Papers by Otilia Menyhart
Abstract P5-08-22: DUSP4 is associated with increased resistance against anti-HER2 therapy in breast cancer
Cancer Research, 2016
Background. The majority of patients develop resistance against suppression of HER2-mediated sign... more Background. The majority of patients develop resistance against suppression of HER2-mediated signaling by trastuzumab in HER2 positive breast cancer (BC). HER2 overexpression activates multiple signaling pathways, including the mitogen-activated protein kinase (MAPK) cascade. MAPK phosphatases (MKPs) are essential regulators of MAPKs and participate in many facets of cellular regulation, including proliferation and apoptosis. We aimed to identify whether differential MKPs are associated with resistance to targeted therapy in patients previously treated with trastuzumab. Methods. Using Affymetrix HGU133plus2 gene chip data of 88 HER2-positive, trastuzumab treated BC patients, candidate MKPs were identified by Receiver Operator Characteristics analysis performed in R. Genes were ranked using their achieved area under the curve (AUC) values and were further constricted to those markers significantly associated to worse survival. Functional significance of the two strongest predictive b...
bioRxiv (Cold Spring Harbor Laboratory), Jan 11, 2021
Scientists from nearly all disciplines face the problem of simultaneously evaluating many hypothe... more Scientists from nearly all disciplines face the problem of simultaneously evaluating many hypotheses. Conducting multiple comparisons increases the likelihood that a non-negligible proportion of associations will be false positives, clouding real discoveries. Drawing valid conclusions require taking into account the number of performed statistical tests and adjusting the statistical confidence measures. Several strategies exist to overcome the problem of multiple hypothesis testing. We aim to summarize critical statistical concepts and widely used correction approaches while also draw attention to frequently misinterpreted notions of statistical inference. We provide a step-by-step description of each multiple-testing correction method with clear examples and present an easy-to-follow guide for selecting the most suitable correction technique. To facilitate multiple-testing corrections, we developed a fully automated solution not requiring programming skills or the use of a command line. Our registration free online tool is available at www.multipletesting.com and compiles the five most frequently used adjustment tools, including the Bonferroni, the Holm (step-down), the Hochberg (step-up) corrections, allows to calculate False Discovery Rates (FDR) and q-values. The current summary provides a much needed practical synthesis of basic statistical concepts regarding multiple hypothesis testing in a comprehensible language with well-illustrated examples. The web tool will fill the gap for life science researchers by providing a user-friendly substitute for command-line alternatives. .
A molekuláris onkológia térnyerésével számos új lehetőség érhető el a daganatos betegek hatékonya... more A molekuláris onkológia térnyerésével számos új lehetőség érhető el a daganatos betegek hatékonyabb kezelésére. Ilyen a klinikai vizsgálatokban alkalmazott, a valóban személyre szabott kezelést elősegítő génpanelelemzés, illetve a célzott kezelés szövettípustól független alkalmazása. A személyre szabott terápiák jelentős hányada valamelyik kinázt gátolja. Az összefoglalónkban bemutatjuk a RAS jelátviteli út sejten belüli komplex szabályozását, valamint ismertetjük az útvonal további farmakológiai szempontból kiaknázható célpontjait nemzetközi és saját eredményeink alapján. A kinázokat érintő gyakori mutációk ellenére számos daganattípusban nem áll rendelkezésre személyre szabott terápia. A hagyományos terápiával nem kezelhető agydaganatok példáján keresztül bemutatjuk a tirozin-kinázok várható jövőbeli terápiás jelentőségét.
Supplementary material from "Determining consistent prognostic biomarkers of overall survival and vascular invasion in hepatocellular carcinoma
<i>Background:</i> Potential prognostic biomarker candidates for hepatocellular carci... more <i>Background:</i> Potential prognostic biomarker candidates for hepatocellular carcinoma (HCC) are abundant, but their generalizability is unexplored. We cross-validated markers of overall survival (OS) and vascular invasion in independent datasets. <i>Methods:</i> The literature search yielded 318 genes related to survival and 52 related to vascular invasion. Validation was performed in three datasets (RNA-seq, <i>n</i> = 371; Affymetrix arrays, <i>n</i> = 91; Illumina gene chips, <i>n</i> = 135) by uni- and multivariate Cox regression and Mann–Whitney <i>U</i>-test, separately for Asian and Caucasian patients. <i>Results:</i> One hundred and eighty biomarkers remained significant in Asian and 128 in Caucasian subjects at <i>p</i> BIRC5 (<i>p</i> = 1.9 × 10<sup>−10</sup>), <i>CDC20</i> (<i>p</i> = 2.5 × 10<sup>−9</sup>) and <i>PLK1</i> (<i>p</i> = 3 × 10<sup>−9</sup>) endured as best performing genes in Asian patients; however, none remained significant in the Caucasian cohort. In a multivariate analysis, significance was reached by stage (<i>p</i> = 0.0018) and expression of <i>CENPH</i> (<i>p</i> = 0.0038) and <i>CDK4</i> (<i>p</i> = 0.038). <i>KIF18A</i> was the only gene predicting vascular invasion in the Affymetrix and Illumina cohorts (<i>p</i> = 0.003 and <i>p</i> = 0.025, respectively). <i>Conclusion:</i> Overall, about half of biomarker candidates failed to retain prognostic value and none were better than stage predicting OS. Impact: Our results help to eliminate biomarkers with limited capability to predict OS and/or vascular invasion.
Carcinogenesis, Mar 22, 2021
Despite advances in molecular characterization of glioblastoma multiforme (GBM), only a handful o... more Despite advances in molecular characterization of glioblastoma multiforme (GBM), only a handful of predictive biomarkers exist with limited clinical relevance. We aimed to identify differentially expressed genes in tumor samples collected at surgery associated with response to subsequent treatment, including temozolomide (TMZ) and nitrosoureas. Gene expression was collected from multiple independent datasets. Patients were categorized as responders/nonresponders based on their survival status at 16 months postsurgery. For each gene, the expression was compared between responders and nonresponders with a Mann-Whitney U-test and receiver operating characteristic. The package 'roc' was used to calculate the area under the curve (AUC). The integrated database comprises 454 GBM patients from 3 independent datasets and 10 103 genes. The highest proportion of responders (68%) were among patients treated with TMZ combined with nitrosoureas, where FCGR2B upregulation provided the strongest predictive value (AUC = 0.72, P < 0.001). Elevated expression of CSTA and MRPS17 was associated with a lack of response to multiple treatment strategies. DLL3 upregulation was present in subsequent responders to any treatment combination containing TMZ. Three genes (PLSCR1, MX1 and MDM2) upregulated both in the younger cohort and in patients expressing low MGMT delineate a subset of patients with worse prognosis within a population generally associated with a favorable outcome. The identified transcriptomic changes provide biomarkers of responsiveness, offer avenues for preclinical studies and may enhance future GBM patient stratifications. The described methodology provides a reliable pipeline for the initial testing of potential biomarker candidates for future validation studies.
Orvosi Hetilap, Dec 18, 2022
Az újgenerációs szekvenáláson (NGS) alapuló diagnosztika legnagyobb előnye, hogy nagyszámú gén pá... more Az újgenerációs szekvenáláson (NGS) alapuló diagnosztika legnagyobb előnye, hogy nagyszámú gén párhuzamos szekvenálása révén a genetikai rendellenességek kiterjedt repertoárját képes egyetlen vizsgálattal lefedni. Az analízis viszonylag kisebb költsége és az adatmennyiség kezelhetőbb mennyisége folytán a célzott génpanelek használata, illetve a teljesexom-szekvenálás (WES) a leginkább elérhető NGS-alapú módszer. Összefoglalónkban az NGS létjogosultságát vizsgáljuk gyermekkori genetikai rendellenességek diagnosztikájában. Áttekintjük az öröklött anyagcserezavarok, daganatos megbetegedések és egyéb gyermekkori genetikai rendellenességek NGS-alapú diagnosztikájában fontos szerepet játszó géneket. A kora gyermekkori rendellenességek NGS-alapú diagnosztikájának rutinszerű használata előtt számos technikai és klinikai kérdés vár még megválaszolásra. Jelenleg a legnagyobb kihívást a ritka genetikai variánsok értelmezése és a mutációk patogenitásának igazolása jelenti.
[Subgroup-specific genomic alterations and potential prognostic biomarkers in childhood medulloblastomas]
PubMed, Dec 9, 2019
Despite continuing advances in therapeutic strategies, survival of childhood medulloblastoma (MB)... more Despite continuing advances in therapeutic strategies, survival of childhood medulloblastoma (MB) patients has reached a plateau in the past decade. Current clinical approaches divide patients into average- and high-risk treatment categories, although this categorization does not take patient heterogeneity into account. Advanced genomics has initiated an exciting transition that lead to a consensus of four distinct molecular entities within MBs (WNT-activated, SHH-activated, Group 3 MB, and Group 4 MB), each with distinct origins, demographics, molecular alterations and clinical outcomes. Within each of the four primary subgroups additional subtypes started to emerge with distinct biological backgrounds and clinical outcomes. Here we summarize subgroup-specific genomic alterations, affected signaling pathways and potential prognostic biomarkers. The poor prognosis associated with recurrent disease is responsible for the stagnant survival rates. Nevertheless, the mortality is unlikely to change without new biomarkers linked to different mechanisms of pathway activation.
Annals of clinical and translational neurology, Mar 19, 2019
SHH-activated medulloblastomas (SHH-MB) account for 25-30% of all medulloblastomas (MB) and occur... more SHH-activated medulloblastomas (SHH-MB) account for 25-30% of all medulloblastomas (MB) and occur with a bimodal age distribution, encompassing many infant and adult, but fewer childhood cases. Different age groups are characterized by distinct survival outcomes and age-specific alterations of regulatory pathways. Here, we review SHH-specific genetic aberrations and signaling pathways. Over 95% of SHH-MBs contain at least one driver eventthe activating mutations frequently affect sonic hedgehog signaling (PTCH1, SMO, SUFU), genome maintenance (TP53), and chromatin modulation (KMT2D, KMT2C, HAT complexes), while genes responsible for transcriptional regulation (MYCN) are recurrently amplified. SHH-MBs have the highest prevalence of damaging germline mutations among all MBs. TP53-mutant MBs are enriched among older children and have the worst prognosis among all SHH-MBs. Numerous genetic aberrations, including mutations of TERT, DDX3X, and the PI3K/AKT/mTOR pathway are almost exclusive to adult patients. We elaborate on the newest development within the evolution of molecular subclassification, and compare proposed risk categories across emerging classification systems. We discuss discoveries based on preclinical models and elaborate on the applicability of potential new therapies, including BET bromodomain inhibitors, statins, inhibitors of SMO, AURK, PLK, cMET, targeting stem-like cells, and emerging immunotherapeutic strategies. An enormous amount of data on the genetic background of SHH-MB have accumulated, nevertheless, subgroup affiliation does not provide reliable prediction about response to therapy. Emerging subtypes within SHH-MB offer more layered risk stratifications. Rational clinical trial designs with the incorporation of available molecular knowledge are inevitable. Improved collaboration across the scientific community will be imperative for therapeutic breakthroughs. 5 years after diagnosis, and survivors face treatmentrelated long-term adverse effects. 5 MB treatment strategy involves maximal safe resection followed by craniospinal irradiation and cytotoxic chemotherapy, with specific type and intensity for high-or standard/average-risk disease. Average-risk patients are over 3 years of age with total or near-total resection and no disease dissemination, while patients with suboptimal tumor resection, metastasis, and/or large cell/anaplastic (LCA) histology are treated for high-risk disease. 6 Infants 990
Scientia et securitas, Oct 10, 2021
A molekuláris onkológia térnyerésével számos új lehetőség érhető el a daganatos betegek hatékonya... more A molekuláris onkológia térnyerésével számos új lehetőség érhető el a daganatos betegek hatékonyabb kezelésére. Ilyen a klinikai vizsgálatokban alkalmazott, a valóban személyre szabott kezelést elősegítő génpanelelemzés, illetve a célzott kezelés szövettípustól független alkalmazása. A személyre szabott terápiák jelentős hányada valamelyik kinázt gátolja. Az összefoglalónkban bemutatjuk a RAS jelátviteli út sejten belüli komplex szabályozását, valamint ismertetjük az útvonal további farmakológiai szempontból kiaknázható célpontjait nemzetközi és saját eredményeink alapján. A kinázokat érintő gyakori mutációk ellenére számos daganattípusban nem áll rendelkezésre személyre szabott terápia. A hagyományos terápiával nem kezelhető agydaganatok példáján keresztül bemutatjuk a tirozin-kinázok várható jövőbeli terápiás jelentőségét.
Clinical Epidemiology, Aug 1, 2018
Background: Population aging is a common demographic pattern in developed countries, and aging in... more Background: Population aging is a common demographic pattern in developed countries, and aging increases the risk of cancer. The disproportionately high cancer burden, as a consequence, is especially pronounced in Central and Eastern European countries, including Hungary. Methods: We summarized current and projected future cancer incidences and mortalities utilizing data from the last two decades. Predictions are based on cancer incidence and mortality collected between 1996 and 2015 in Hungary. In addition to the crude rates, data were age standardized to the European standard population (ESP) of 2013, ESP of 1976, and local census of 2011. Results: The lifetime probability of developing cancer and cancer-related mortality has already reached 56.9% and 27.6% in men, respectively, and 51.9% and 21.7% in women. Between 2016 and 2030, the total population is expected to shrink by 6%, while the number of 60-year olds and above will grow by 18%. This will lead to a 35% increase in cancer incidence and 30% increase in cancer death among 65-85-year olds. Joinpoint regression identified the period 2007-2015 as starting point for this coming increase in new cases. In women, lung and breast cancer will increase yearly by 1.9% and 1.7%, respectively, between 2016 and 2030, while in men, the prostate and colorectal cancer rates will increase yearly by 3.6% and 2.1%. Conclusion: In the aging population of Hungary, cancer incidence will increase considerably over previous projections. Although a large portion of the most rapidly rising cancers are avoidable by implementing public health programs, a substantial portion remains inevitably incurable.
Royal Society Open Science, Dec 1, 2018
Computational and structural biotechnology journal, 2021
While cost-effective high-throughput technologies provide an increasing amount of data, the analy... more While cost-effective high-throughput technologies provide an increasing amount of data, the analyses of single layers of data seldom provide causal relations. Multi-omics data integration strategies across different cellular function levels, including genomes, epigenomes, transcriptomes, proteomes, metabolomes, and microbiomes offer unparalleled opportunities to understand the underlying biology of complex diseases, such as cancer. We review some of the most frequently used data integration methods and outline research areas where multi-omics significantly benefit our understanding of the process and outcome of the malignant transformation. We discuss algorithmic frameworks developed to reveal cancer subtypes, disease mechanisms, and methods for identifying driver genomic alterations and consider the significance of multi-omics in tumor classifications, diagnostics, and prognostications. We provide a comprehensive summary of each omics strategy's most recent advances within the clinical context and discuss the main challenges facing their clinical implementations. Despite its unparalleled advantages, multi-omics data integration is slow to enter everyday clinics. One major obstacle is the uneven maturity of different omics approaches and the growing gap between generating large volumes of data compared to data processing capacity. Progressive initiatives to enforce the standardization of sample processing and analytical pipelines, multidisciplinary training of experts for data analysis and interpretation are vital to facilitate the translatability of theoretical findings.
Preserved correlation matrices pinpoint extracellular matrix organization as a critical factor in pancreatic ductal adenocarcinoma
F1000Research, Apr 18, 2023
Orvosi Hetilap
Az újgenerációs szekvenáláson (NGS) alapuló diagnosztika legnagyobb előnye, hogy nagyszámú gén pá... more Az újgenerációs szekvenáláson (NGS) alapuló diagnosztika legnagyobb előnye, hogy nagyszámú gén párhuzamos szekvenálása révén a genetikai rendellenességek kiterjedt repertoárját képes egyetlen vizsgálattal lefedni. Az analízis viszonylag kisebb költsége és az adatmennyiség kezelhetőbb mennyisége folytán a célzott génpanelek használata, illetve a teljesexom-szekvenálás (WES) a leginkább elérhető NGS-alapú módszer. Összefoglalónkban az NGS létjogosultságát vizsgáljuk gyermekkori genetikai rendellenességek diagnosztikájában. Áttekintjük az öröklött anyagcserezavarok, daganatos megbetegedések és egyéb gyermekkori genetikai rendellenességek NGS-alapú diagnosztikájában fontos szerepet játszó géneket. A kora gyermekkori rendellenességek NGS-alapú diagnosztikájának rutinszerű használata előtt számos technikai és klinikai kérdés vár még megválaszolásra. Jelenleg a legnagyobb kihívást a ritka genetikai variánsok értelmezése és a mutációk patogenitásának igazolása jelenti. Orv Hetil. 2022; 163(...
Cancer and Metastasis Reviews, 2020
Medulloblastoma (MB) is the most common malignant childhood tumor of the brain. Multimodal treatm... more Medulloblastoma (MB) is the most common malignant childhood tumor of the brain. Multimodal treatment consisting of surgery, radiation therapy, and chemotherapy reduced cumulative incidence of late mortality but increased the incidence of subsequent neoplasms and severe, incapacitating chronic health conditions. Present treatment strategies fail to recognize heterogeneity within patients despite wide divergence in individual responses. The persistent mortality rates and serious side effects of non-targeted cytotoxic therapies indicate a need for more refined therapeutic approaches. Advanced genomic research has led to the accumulation of an enormous amount of genetic information and resulted in a consensus distinguishing four molecular subgroups, WNT-activated, SHH-activated, and Group 3 and 4 medulloblastomas. These have distinct origin, demographics, molecular alterations, and clinical outcomes. Although subgroup affiliation does not predict response to therapy, new subgroup-specif...
Journal of Hematology & Oncology, 2019
Childhood medulloblastomas (MB) are heterogeneous and are divided into four molecular subgroups. ... more Childhood medulloblastomas (MB) are heterogeneous and are divided into four molecular subgroups. The provisional non-wingless-activated (WNT)/non-sonic hedgehog-activated (SHH) category combining group 3 and group 4 represents over two thirds of all MBs, coupled with the highest rates of metastases and least understood pathology. The molecular era expanded our knowledge about molecular aberrations involved in MB tumorigenesis, and here, we review processes leading to non-WNT/non-SHH MB formations. The heterogeneous group 3 and group 4 MBs frequently harbor rare individual genetic alterations, yet the emerging profiles suggest that infrequent events converge on common, potentially targetable signaling pathways. A mutual theme is the altered epigenetic regulation, and in vitro approaches targeting epigenetic machinery are promising. Growing evidence indicates the presence of an intermediate, mixed signature group along group 3 and group 4, and future clarifications are imperative for concordant classification, as misidentifying patient samples has serious implications for therapy and clinical trials. To subdue the high MB mortality, we need to discern mechanisms of disease spread and recurrence. Current preclinical models do not represent the full scale of group 3 and group 4 heterogeneity: all of existing group 3 cell lines are MYC-amplified and most mouse models resemble MYC-activated MBs. Clinical samples provide a wealth of information about the genetic divergence between primary tumors and metastatic clones, but recurrent MBs are rarely resected. Molecularly stratified treatment options are limited, and targeted therapies are still in preclinical development. Attacking these aggressive tumors at multiple frontiers will be needed to improve stagnant survival rates.
PLOS ONE, Jun 9, 2021
Scientists from nearly all disciplines face the problem of simultaneously evaluating many hypothe... more Scientists from nearly all disciplines face the problem of simultaneously evaluating many hypotheses. Conducting multiple comparisons increases the likelihood that a non-negligible proportion of associations will be false positives, clouding real discoveries. Drawing valid conclusions require taking into account the number of performed statistical tests and adjusting the statistical confidence measures. Several strategies exist to overcome the problem of multiple hypothesis testing. We aim to summarize critical statistical concepts and widely used correction approaches while also draw attention to frequently misinterpreted notions of statistical inference. We provide a step-by-step description of each multiple-testing correction method with clear examples and present an easy-to-follow guide for selecting the most suitable correction technique. To facilitate multiple-testing corrections, we developed a fully automated solution not requiring programming skills or the use of a command line. Our registration free online tool is available at www.multipletesting.com and compiles the five most frequently used adjustment tools, including the Bonferroni, the Holm (step-down), the Hochberg (step-up) corrections, allows to calculate False Discovery Rates (FDR) and q-values. The current summary provides a much needed practical synthesis of basic statistical concepts regarding multiple hypothesis testing in a comprehensible language with well-illustrated examples. The web tool will fill the gap for life science researchers by providing a user-friendly substitute for command-line alternatives.
Pogány, Á., Dijk, R., Menyhárt, O., Miklósi, Á., Devoogd, T., Székely, T. (2013): Acoustic Signal... more Pogány, Á., Dijk, R., Menyhárt, O., Miklósi, Á., Devoogd, T., Székely, T. (2013): Acoustic Signalling In Eurasian Penduline Tits Remiz Pendulinus: Repertoire Size Signals Male Nest Defence. Acta Zoologica Academiae Scientiarum Hungaricae 59 (1): 81-96, DOI: http://doi.org/10.5281/zenodo.5736131
MOESM3 of The prognostic association of SPAG5 gene expression in breast cancer patients with systematic therapy
Additional file 3: Table S1. Datasets used for the analysis. Table S2. SPAG5 expression in all br... more Additional file 3: Table S1. Datasets used for the analysis. Table S2. SPAG5 expression in all breast cancer patients with different subtypes. Table S3. The comparison of gene expression level using Mann-Whitney U test or Kruskal-Wallis test. Table S4. The comparison and correlation of SPAG5 with other markers of progression in assessing independent value. Table S5. Subgroup analyses of SPAG5 gene in association with RFS in ER+/- breast cancer subtype.
MOESM2 of The prognostic association of SPAG5 gene expression in breast cancer patients with systematic therapy
Additional file 2: Figure S2. Survival curves for the ER+ and ER- breast cancer subset. A. ER+ br... more Additional file 2: Figure S2. Survival curves for the ER+ and ER- breast cancer subset. A. ER+ breast cancer patients; B. ER- breast cancer patients.
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Papers by Otilia Menyhart