Publications by authors named "Otilia Menyhart"

21 Publications

  • Page 1 of 1

Gene expression-based biomarkers designating glioblastomas resistant to multiple treatment strategies.

Carcinogenesis 2021 Mar 23. Epub 2021 Mar 23.

Semmelweis University, Department of Bioinformatics and 2ndDepartment of Pediatrics, Budapest, Hungary.

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 post-surgery. 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 three 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/carcin/bgab024DOI Listing
March 2021

Multi-omics approaches in cancer research with applications in tumor subtyping, prognosis, and diagnosis.

Comput Struct Biotechnol J 2021 22;19:949-960. Epub 2021 Jan 22.

Semmelweis University, Department of Bioinformatics and 2 Department of Pediatrics, H-1094 Budapest, Hungary.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.csbj.2021.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868685PMC
January 2021

Molecular stratifications, biomarker candidates and new therapeutic options in current medulloblastoma treatment approaches.

Cancer Metastasis Rev 2020 03;39(1):211-233

2nd Department of Pediatrics and Department of Bioinformatics, Semmelweis University, Budapest, Hungary.

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-specific markers of prognosis can enable a more layered risk stratification with additional subtypes within each primary subgroup. Here, we summarize subgroup-specific genetic alterations and their utility in current treatment strategies. The transition toward molecularly targeted interventions for newly diagnosed MBs remains slow, and prospective trials are needed to confirm stratifications based on molecular alterations. At the same time, numerous studies focus at fine-tuning the intensity of invasive radio- and chemotherapies to reduce intervention-related long-term morbidity. There are an increasing number of immunotherapy-based treatment strategies including immune checkpoint-inhibitors, oncolytic viruses, CAR-T therapy, and NK cells in recurrent and refractory MBs. Although most trials are in early phase, there is hope for therapeutic breakthroughs for advanced MBs within the next decade.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10555-020-09854-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098941PMC
March 2020

[Subgroup-specific genomic alterations and potential prognostic biomarkers in childhood medulloblastomas].

Magy Onkol 2019 Dec 19;63(4):331-345. Epub 2019 Nov 19.

Lendület Onkológiai Biomarker Kutatócsoport, Természettudományi Kutatóközpont, Budapest, Hungary.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2019

The prognostic association of SPAG5 gene expression in breast cancer patients with systematic therapy.

BMC Cancer 2019 Nov 5;19(1):1046. Epub 2019 Nov 5.

Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210009, Jiangsu, China.

Background: Despite much effort on the treatment of breast cancer over the decades, a great uncertainty regarding the appropriate molecular biomarkers and optimal therapeutic strategy still exists. This research was performed to analyze the association of SPAG5 gene expression with clinicopathological factors and survival outcomes.

Methods: We used a breast cancer database including 5667 patients with a mean follow-up of 69 months. Kaplan-Meier survival analyses for relapse free survival (RFS), overall survival (OS), and distant metastasis-free survival (DMFS) were performed. In addition, ROC analysis was performed to validate SPAG5 as a prognostic candidate gene.

Results: Mean SPAG5 expression value was significantly higher with some clinicopathological factors that resulted in tumor promotion and progression, including poor differentiated type, HER2 positive or TP53 mutated breast cancer. Based on ROC-analysis SPAG 5 is a suitable prognostic marker of poor survival. In patients who received chemotherapy alone, SPAG5 had only a moderate and not significant predictive impact on survival outcomes. However, in hormonal therapy, high SPAG5 expression could strongly predict prognosis with detrimental RFS (HR = 1.57, 95% CI 1.2-2.06, p = 0.001), OS (HR = 2, 95% CI 1.05-3.8, p = 0.03) and DMFS (HR = 2.36, 95% CI 1.57-3.54, p <  0.001), respectively. In addition, SPAG5 could only serve as a survival predictor in ER+, but not ER- breast cancer patients. Patients might also be at an increased risk of relapse despite being diagnosed with a lower grade cancer (well differentiated type).

Conclusions: SPAG5 could be used as an independent prognostic and predictive biomarker that might have clinical utility, especially in ER+ breast cancer patients who received hormonal therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-019-6260-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833211PMC
November 2019

Uncovering Potential Therapeutic Targets in Colorectal Cancer by Deciphering Mutational Status and Expression of Druggable Oncogenes.

Cancers (Basel) 2019 Jul 14;11(7). Epub 2019 Jul 14.

2nd Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, H-1094 Budapest, Hungary.

Background: Numerous driver mutations have been identified in colorectal cancer (CRC), but their relevance to the development of targeted therapies remains elusive. The secondary effects of pathogenic driver mutations on downstream signaling pathways offer a potential approach for the identification of therapeutic targets. We aimed to identify differentially expressed genes as potential drug targets linked to driver mutations.

Methods: Somatic mutations and the gene expression data of 582 CRC patients were utilized, incorporating the mutational status of 39,916 and the expression levels of 20,500 genes. To uncover candidate targets, the expression levels of various genes in wild-type and mutant cases for the most frequent disruptive mutations were compared with a Mann-Whitney test. A survival analysis was performed in 2100 patients with transcriptomic gene expression data. Up-regulated genes associated with worse survival were filtered for potentially actionable targets. The most significant hits were validated in an independent set of 171 CRC patients.

Results: Altogether, 426 disruptive mutation-associated upregulated genes were identified. Among these, 95 were linked to worse recurrence-free survival (RFS). Based on the druggability filter, 37 potentially actionable targets were revealed. We selected seven genes and validated their expression in 171 patient specimens. The best independently validated combinations were ( = 2.6 × 10) in mutated (7.7%) patients; ( = 1.6 × 10) in mutated (8.1%) patients; ( = 1.35 × 10) in mutated patients; ( = 2.6 × 10) in mutated (7.6%) patients, and ( = 7.1 × 10) in mutated (8.2%) patients.

Conclusions: The results uncovered potentially druggable genes in colorectal cancer. The identified mutations could enable future patient stratification for targeted therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11070983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679198PMC
July 2019

Gene Expression Indicates Altered Immune Modulation and Signaling Pathway Activation in Ovarian Cancer Patients Resistant to Topotecan.

Int J Mol Sci 2019 Jun 5;20(11). Epub 2019 Jun 5.

2nd Department of Pediatrics, Semmelweis University, Tűzoltó u. 7-9, H-1094 Budapest, Hungary.

Epithelial ovarian cancer (EOC) is one of the deadliest gynecological malignancies. Topotecan remains an essential tool in second-line therapy; even so, most patients develop resistance within a short period of time. We aimed to identify biomarkers of topotecan resistance by using gene expression signatures derived from patient specimens at surgery and available subsequent responses to therapy. Gene expression was collected for 1436 patients and 10,103 genes. Based on disease progression, patients were categorized as responders/nonresponders depending on their progression free survival (PFS) state at 9, 12, 15 and 18 months after surgery. For each gene, the median expression was compared between responders and nonresponders for two treatment regimens (chemotherapy including/excluding topotecan) with Mann-Whitney U test at each of the four different PFS cutoffs. Statistical significance was accepted in the case of < 0.05 with a fold change (FC) ≥ 1.44. Four genes (, , and ) were consistently overexpressed across multiple PFS cutoff times in initial tumor samples of patients with disease progression following topotecan treatment. A common theme linked to topotecan resistance was altered immune modulation. Genes associated with disease progression after systemic chemotherapy emphasize the role of the initial organization of the tumor microenvironment in therapy resistance. Our results uncover biomarkers with potential utility for patient stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20112750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600443PMC
June 2019

Principles of tumorigenesis and emerging molecular drivers of SHH-activated medulloblastomas.

Ann Clin Transl Neurol 2019 May 19;6(5):990-1005. Epub 2019 Mar 19.

2nd Department of Pediatrics Semmelweis University H-1094 Budapest Hungary.

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 event - the 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529984PMC
May 2019

Molecular markers and potential therapeutic targets in non-WNT/non-SHH (group 3 and group 4) medulloblastomas.

J Hematol Oncol 2019 03 15;12(1):29. Epub 2019 Mar 15.

2nd Department of Pediatrics, Semmelweis University, Tűzoltó u. 7-9, Budapest, H-1094, Hungary.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13045-019-0712-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420757PMC
March 2019

Mutations Defining Patient Cohorts With Elevated PD-L1 Expression in Gastric Cancer.

Front Pharmacol 2018 8;9:1522. Epub 2019 Jan 8.

2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.

The immunotherapy agent pembrolizumab has been approved for gastric cancer (GC) patients with recurrent or advanced disease who are PD-L1 positive. Mutations in the primary lesion may drive the expression of immune targets thereby priming the tumor to therapeutic sensitivity. In this study, we aimed to uncover mutations associated with elevated PD-L1 expression in GC patients. Data from 410 GC patients were available, including the mutational spectrum of 39,916 genes and expression values of 20,500 genes. PD-L1 gene expression was compared to the mutational status of each gene separately by using a Mann-Whitney -test and a Receiver Operating Characteristic test. Only mutations with a prevalence over 5% were considered. Significance was accepted in cases of < 1E-05 and a fold change over 1.44. Mutations in 209 genes were associated with increased PD-L1 expression. These mutations were enriched in genes related to microtubule-based movement ( = 3.4E-4), cell adhesion ( = 4.9E-4), response to DNA-damage ( = 6.9E-4), and double-strand break-repair ( = 1.6E-3). Mutations in ( = 8.8E-10, AUC = 0.77), ( = 2.0E-9, AUC = 0.74), ( = 2.5E-9, AUC = 0.75), and ( = 3.3E-9, AUC = 0.74) had the strongest link to elevated PD-L1 expression. Finally, we established a decision tree based on mutations in , and capable to separate patient sub-cohorts with elevated PD-L1 expression. In summary, we identified mutations associated with elevated PD-L1 expression that facilitate the development of better prognostic biomarkers for GC, and might offer insight into the underlying tumor biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2018.01522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331584PMC
January 2019

Determining consistent prognostic biomarkers of overall survival and vascular invasion in hepatocellular carcinoma.

R Soc Open Sci 2018 Dec 5;5(12):181006. Epub 2018 Dec 5.

2nd Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary.

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. The literature search yielded 318 genes related to survival and 52 related to vascular invasion. Validation was performed in three datasets (RNA-seq, = 371; Affymetrix arrays, = 91; Illumina gene chips, = 135) by uni- and multivariate Cox regression and Mann-Whitney -test, separately for Asian and Caucasian patients. One hundred and eighty biomarkers remained significant in Asian and 128 in Caucasian subjects at < 0.05. After multiple testing correction ( = 1.9 × 10), ( = 2.5 × 10) and ( = 3 × 10) 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 ( = 0.0018) and expression of ( = 0.0038) and ( = 0.038). was the only gene predicting vascular invasion in the Affymetrix and Illumina cohorts ( = 0.003 and = 0.025, respectively). 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1098/rsos.181006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304123PMC
December 2018

Demographic shift disproportionately increases cancer burden in an aging nation: current and expected incidence and mortality in Hungary up to 2030.

Clin Epidemiol 2018 29;10:1093-1108. Epub 2018 Aug 29.

MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary,

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/CLEP.S155063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121756PMC
August 2018

Author Correction: Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets.

Sci Rep 2018 Jul 26;8(1):11515. Epub 2018 Jul 26.

MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Magyar Tudósok körútja 2, 1117, Budapest, Hungary.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-29514-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060132PMC
July 2018

Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets.

Sci Rep 2018 06 15;8(1):9227. Epub 2018 Jun 15.

MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Magyar Tudósok körútja 2, 1117, Budapest, Hungary.

Multiple studies suggested using different miRNAs as biomarkers for prognosis of hepatocellular carcinoma (HCC). We aimed to assemble a miRNA expression database from independent datasets to enable an independent validation of previously published prognostic biomarkers of HCC. A miRNA expression database was established by searching the TCGA (RNA-seq) and GEO (microarray) repositories to identify miRNA datasets with available expression and clinical data. A PubMed search was performed to identify prognostic miRNAs for HCC. We performed a uni- and multivariate Cox regression analysis to validate the prognostic significance of these miRNAs. The Limma R package was applied to compare the expression of miRNAs between tumor and normal tissues. We uncovered 214 publications containing 223 miRNAs identified as potential prognostic biomarkers for HCC. In the survival analysis, the expression levels of 55 and 84 miRNAs were significantly correlated with overall survival in RNA-seq and gene chip datasets, respectively. The most significant miRNAs were hsa-miR-149, hsa-miR-139, and hsa-miR-3677 in the RNA-seq and hsa-miR-146b-3p, hsa-miR-584, and hsa-miR-31 in the microarray dataset. Of the 223 miRNAs studied, the expression was significantly altered in 102 miRNAs in tumors compared to normal liver tissues. In summary, we set up an integrated miRNA expression database and validated prognostic miRNAs in HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-27521-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003936PMC
June 2018

DUSP4 is associated with increased resistance against anti-HER2 therapy in breast cancer.

Oncotarget 2017 Sep 24;8(44):77207-77218. Epub 2017 Aug 24.

Semmelweis University 2nd Department of Pediatrics, Budapest, Hungary.

The majority of patients develop resistance against suppression of HER2-signaling mediated 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. Using 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 restricted to markers significantly associated with worse survival. Functional significance of the two strongest predictive markers was evaluated by gene silencing in HER2 overexpressing, trastuzumab resistant BC cell lines SKTR and JIMT-1. The strongest predictive MKPs were DUSP4/MKP-2 (AUC=0.75, =0.0096) and DUSP6/MKP-3 (AUC=0.77, =5.29E-05). Higher expression for these correlated to worse survival (DUSP4: HR=2.05, =0.009 and DUSP6: HR=2, =0.0015). Silencing of DUSP4 had significant sensitization effects - viability of DUSP4 siRNA transfected, trastuzumab treated cells decreased significantly compared to scramble-siRNA transfected controls (SKTR: =0.016; JIMT-1: =0.016). In contrast, simultaneous treatment with DUSP6 siRNA and trastuzumab did not alter cell proliferation. Our findings suggest that DUSP4 may represent a new potential target to overcome trastuzumab resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.20430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652774PMC
September 2017

Propagation on Molecular Interaction Networks: Prediction of Effective Drug Combinations and Biomarkers in Cancer Treatment.

Curr Pharm Des 2017 ;23(1):5-28

Faculty of Information Technology, Pázmány Péter Catholic University 1083 Budapest, Práter str. 50/A, Budapest, Hungary.

Background: Biomedical sciences use a variety of data sources on drug molecules, genes, proteins, diseases and scientific publications etc. This system can be best pictured as a giant data-network linked together by physical, functional, logical and similarity relationships. A new hypothesis or discovery can be considered as a new link that can be deduced from the existing connections. For instance, interactions of two pharmacons - if not already known - represent a testable novel hypothesis. Such implicit effects are especially important in complex diseases such as cancer.

Methods: The method we applied was to test whether novel drug combinations or novel biomarkers can be predicted from a network of existing oncological databases. We start from the hypothesis that novel, implicit links can be discovered between the network neighborhoods of data items.

Results: We showed that the overlap of network neighborhoods is strongly correlated with the pairwise interaction strength of two pharmacons used in cancer therapy, and it is also well correlated with clinical data. In a second case study we employed this strategy to the discovery of novel biomarkers based on text analysis. In 2012 we prioritized 10 potential biomarkers for ovarian cancers, 2 of which were in fact described as such in the subsequent years.

Conclusion: The strategy seems to hold promises for prioritizing new drug combinations or new biomarkers for experimental testing. Its use is naturally limited by the sparsity and the quality of experimental data, however both of these aspects are expected to improve given the development of current databases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1381612822666161021162727DOI Listing
January 2018

Guidelines for the selection of functional assays to evaluate the hallmarks of cancer.

Biochim Biophys Acta 2016 12 11;1866(2):300-319. Epub 2016 Oct 11.

MTA TTK Lendület Cancer Biomarker Research Group, Magyar tudósok körútja 2, H-1117 Budapest, Hungary; 2nd Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary. Electronic address:

The hallmarks of cancer capture the most essential phenotypic characteristics of malignant transformation and progression. Although numerous factors involved in this multi-step process are still unknown to date, an ever-increasing number of mutated/altered candidate genes are being identified within large-scale cancer genomic projects. Therefore, investigators need to be aware of available and appropriate techniques capable of determining characteristic features of each hallmark. We review the methods tailored to experimental cancer researchers to evaluate cell proliferation, programmed cell death, replicative immortality, induction of angiogenesis, invasion and metastasis, genome instability, and reprogramming of energy metabolism. Selecting the ideal method is based on the investigator's goals, available equipment and also on financial constraints. Multiplexing strategies enable a more in-depth data collection from a single experiment - obtaining several results from a single procedure reduces variability and saves time and relative cost, leading to more robust conclusions compared to a single end point measurement. Each hallmark possesses characteristics that can be analyzed by immunoblot, RT-PCR, immunocytochemistry, immunoprecipitation, RNA microarray or RNA-seq. In general, flow cytometry, fluorescence microscopy, and multiwell readers are extremely versatile tools and, with proper sample preparation, allow the detection of a vast number of hallmark features. Finally, we also provide a list of hallmark-specific genes to be measured in transcriptome-level studies. Although our list is not exhaustive, we provide a snapshot of the most widely used methods, with an emphasis on methods enabling the simultaneous evaluation of multiple hallmark features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbcan.2016.10.002DOI Listing
December 2016

HOXC10 Expression Supports the Development of Chemotherapy Resistance by Fine Tuning DNA Repair in Breast Cancer Cells.

Cancer Res 2016 08 14;76(15):4443-56. Epub 2016 Jun 14.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Development of drug resistance is a major factor limiting the continued success of cancer chemotherapy. To overcome drug resistance, understanding the underlying mechanism(s) is essential. We found that HOXC10 is overexpressed in primary carcinomas of the breast, and even more significantly in distant metastasis arising after failed chemotherapy. High HOXC10 expression correlates with shorter recurrence-free and overall survival in patients with estrogen receptor-negative breast cancer undergoing chemotherapy. We found that HOXC10 promotes survival in cells treated with doxorubicin, paclitaxel, or carboplatin by suppressing apoptosis and upregulating NF-κB Overexpressed HOXC10 increases S-phase-specific DNA damage repair by homologous recombination (HR) and checkpoint recovery in cells at three important phases. For double-strand break repair, HOXC10 recruits HR proteins at sites of DNA damage. It enhances resection and lastly, it resolves stalled replication forks, leading to initiation of DNA replication following DNA damage. We show that HOXC10 facilitates, but is not directly involved in DNA damage repair mediated by HR. HOXC10 achieves integration of these functions by binding to, and activating cyclin-dependent kinase, CDK7, which regulates transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II. Consistent with these findings, inhibitors of CDK7 reverse HOXC10-mediated drug resistance in cultured cells. Blocking HOXC10 function, therefore, presents a promising new strategy to overcome chemotherapy resistance in breast cancer. Cancer Res; 76(15); 4443-56. ©2016 AACR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-16-0774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970943PMC
August 2016

A Comprehensive Outline of Trastuzumab Resistance Biomarkers in HER2 Overexpressing Breast Cancer.

Curr Cancer Drug Targets 2015 ;15(8):665-83

MTA TTK Lendület Cancer Biomarker Research Group, Magyar Tudosok Korutja 2, H-1117 Budapest, Hungary.

The introduction of trastuzumab for anti-HER2 therapy dramatically changed the clinical outcome for HER2 (ERBB2, neu) positive breast cancer patients. Today, patients eligible for trastuzumab are selected using HER2 expression/amplification status of the primary tumor. However, acquired and inherent resistance to anti-HER2 therapy in these patients poses a significant challenge, and better patient stratification will be needed to improve clinical response. Here, we provide a wide-ranging overview of potential biomarkers capable of stratifying patients regarding their response to trastuzumab. These include HER2 amplification, impaired access to the binding site (p95HER2, Δ16HER-2, MUC4), augmented signaling through other ERBB family receptors (HER1, HER3, HER4) and their ligands, activation of HER2 targets by alternate heterodimers (EphA2, IGF-1R, GDF15, MUC1*), signaling triggered by downstream members (PIK3CA, PTEN, SRC, mTOR), altered expression of cell cycle and apoptotic regulators (CDKs, p27(kip1), Bcl-2), hormone receptor status, resistance to antibody-dependent cellular cytotoxicity (FcγR), and altered miRNA expression signatures. Multigenic molecular profile analyses have revealed further genes not directly associated with classical oncogenic pathways. Although numerous biomarkers have shown promise in pre-clinical studies, many have delivered controversial results when evaluated in clinical trials. One of the keys for targeting ERBB2 will be to consider the entire ERBB family and downstream associated pathways responsible for the malignant transformation. The heterogeneity of the disease is likely to represent a significant obstacle to accurately predicting the course of resistance. The future most probably involves the incorporation of multiple biomarkers into a unified predictor enabling selection of patients for superior targeted drug administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/156800961508151001101742DOI Listing
July 2016

Juvenile zebra finches learn the underlying structural regularities of their fathers' song.

Front Psychol 2015 8;6:571. Epub 2015 May 8.

Department of Psychology, Cornell University, Ithaca, NY USA.

Natural behaviors, such as foraging, tool use, social interaction, birdsong, and language, exhibit branching sequential structure. Such structure should be learnable if it can be inferred from the statistics of early experience. We report that juvenile zebra finches learn such sequential structure in song. Song learning in finches has been extensively studied, and it is generally believed that young males acquire song by imitating tutors (Zann, 1996). Variability in the order of elements in an individual's mature song occurs, but the degree to which variation in a zebra finch's song follows statistical regularities has not been quantified, as it has typically been dismissed as production error (Sturdy et al., 1999). Allowing for the possibility that such variation in song is non-random and learnable, we applied a novel analytical approach, based on graph-structured finite-state grammars, to each individual's full corpus of renditions of songs. This method does not assume syllable-level correspondence between individuals. We find that song variation can be described by probabilistic finite-state graph grammars that are individually distinct, and that the graphs of juveniles are more similar to those of their fathers than to those of other adult males. This grammatical learning is a new parallel between birdsong and language. Our method can be applied across species and contexts to analyze complex variable learned behaviors, as distinct as foraging, tool use, and language.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyg.2015.00571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424812PMC
May 2015

Gene expression-based prognostic and predictive tools in breast cancer.

Breast Cancer 2015 May 10;22(3):245-52. Epub 2015 Feb 10.

MTA-SE Pediatrics and Nephrology Research Group, Semmelweis University, Bókay u. 53, Budapest, 1083, Hungary,

Genomic assays measuring the expression of multiple genes have made their way into clinical practice and their utilization is now recommended by major international guidelines. A basic property of these tests is their capability to sub-divide patients into high- and low-risk cohorts thereby providing prognostic, and in certain settings, predictive decision support. Here, we summarize commercially available assays for breast cancer including RT-PCR and gene chip-based tests. Given the relative uncertainty in cancer treatment, multigene tests have the potential for a significant cost reduction as they can pinpoint those patients for whom chemotherapy proves to be unnecessary. However, concordance of risk assessment for an individual patient is still far from optimal. Additionally, emerging multigene approaches focus on predicting therapy response, which is a black spot of current tests. Promising techniques include the homologous recombination deficiency score, utilization of massive parallel sequencing to identify driver genes, employment of internet-based meta-analysis tools and investigation of miRNA expression signatures. Combination of multiple simultaneous analyses at diagnosis, including classical histopathological diagnostics, monogenic markers, genomic signatures and clinical parameters will most likely bring maximal benefit for patients. As the main driving force behind such genomic tests is the power to achieve cost reduction due to avoiding unnecessary systemic treatment, the future is most likely to hold a further proliferation of such assays.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12282-015-0594-yDOI Listing
May 2015