodendrogliomas, or oligoastrocytomas in tumor samples collected at the time of the diagnosis and in samples of the same tumors at tumor recurrence. Gene amplifications were investigated using either chromogenic in situ hybridization or fluorescence in situ hybridization, and protein expression using immunohistochemistry. In samples collected at glioma diagnosis, KIT and PDGFRA amplifications were more frequent in anaplastic astrocytomas than in astrocytomas, oligodendrogliomas, and oligoastrocytomas [28% versus 5% (P = 0.012) and 33% versus 2% (P = 0.0008), respectively]. VEGFR2 amplifications occurred in 6% to 17% of the gliomas at diagnosis, and EGFR amplifications in 0% to 12%. Amplified KIT was more frequently present in recurrent gliomas than in newly diagnosed gliomas (P = 0.0066). KIT amplification was associated with KIT protein expression and with presence of PDGFRA and EGFR amplifications both at the time of the first glioma diagnosis and at tumor recurrence, and with VEGFR2 amplification at tumor recurrence. Three (4%) primary gliomas and 10 (14%) recurrent gliomas that were evaluable for coamplification of KIT, PDGFRA, and VEGFR2 showed amplification of at least two of these genes; the amplicon contained amplified KIT in all 13 cases. In conclusion, besides glioblastoma, amplified KIT, PDGFRA, and VEGFR may also occur in lower-grade gliomas and in their recurrent tumors. It is currently not known whether specific tyrosine kinase inhibitors are effective in the treatment of such gliomas.
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http://dx.doi.org/10.1158/1541-7786.MCR-06-0085DOI Listing
December 2006

Molecular genetic analysis of the REST/NRSF gene in nervous system tumors.

Acta Neuropathol 2006 Oct 6;112(4):483-90. Epub 2006 Jul 6.

Molecular Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, P.O. Box 180, 00014 Helsinki, Finland.

The gene for RE1-silencing transcription factor (REST) alias neuron-restrictive silencer factor NRSF, acts as a transcriptional repressor in the neuronal differentiation pathways in non-neuronal cells, and plays an important role in neuronal development. Inactivating mutations or overexpression of REST have previously been reported in various types of cancer, but no data is available for the role of REST alterations in gliomas. REST gene was screened for mutations in 161 nervous system tumors consisting of astrocytomas, glioblastomas, oligodendrogliomas, oligoastrocytomas, medulloblastomas, meningiomas and schwannomas. REST exons 1-3 were analyzed using denaturing high-performance liquid chromatography (DHPLC) and direct sequencing. The gene copy numbers of REST were investigated by chromogenic (CISH) and fluorescence in situ hybridization (FISH) techniques. Non-synonymous SNPs (P797L, P815S) were found in eight different brain tumor samples. No truncating or activating novel mutations of REST were discovered. Since REST is located at 4q12, a chromosome region implicated in brain tumorigenesis, we conducted gene copy number analyses in medulloblastomas and gliomas. The majority of gliomas (67%) demonstrated low-level amplifications of REST, and only one oligodendroglioma showed high-level amplification of the gene. In medulloblastomas, 38% of samples were determined as aneuploidic, no high-level amplifications were found. Our data suggests that REST is neither activated nor inactivated via mutations in gliomas, while high-level amplification may rarely occur.
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http://dx.doi.org/10.1007/s00401-006-0102-8DOI Listing
October 2006