Association of TP53 Alteration with Tissue Specificity and Patient Outcome of IDH1-Mutant Glioma.

Since the initial discovery of recurrent isocitrate dehydrogenase 1 (IDH1) mutations at Arg132 in glioma, IDH1 hotspot mutations have been identified in cholangiocarcinoma, chondrosarcoma, leukemia, and various other types of cancer of sporadic incidence. Studies in glioma and leukemia have helped promote the theory that IDH1 mutations are an oncogenic event that drives tumorigenesis in general. Through bioinformatic analysis of more than 45,000 human pan-cancer samples from three independent datasets, we show here that IDH1 mutations are rare events in human cancer but are exclusively prevalent in WHO grade II and grade III (lower-grade) glioma. Interestingly, alterations in the tumor-suppressor gene TP53 (tumor protein p53) co-occur significantly with IDH1 mutations and show a tendency of exclusivity to IDH2 mutations. The co-occurrence of IDH1 mutation and TP53 alteration is widespread in glioma, particularly in those harboring IDH1R132H, IDH1R132G, and IDH1R132S, whereas co-occurrence of IDH1R132C and TP53 alteration can be found sporadically in other cancer types. In keeping with the importance of p53 in tumor suppression, TP53 status is an independent predictor of overall survival irrespective of histological and molecular subgroups in lower-grade glioma. Together, these results indicate tissue specificity of IDH1 hotspot mutation and TP53 alteration and the importance of TP53 status as a predictor of patient outcome in lower-grade glioma.

Tyrosine Kinase Inhibitor Imatinib Mesylate Alters DMBA-Induced Early Onco/Suppressor Gene Expression with Tissue-Specificity in Mice.

Tyrosine kinases play crucial roles in cellular development and tumorigenesis. Tyrosine kinase inhibitors (TKIs) are effective and widely used drug molecules in targeted cancer therapies. Altered expressions of protooncogenes and tumor suppressor genes after DMBA (7,12-dimethylbenz[a]anthracene) treatment have been described as early markers of tumor induction; however their tissue-specific effects remain still unclear. Our study was aimed at examining the short-term possible antineoplastic and chemopreventive effects of a TKI compound (imatinib mesylate) on a DMBA-induced mouse tumor model. In addition, we also investigated the tissue-specific expressions of Hras, Kras, Myc, and Trp53 genes in the brain, bone marrow, spleen, liver, abdominal lymph nodes, thymus, lungs, and kidneys, respectively. 24 hours after the imatinib mesylate injection, we observed significant Kras downregulation in the bone marrow and lung of the DMBA-treated mice. Moreover, the mRNA expression of Myc was also found to be decreased significantly in the spleen. Interestingly, while Trp53 expression was significantly increased in the lung, it was decreased in the other tissues. However, there was also a tendency in the decreased Myc level in the bone marrow, brain, kidneys, lungs, and lymph nodes and in the decreased Hras level in the bone marrow, kidneys, and lungs, although no significant differences were observed. Our findings indicate rapid tissue-specific impact of imatinib mesylate on DMBA-induced gene expression in vivo, supporting the chemopreventive potential of imatinib mesylate in cancer.

Molecular Subgroups of Glioblastoma- an Assessment by Immunohistochemical Markers.

Comprehensive molecular characterization of and novel therapeutic approaches to glioblastoma have been explored as a result of advancements in biotechnologies. In this study, we aimed to bring basic research discoveries closer to clinical practice and ultimately incorporate molecular classification into the routine histopathological evaluation of grade IV gliomas. Integrated results of genome-wide sequencing, transcriptomic and epigenomic analyses by The Cancer Genome Atlas Network defined the classic, proneural, neural and mesenchymal subtypes of this tumor. In a retrospective cohort, we analyzed selected subgroup-defining molecular markers in formalin-fixed paraffin-embedded surgical specimens by immunohistochemistry. Quantitative and qualitative scores of marker expression were tested in hierarchical cluster analyses to evaluate segregations of the molecular subgroups, which then were correlated with clinical parameters including patients' age, gender and overall survival. Our study has confirmed the separation of molecular glioblastoma subgroups with clear trends regarding clinical correlations. Future analyses in a larger, prospective cohort using similar methods are expected to facilitate the development of a molecular diagnostic panel that may complement routine histological work up and support prognostication as well as treatment decisions in glioblastoma.

The Melanin-concentrating Hormone System in Human, Rodent and Avian Brain.

Melanin-concentrating hormone (MCH) is a cyclic 19 amino acid orexigenic hypothalamic peptide. MCH is located in the lateral and dorsal hypothalamus, as well as in the zona incerta. In mammals MCH increases food intake, contributes to regulation of energy balance, temperature, reproductive function, endocrine homeostasis and biological rhythms. Several studies have proved the significance of MCH in obesity, diabetes and depression. Although the peptide is well-characterized in mouse models, much less is known about its functions in avians. In birds the MCH system especially in the lateral and basal hypothalamus has important connections to the limbic system and it coordinates the vegetative and endocrine functions, as well as the emotional behaviour. Pharmacological modulation of MCH system could contribute to the therapy of eating disorders and improve agricultural efficiency regarding avians. Reviewing the current knowledge on MCH system in human, rodents and avians may stimulate a new wave of studies in the field.

Pathophysiology of Meningioma Growth in Pregnancy.

Meningioma is among the most frequent brain tumours predominantly affecting elderly women. Epidemiological studies have shown that at the age of fertility the incidence is relatively low. The biological behaviour of meningioma in pregnancy is different from other meningiomas. The possible explanation is rooted in the complex physiological changes and hormonal differences during pregnancy. The increased meningioma growth observed in pregnancy is presumably the result of endocrine mechanisms. These include increase in progesterone, human placental lactogen (hPL) and prolactin (PRL) serum levels. In contrast, levels of pituitary hormones such as follicle stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotropin (hCG) produced by the placenta are decreasing in the mother prior to childbirth. Besides, vascular factors also play a crucial role. Peritumoral brain edema (PTBE), with well-known causative association with vascular endothelial growth factor (VEGF), can often be seen both with imaging and in the surgical specimens. Our aim is to assess published research on this topic including diagnostic and therapeutic guidelines, and to provide a clinically useful overview on the pathophysiology and biological behaviour of this rare complication of pregnancy.

[Molecular background of the melanoma and the brain metastasis]. / A melanoma és az agyi áttétképzodés molekuláris háttere.

Malignant melanoma is one of the most aggressive tumors which often gives metastasis to distant organs thereby limiting the chances of survival. Brain metastasis occurs in nearly half of the advanced tumors. In order to improve outcome early diagnosis is important. The discovery and better understanding of genetic and epigenetic changes is essential for developing new effective therapies, which can designate promising therapeutic targets. Melanoma most often is caused by gene mutations of the mitogen-activated protein kinase pathway, the phosphatidylinositol 3-kinase signaling pathway, and the cell cycle regulatory molecules, respectively. The molecular process of brain metastasis has not been fully elucidated. In our review we summarize the genetic alterations and molecular mechanisms playing a role in the development of melanoma and its brain metastasis. Orv Hetil. 2017; 158(28): 1083-1091.

PARP1 expression and its correlation with survival is tumour molecular subtype dependent in glioblastoma.

Overexpression of PARP1 exists in various cancers, including glioblastoma (GBM). Although PARP1 inhibition is a promising therapeutic target, no comprehensive study has addressed PARP1's expression characteristics and prognostic role regarding molecular heterogeneity in astrocytomas including GBM. Our aim was to evaluate PARP1's associations with survival, WHO grade, lineage specific markers, and GBM transcriptomic subtypes. We collected genomic and clinical data from the latest glioma datasets of The Cancer Genome Atlas and performed PARP1, ATRX, IDH1, and p53 immunohistochemistry on GBM tissue samples. We demonstrated that PARP1 gain and increased mRNA expression are characteristics of high-grade astrocytomas, particularly of Proneural and Classical GBM subtypes. Additionally, higher PARP1 levels exhibited an inverse correlation with patient survival (p<0.005) in the Classical subgroup. ATRX (p=0.006), and TP53 (p=0.015) mutations were associated with increased PARP1 expression and PARP1 protein level correlated with ATRX loss and p53 overexpression. Furthermore, higher PARP1 expression together with wildtype TP53 indicated shorter survival (p=0.039). Therefore, due to subtype specificity, PARP1 expression level and TP53 mutation status are reliable marker candidates to distinguish Proneural and Classical subtypes, with prognostic and therapeutic implications in GBM.

[Clinical and neuropathological characteristics of dementia with Lewy bodies]. / A Lewy-testes demencia klinikai és neuropatológiai jellemzoi.

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia. The accurate diagnosis is often possible only by neuropathological examination. The morphologic hallmarks are the presence of α-synuclein-rich Lewy bodies and Lewy neurites, identical to those seen in Parkinson's disease (PD) and Parkinson's disease dementia (PDD). Neurotransmitter deficits, synaptic and ubiquitin-proteasome system (UPS) dysfunction play major role in the pathomechanism. Characteristic symptoms are cognitive fluctuation, parkinsonism and visual hallucinations. Due to the often atypical clinical presentation novel imaging techniques and biomarkers could help the early diagnosis. Although curative treatment is not available, therapies can improve quality of life. Clinicopathological studies are important in exploring pathomechanisms, ensuring accurate diagnosis and identifying therapeutic targets. Orv Hetil. 2017; 158(17): 643-652.

Immunohistochemical correlates of TP53 somatic mutations in cancer.

Despite controversy on the correlation between p53 accumulation and TP53 mutational status, immunohistochemical (IHC) detection of overexpressed protein has long been used as a surrogate method for mutation analysis. The aim of our study was to characterise the IHC expression features of TP53 somatic mutations and define their occurrence in human cancers. A large-scale database analysis was conducted in the IARC TP53 Database (R17); 7878 mutations with IHC features were retrieved representing 60 distinct tumour sites. The majority of the alterations were immunopositive (p <0.001). Sex was known for 4897 mutations showing a female dominance (57.2%) and females carrying negative mutations were significantly younger. TP53 mutations were divided into three IHC groups according to mutation frequency and IHC positivity. Each group had female dominance. Among the IHC groups, significant correlations were observed with age at diagnosis in breast, bladder, liver, haematopoietic system and head & neck cancers. An increased likelihood of false negative IHC associated with rare nonsense mutations was observed in certain tumour sites. Our study demonstrates that p53 immunopositivity largely correlates with TP53 mutational status but expression is absent in certain mutation types.Besides, describing the complex IHC expression of TP53 somatic mutations, our results reveal some caveats for the diagnostic practice.

Haemorrhagic transformation in ischaemic stroke is more frequent than clinically suspected - A neuropathological study.

OBJECTIVES: The vast majority of literature on the frequency of the haemorrhagic transformation of ischaemic stroke is based on imaging studies. The purpose of the present study was to assess the added value of autopsy and neuropathological analysis in a neurology centre with emphasis on acute stroke care. METHODS: We retrospectively analysed the findings of 100 consecutive brain autopsies followed by detailed clinical correlation. RESULTS: The clinical diagnosis was confirmed by neuropathology in every patient with intracerebral haemorrhage and with non-cerebrovascular neurological disorders (e.g. primary tumours, metastases, infections). At admission 64 patients (age 62years, SD 6.5) were diagnosed with acute ischaemic stroke. In 10 of these patients (16%) haemorrhagic transformation was diagnosed clinically by a second CT. In 24 cases (38%) haemorrhagic transformation was detected only at autopsy. The distribution of haemorrhagic transformation in our material was the following: small petechiae in 26.5%, more confluent petechiae in 29.4%, ≤30% of the infarcted area with some mild space-occupying effect in 29.4% and >30% of the infarcted area with significant space-occupying effect or clot remote from infarcted area in 14.7%. Most of the PH1-2 transformations developed in thrombolysed patients and all of the PH2 type transformations were diagnosed already clinically. CONCLUSIONS: We demonstrated that haemorrhagic transformation is frequent and often undiscovered in vivo. Our findings underline the importance of post-mortem neuropathological examination also in the era of advanced imaging techniques and prove that autopsy is the ultimate yardstick of our diagnostic and therapeutic efforts. The high number of haemorrhagic transformations diagnosed only after death is an important novel finding with clinical implications.

[MOLECULAR PATHOLOGY OF MENINGIOMAS]. / A MENINGEOMÁK MOLEKULÁRIS PATOLÓGIÁJA.

Meningiomas represent nearly one-third of all adult primary brain tumours. According to their clinical and histologic appearance, they can be divided into WHO grades I-III. Almost 90% of meningiomas are benign, showing favourable response to conventional therapies, however, patients diagnosed with grade 2 and 3 tumours may have a poor prognosis. In addition, high frequency of tumour recurrence renders treatments more challenging even in benign meningiomas. Molecular-pathological profiling of meningiomas could lead to development of more effective therapies. Although the cytogenetic background of these tumours are already well-characterised, the majority of related genes and mutations is still unknown. Recently, high-throughput techniques enabled better characterisation of mechanisms involved in meningioma development, progression and recurrence. Furthermore, epigenetic dysregulation could offer new opportunities for both diagnosis and treatment of meningiomas. We provide a comprehensive overview of cytogenetic and molecular genetic defects as well as epigenetic alterations in meningiomas. Many of these may serve as biomarker or therapeutic target in the near future.

Epigenetics of Meningiomas.

Meningiomas account for one-third of all adult central nervous system tumours and are divided into three WHO grades. In contrast to the relatively well characterized genetic alterations, our current understanding of epigenetic modifications involved in the meningioma-genesis and progression is rather incomplete. Contrary to genetic alterations, epigenetic changes do not alter the primary DNA sequence and their reversible nature serves as an excellent basis for prevention and development of novel personalised tumour therapies. Indeed, growing body of evidence suggests that disturbed epigenetic regulation plays a key role in the pathogenesis of meningiomas. Altered DNA methylation, microRNA expression, histone, and chromatin modifications are frequently noted in meningiomas bearing prognostic and therapeutic relevance. In this review we provide an overview on recently identified epigenetic alterations in meningiomas and discuss their role in tumour initiation, progression, and recurrence.

[Molecular genetics of familial tumour syndromes of the central nervous system]. / A központi idegrendszert érinto családi daganatszindrómák molekuláris háttere.

Although most of the central nervous system tumours are sporadic, rarely they are associated with familial tumour syndromes. These disorders usually present with an autosomal dominant inheritance and neoplasia develops at younger age than in sporadic cases. Most of these tumours are bilateral, multiplex or multifocal. The causative mutations occur in genes involved in cell cycle regulation, cell growth, differentiation and DNA repair. Studying these hereditary cancer predisposition syndromes associated with nervous system tumours can facilitate the deeper understanding of the molecular background of sporadic tumours and the development of novel therapeutic agents. This review is an update on hereditary tumour syndromes with nervous system involvement with emphasis on molecular genetic characteristics and their clinical implications.

Inclusion body myositis - pathomechanism and lessons from genetics.

Inclusion body myositis is a rare, late-onset myopathy. Both inflammatory and myodegenerative features play an important role in their pathogenesis. Overlapping clinicopathological entities are the familial inclusion body myopathies with or without dementia. These myopathies share several clinical and pathological features with the sporadic inflammatory disease. Therefore, better understanding of the genetic basis and pathomechanism of these rare familial cases may advance our knowledge and enable more effective treatment options in sporadic IBM, which is currently considered a relentlessly progressive incurable disease.

Poly(ADP-ribose) polymerase-1 (PARP1) and p53 labelling index correlates with tumour grade in meningiomas.

Meningiomas are one of the most frequent intracranial tumours, with 13 histological types and three grades according to the 2007 WHO Classification of Tumours of the Central Nervous System. p53, as one of the most potent tumour suppressor proteins, plays a role in nearly 50% of human tumours. Poly(ADP-ribose) polymerase (PARP) is a DNA repair enzyme with high ATP demand. It plays a role in apoptosis by activating an apoptosis inducing factor, and in necrosis by consuming NAD+ and ATP. Only PARP1 has been investigated in detail in tumours out of the 17 members of the PARP superfamily; however, its role has not been studied in meningiomas yet. The aim of this study was to determine the role of p53 and PARP1 in meningiomas of different grade and to establish whether there is any correlation between the p53 and PARP1 expression. Both PARP1 and p53 have been expressed in all examined meningiomas. PARP1 labelled grade II tumours with a higher intensity as compared to grade I and III neoplasms, respectively. An increased p53 expression was noted in grade III meningiomas. There was no statistical correlation between p53 and PARP1 expression. Our data indicate that both PARP1 and p53 activation is a feature in meningiomas of higher grade, PARP1 overexpression being an early, whereas p53 overexpression, a late event in tumour progression.

[Occurrence and molecular pathology of low grade gliomas]. / Alacsony grádusú glialis daganatok elofordulása és molekuláris patológiája.

BACKGROUND: The WHO grade I. and II. low-grade gliomas represent nearly the 15% of all primary brain tumors. These tumours contain clinically, histologically and molecularly distinct tumor types. According to their histologic characteristic, grade II glial tumours are the diffuse astrocytoma, oligodendroglioma and oligoastrocytoma subgroups; ependymal tumors are not included in this study. METHODS: In our publication, we analysed the histologically diagnosed glioma cases between 2007 and 2011 at our institution. RESULTS: Low-grade gliomas were diagnosed in 127 cases (62 male / 65 female), and the mean ages were 39 years (+/- 20.3). More than half of the cancers were localized in the frontal lobe, and the second most frequent area was the temporal lobe. Finally, we complete our report with an overview of major molecular pathways in low-grade gliomas.

[Occurrence and molecular pathology of high grade gliomas]. / Magas grádusú gliomák elofordulása és molekuláris patológiája.

BACKGROUND: Glial tumours represent the most frequent type of primary brain cancers. Gliomas are characterized by heterogeneity that makes the diagnosis, histological classification and the choosing of correct therapy more difficult. Despite the advances in developing therapeutic strategies patients with malignant gliomas have a poor prognosis; therefore glial tumours represent one of the most important areas of cancer research. There are no detailed data on the epidemiology of gliomas in Hungary. METHODS: In the first section of our publication, we analysed the histological diagnosed cases between 2007 and 2011 at the Institute of Pathology, University of Debrecen Medical and Health Science Centre. We analyzed the incidence of 214 high-grade gliomas by tumor grades, gender, age, and the anatomical localization. RESULTS: The majority of cases were glioblastoma (182 cases), and the remaining 32 cases were anaplastic gliomas. The mean age of patients was 57 years (+/- 16.4), and the male:female ratio was 1.1:1. The most frequent area of tumors was the frontal lobe followed by the temporal, parietal and occipital lobe. We include new findings published recently about glioma pathogenesis, molecular pathways, mutant genes and chromosomal regions. We explain briefly the role of selected important genes in glioma genesis and give an update on knowledge provided by modern molecular methods, which could beneficially influence future therapy and the diagnosis of gliomas.