Balázs Murnyák

Immunohistochemical correlates of TP53 somatic mutations in cancer

Despite controversy on the correlation between p53 accumulation and TP53 mutational status, ihas 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.

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.

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 PARP1s expression characteristics and prognostic role regarding molecular heterogeneity in astrocytomas including GBM. Our aim was to evaluate PARP1s 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.

A melanoma és az agyi áttétképződés 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.

Inclusion body myositis — a case based clinicopathological update

Inclusion body myositis is a slowly progressive myopathy affecting predominantly the middle-aged and older patient population. It is a major form of the idiopathic inflammatory myopathies which are chronic systemic autoimmune diseases characterized by symmetrical proximal muscle weakness. Unfortunately, there is no effective therapy yet; however, the early diagnosis is essential to provide treatment options which may significantly slow the progression of the disease. In our case-based clinicopathological study the importance of the close collaboration between the clinician and the neuropathologist is emphasised.

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.

A Lewy-testes demencia klinikai és neuropatológiai jellemzői

Absztrakt: A Lewy-testes demencia a masodik leggyakoribb neurodegenerativ demencia. A pontos diagnozisa gyakran csak neuropatologiai vizsgalattal lehetseges. A betegseg fő morfologiai jellemzője a koros α-szinukleinben gazdag Lewy-test es Lewy-neurit – csakugy, mint a rokon korkep Parkinson-kor es az ahhoz tarsulo demencia eseten. A patomechanizmus fontos tenyezői a neurotranszmitter rendszerek zavara, a szinaptikus diszfunkcio es az ubikvitin-proteaszoma rendszer elegtelen műkodese. Jellemző a kognitiv teljesitmeny fluktuacioja, parkinsonizmus es vizualis hallucinacio. Mivel gyakran nem tipusos a klinikai kep es időbeni lefolyas, a kepalkoto eljarasok es biomarkerek elősegithetik a korai felismerest. Noha hatekony oki terapia nincs, eletminőseget javito kezelesek lehetsegesek. A klinikopatologiai vizsgalatok kiemelten fontosak a patomechanizmus jobb megertese, a pontos diagnozis es a hatekony terapia erdekeben. Orv Hetil. 2017; 158(17): 643–652.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 Parkinsons disease (PD) and Parkinsons 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.

Molecular genetics of familial tumour syndromes of the central nervous system

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

Abstract 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.

The melanin-concentrating hormone system in human, rodent and avian brain

Abstract 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.