Publications by authors named "Balázs Győrffy"

282 Publications

A bioinformatic analysis of the inhibin-betaglycan-endoglin/CD105 network reveals prognostic value in multiple solid tumors.

PLoS One 2021 5;16(4):e0249558. Epub 2021 Apr 5.

Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

Inhibins and activins are dimeric ligands belonging to the TGFβ superfamily with emergent roles in cancer. Inhibins contain an α-subunit (INHA) and a β-subunit (either INHBA or INHBB), while activins are mainly homodimers of either βA (INHBA) or βB (INHBB) subunits. Inhibins are biomarkers in a subset of cancers and utilize the coreceptors betaglycan (TGFBR3) and endoglin (ENG) for physiological or pathological outcomes. Given the array of prior reports on inhibin, activin and the coreceptors in cancer, this study aims to provide a comprehensive analysis, assessing their functional prognostic potential in cancer using a bioinformatics approach. We identify cancer cell lines and cancer types most dependent and impacted, which included p53 mutated breast and ovarian cancers and lung adenocarcinomas. Moreover, INHA itself was dependent on TGFBR3 and ENG/CD105 in multiple cancer types. INHA, INHBA, TGFBR3, and ENG also predicted patients' response to anthracycline and taxane therapy in luminal A breast cancers. We also obtained a gene signature model that could accurately classify 96.7% of the cases based on outcomes. Lastly, we cross-compared gene correlations revealing INHA dependency to TGFBR3 or ENG influencing different pathways themselves. These results suggest that inhibins are particularly important in a subset of cancers depending on the coreceptor TGFBR3 and ENG and are of substantial prognostic value, thereby warranting further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249558PLOS
April 2021

TNMplot.com: A Web Tool for the Comparison of Gene Expression in Normal, Tumor and Metastatic Tissues.

Int J Mol Sci 2021 Mar 5;22(5). Epub 2021 Mar 5.

Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary.

Genes showing higher expression in either tumor or metastatic tissues can help in better understanding tumor formation and can serve as biomarkers of progression or as potential therapy targets. Our goal was to establish an integrated database using available transcriptome-level datasets and to create a web platform which enables the mining of this database by comparing normal, tumor and metastatic data across all genes in real time. We utilized data generated by either gene arrays from the Gene Expression Omnibus of the National Center for Biotechnology Information (NCBI-GEO) or RNA-seq from The Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and The Genotype-Tissue Expression (GTEx) repositories. The altered expression within different platforms was analyzed separately. Statistical significance was computed using Mann-Whitney or Kruskal-Wallis tests. False Discovery Rate (FDR) was computed using the Benjamini-Hochberg method. The entire database contains 56,938 samples, including 33,520 samples from 3180 gene chip-based studies (453 metastatic, 29,376 tumorous and 3691 normal samples), 11,010 samples from TCGA (394 metastatic, 9886 tumorous and 730 normal), 1193 samples from TARGET (1 metastatic, 1180 tumorous and 12 normal) and 11,215 normal samples from GTEx. The most consistently upregulated genes across multiple tumor types were TOP2A (FC = 7.8), SPP1 (FC = 7.0) and CENPA (FC = 6.03), and the most consistently downregulated gene was ADH1B (FC = 0.15). Validation of differential expression using equally sized training and test sets confirmed the reliability of the database in breast, colon, and lung cancer at an FDR below 10%. The online analysis platform enables unrestricted mining of the database and is accessible at TNMplot.com.
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http://dx.doi.org/10.3390/ijms22052622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961455PMC
March 2021

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

Prognostic impact of the glypican family of heparan sulfate proteoglycans on the survival of breast cancer patients.

J Cancer Res Clin Oncol 2021 Mar 19. Epub 2021 Mar 19.

Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, 11, 48149, Münster, Germany.

Purpose: Dysregulated expression of proteoglycans influences the outcome and progression of numerous cancers. Several studies have investigated the role of individual glypicans in cancer, however, the impact of the whole glypican family of heparan sulfate proteoglycans on prognosis of a large patient cohort of breast cancer patients has not yet been investigated. In the present study, our aim was to investigate the prognostic power of the glypicans in breast cancer patients.

Methods: We used a public database including both gene expression data and survival information for 3951 breast cancer patients to determine the prognostic value of glypicans on relapse-free survival using Cox regression analysis. Moreover, we performed quantitative Real-Time PCR to determine glypican gene expression levels in seven representative breast cancer cell lines.

Results: We found that high GPC3 levels were associated with a better prognosis in overall breast cancer patients. When stratified by hormone receptor status, we found that in worse prognosis subtypes low GPC1 levels correlate with a longer relapse-free survival, and in more favorable subtypes low GPC6 was associated with longer survival.

Conclusion: Our study concludes that glypicans could act as subtype-specific biomarkers for the prognosis of breast cancer patients and sparks hope for future research on glypicans possibly eventually providing targets for the treatment of the disease.
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http://dx.doi.org/10.1007/s00432-021-03597-4DOI Listing
March 2021

Pancancer survival analysis of cancer hallmark genes.

Sci Rep 2021 Mar 15;11(1):6047. Epub 2021 Mar 15.

Department of Bioinformatics, Semmelweis University, Tüzoltó u. 7-9, 1094, Budapest, Hungary.

Cancer hallmark genes are responsible for the most essential phenotypic characteristics of malignant transformation and progression. In this study, our aim was to estimate the prognostic effect of the established cancer hallmark genes in multiple distinct cancer types. RNA-seq HTSeq counts and survival data from 26 different tumor types were acquired from the TCGA repository. DESeq was used for normalization. Correlations between gene expression and survival were computed using the Cox proportional hazards regression and by plotting Kaplan-Meier survival plots. The false discovery rate was calculated to correct for multiple hypothesis testing. Signatures based on genes involved in genome instability and invasion reached significance in most individual cancer types. Thyroid and glioblastoma were independent of hallmark genes (61 and 54 genes significant, respectively), while renal clear cell cancer and low grade gliomas harbored the most prognostic changes (403 and 419 genes significant, respectively). The eight genes with the highest significance included BRCA1 (genome instability, HR 4.26, p < 1E-16), RUNX1 (sustaining proliferative signaling, HR 2.96, p = 3.1E-10) and SERPINE1 (inducing angiogenesis, HR 3.36, p = 1.5E-12) in low grade glioma, CDK1 (cell death resistance, HR = 5.67, p = 2.1E-10) in kidney papillary carcinoma, E2F1 (tumor suppressor, HR 0.38, p = 2.4E-05) and EREG (enabling replicative immortality, HR 3.23, p = 2.1E-07) in cervical cancer, FBP1 (deregulation of cellular energetics, HR 0.45, p = 2.8E-07) in kidney renal clear cell carcinoma and MYC (invasion and metastasis, HR 1.81, p = 5.8E-05) in bladder cancer. We observed unexpected heterogeneity and tissue specificity when correlating cancer hallmark genes and survival. These results will help to prioritize future targeted therapy development in different types of solid tumors.
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http://dx.doi.org/10.1038/s41598-021-84787-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961001PMC
March 2021

Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer.

Cancers (Basel) 2021 Feb 17;13(4). Epub 2021 Feb 17.

Experimental Therapeutics Unit, Hospital Clínico Universitario San Carlos (HCSC), Instituto de Investigación Sanitaria San Carlos (IdISSC) and Centro de Investigación Biomédica en Red en Oncología (CIBERONC), 28040 Madrid, Spain.

The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis and drug resistance, particularly through their interplay with estrogen receptor signaling and DNA repair. Herein we explored genomic alterations in these processes using RNA-seq and mutation data from TCGA and METABRIC datasets, and analyzed them using a bioinformatic pipeline in search of those with prognostic and predictive capability which could qualify as subjects of drug research. Amplification of , , and conferred a worse prognosis in luminal A/B and basal-like tumors, luminal A/B tumors, and luminal A tumors, respectively. Higher expression levels were predictive of a lower rate of pathological complete response in triple negative breast cancer patients following neoadjuvant chemotherapy, whereas and expression was higher in luminal A patients with tumor relapse within 5 years of endocrine therapy or chemotherapy. The transcriptomic signatures of and gene mutations also conferred worse prognosis in luminal A, HER2-enriched, and basal-like tumors, and in luminal A tumors, respectively. In conclusion, we identified and characterized the clinical value of a group of genomic alterations in ubiquitination, SUMOylation, and neddylation enzymes, with potential for drug development in breast cancer.
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http://dx.doi.org/10.3390/cancers13040833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922122PMC
February 2021

The prognostic significance of FOXC2 gene expression in cancer: A comprehensive analysis of RNA-seq data from the cancer genome atlas.

Cancer Genet 2021 Jun 13;254-255:58-64. Epub 2021 Feb 13.

Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Brown Student Center, Box 837, Hampden-Sydney, VA 23943, USA.

The FOXC2 transcription factor is a key regulator of tumor progression in many cancer types. Known to exhibit an array of oncogenic functions when dysregulated, FOXC2 has emerged as a useful biomarker for predicting disease aggression and patient outcome. In this regard, increased expression and nuclear localization of FOXC2 protein in tumor tissue have become well-established as poor prognostic factors for many cancer types. However, whether FOXC2 gene expression can serve as a similarly useful RNA-level biomarker has remained largely unexplored. Therefore, we conducted a comprehensive analysis of TCGA RNA-seq data to evaluate whether FOXC2 gene expression levels in primary tumor biopsies correlate with patient outcome. We report herein that increased expression of FOXC2 RNA in tumor tissue is a poor prognostic factor for patient survival in many cancer types. Moreover, we also found that FOXC2 gene expression predicts cancer patient response to several commonly prescribed chemotherapeutics. Together, these data highlight FOXC2 RNA expression in tumor tissue as an important biomarker with prognostic significance for solid tumors of diverse origin.
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http://dx.doi.org/10.1016/j.cancergen.2021.02.005DOI Listing
June 2021

Identification of Neuronal Pentraxins as Synaptic Binding Partners of C1q and the Involvement of NP1 in Synaptic Pruning in Adult Mice.

Front Immunol 2020 8;11:599771. Epub 2021 Feb 8.

ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary.

Elements of the immune system particularly that of innate immunity, play important roles beyond their traditional tasks in host defense, including manifold roles in the nervous system. Complement-mediated synaptic pruning is essential in the developing and healthy functioning brain and becomes aberrant in neurodegenerative disorders. C1q, component of the classical complement pathway, plays a central role in tagging synapses for elimination; however, the underlying molecular mechanisms and interaction partners are mostly unknown. Neuronal pentraxins (NPs) are involved in synapse formation and plasticity, moreover, NP1 contributes to cell death and neurodegeneration under adverse conditions. Here, we investigated the potential interaction between C1q and NPs, and its role in microglial phagocytosis of synapses in adult mice. We verified that NPs interact with C1q, as well as activate the complement system. Flow cytometry, immunostaining and co-immunoprecipitation showed that synapse-bound C1q colocalizes and interacts with NPs. High-resolution confocal microscopy revealed that microglia-surrounded C1q-tagged synapses are NP1 positive. We have also observed the synaptic occurrence of C4 suggesting that activation of the classical pathway cannot be ruled out in synaptic plasticity in healthy adult animals. In summary, our results indicate that NPs play a regulatory role in the synaptic function of C1q. Whether this role can be intensified upon pathological conditions, such as in Alzheimer's disease, is to be disclosed.
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http://dx.doi.org/10.3389/fimmu.2020.599771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897678PMC
February 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.
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http://dx.doi.org/10.1016/j.csbj.2021.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868685PMC
January 2021

Complement-mediated hypersensitivity reactions to an amphotericin B-containing lipid complex (Abelcet) in pediatric patients and anesthetized rats: Benefits of slow infusion.

Nanomedicine 2021 Feb 5;34:102366. Epub 2021 Feb 5.

Institute of Translational Medicine, Semmelweis University, Budapest, Hungary; SeroScience LCC, Budapest, Hungary; Cancer Biomarker Research Group, Institute of Enzymology, Research Center for Natural Sciences, Budapest, Hungary; Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, Hungary. Electronic address:

Intravenous administration of lipid-based nanodrugs can cause hypersensitivity, also known as infusion reactions (IRs), that can be attenuated by slow infusion in adult patients. We studied the role of infusion rate and complement (C) activation in IRs in pediatric patients treated with Abelcet, and also in anesthetized rats. IRs were observed in 6 out of 10 (60%) patients who received Abelcet infusion in 4 h or less, while no patients who received the infusion in 6 h showed C activation or IRs. The rat model indicated an inverse relationship between infusion speed and Abelcet-induced hypotension, taken as an experimental endpoint of IRs, while the rise of C3a in blood, an index of C activation, directly correlated with hypotension. The results suggest that pediatric patients are more prone to produce IRs, and that the optimal infusion time of Abelcet may be much longer than the presently recommended 2 h.
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http://dx.doi.org/10.1016/j.nano.2021.102366DOI Listing
February 2021

In silico transcriptomic mapping of integrins and immune activation in Basal-like and HER2+ breast cancer.

Cell Oncol (Dordr) 2021 Jan 19. Epub 2021 Jan 19.

Experimental Therapeutics Unit, Medical Oncology Department, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria (IdISSC) and CIBERONC, Calle Del Prof Martín Lagos, s/n, 28040, Madrid, Spain.

Purpose: Integrins, transmembrane receptors that mediate cell-extracellular matrix and cell-cell interactions, have been linked to several cancer-associated features. A less explored function of integrins in cancer is their role in leukocyte homing and activation. Understanding their relationship with immune cell infiltrates and immune checkpoints is an area of interest in cancer research.

Methods: The expression of 33 different integrins was evaluated in relation with breast cancer patient outcome using transcriptomic data (Affymetrix dataset, exploratory cohort) and the METABRIC study (validation cohort). The TIMER online tool was used to assess the association of the identified integrin genes with immune cell infiltration, and the TCGA and METABRIC studies to assess correlations between integrin gene expression and genomic signatures of immune activation.

Results: We identified 7 genes coding for integrin α and β subunits, i.e., ITGA4, ITGB2, ITGAX, ITGB7, ITGAM, ITGAL and ITGA8, which predict a favorable prognosis in Basal-like and HER2+ breast cancers. Their expression positively correlated with the presence of immune cell infiltrates within the tumor (dendritic cells, CD4+ T-cells, neutrophils, CD8+ T-cells and B-cells), with markers of T-cell activation and antigen presentation, and with gene signatures of immune surveillance (cytotoxic T lymphocyte activation and IFN gamma signature). By contrast, we found that genes coding for integrins that predicted a detrimental outcome (IBSP, ITGB3BP, ITGB6, ITGB1 and ITGAV) were not associated with any of these parameters.

Conclusions: We identified an integrin signature composed of 7 genes with potential to recognize immune infiltrated and activated Basal-like and HER2+ breast cancers with a favorable prognosis.
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http://dx.doi.org/10.1007/s13402-020-00583-9DOI Listing
January 2021

Prognostic significance of hedgehog signaling network-related gene expression in breast cancer patients.

J Cell Biochem 2021 May 8;122(5):577-597. Epub 2021 Jan 8.

Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany.

Breast cancer continues to be a serious public health problem. The role of the hedgehog pathway in normal development of the mammary gland as well as in carcinogenesis and progression of breast cancer is the subject of intense investigation, revealing functional interactions with cell surface heparan sulfate. Nevertheless, its influence on breast cancer prognosis, and its relation to specific sulfation motifs in heparan sulfate have only been poorly studied in large patient cohorts. Using the public database KMplotter that includes gene expression and survival data of 3951 patients, we found that the higher expression of SHH, HHAT, PTCH1, GLI1, GLI2, and GLI3 positively influences breast cancer prognosis. Stratifying patients according to the expression of hormone receptors, histological grade, lymph node metastasis, and systemic therapy, we observed that GLI1, GLI2, and GLI3 expression, as well as co-expression of SHH and ELP1 were associated with worse relapse-free survival in patients with HER2-positive tumors. Moreover, GLI1 expression in progesterone receptor-negative tumors and GLI3 expression in grade 3 tumors correlated with poor prognosis. SHH, in a panel of cell lines representing different breast cancer subtypes, and HHAT, PTCH1, GLI1, GLI2, and GLI3 were mostly expressed in cell lines classified as HER2-positive and basal-like. Expression of SHH, HHAT, GLI2, and GLI3 was differentially affected by overexpression of the heparan sulfate sulfotransferases HS2ST1 and HS3ST2 in vitro. Although high HS2ST1 expression was associated with poor prognosis in KMplotter analysis, high levels of HS3ST2 were associated with a good prognosis, except for ER-positive breast cancer. We suggest the GLI transcription factors as possible markers for the diagnosis, treatment, and prognosis of breast cancer especially in HER2-positive tumors, but also in progesterone receptor-negative and grade-3 tumors. The pathway interaction and prognostic impact of specific heparan sulfate sulfotransferases provide novel perspectives regarding a therapeutical targeting of the hedgehog pathway in breast cancer.
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http://dx.doi.org/10.1002/jcb.29886DOI Listing
May 2021

miRNA Expression Signatures of Therapy Response in Squamous Cell Carcinomas.

Cancers (Basel) 2020 Dec 28;13(1). Epub 2020 Dec 28.

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

Introduction: Squamous cell carcinomas (SCC) are a major subgroup of malignant tumors with a platinum-based first-line systematic chemotherapy. miRNAs play a role in various diseases and modulate therapy response as well. The aim of this study was to identify predictive miRNAs in platinum-treated SCCs.

Methods: miRNA expression data of platinum-treated head and neck (HNSC), cervical (CESC) and lung (LUSC) cancer were collected from the TCGA repositories. Treatment response was defined based on presence or absence of disease progression at 18 months. Responder and nonresponder cohorts were compared using Mann-Whitney and Receiver Operating Characteristic tests. Logistic regression was developed to establish a predictive miRNA signature. Significance was set at FDR < 5%.

Results: The integrated database includes 266 SCC patient samples with platinum-based therapy and available follow-up. We uncovered 16, 103, and 9 miRNAs correlated to chemotherapy response in the CESC, HNSC, and LUSC cohorts, respectively. Eight miRNAs overlapped between the CESC and HNSC subgroups, and three miRNAs overlapped between the LUSC and HNSC subgroups. We established a logistic regression model in HNSC and CESC which included six miRNAs: hsa-miR-5586 (Exp (B): 2.94, = 0.001), hsa-miR-632 (Exp (B): 10.75, = 0.002), hsa-miR-2355 (Exp (B): 0.48, = 0.004), hsa-miR-642a (Exp (B): 2.22, = 0.01), hsa-miR-101-2 (Exp (B): 0.39, = 0.013) and hsa-miR-6728 (Exp (B): 0.21, = 0.016). The model using these miRNAs was able to predict chemotherapy resistance with an AUC of 0.897.

Conclusions: We performed an analysis of RNA-seq data of squamous cell carcinomas samples and identified significant miRNAs correlated to the response against platinum-based therapy in cervical, head and neck, and lung tumors.
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http://dx.doi.org/10.3390/cancers13010063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794682PMC
December 2020

Different mutations in SARS-CoV-2 associate with severe and mild outcome.

Int J Antimicrob Agents 2021 Feb 23;57(2):106272. Epub 2020 Dec 23.

Department of Bioinformatics, Semmelweis University, Budapest, Hungary; TTK Momentum Cancer Biomarker Research Group, Budapest, Hungary. Electronic address:

Introduction: Genomic alterations in a viral genome can lead to either better or worse outcome and identifying these mutations is of utmost importance. Here, we correlated protein-level mutations in the SARS-CoV-2 virus to clinical outcome.

Methods: Mutations in viral sequences from the GISAID virus repository were evaluated by using "hCoV-19/Wuhan/WIV04/2019" as the reference. Patient outcomes were classified as mild disease, hospitalization and severe disease (death or documented treatment in an intensive-care unit). Chi-square test was applied to examine the association between each mutation and patient outcome. False discovery rate was computed to correct for multiple hypothesis testing and results passing FDR cutoff of 5% were accepted as significant.

Results: Mutations were mapped to amino acid changes for 3,733 non-silent mutations. Mutations correlated to mild outcome were located in the ORF8, NSP6, ORF3a, NSP4, and in the nucleocapsid phosphoprotein N. Mutations associated with inferior outcome were located in the surface (S) glycoprotein, in the RNA dependent RNA polymerase, in ORF3a, NSP3, ORF6 and N. Mutations leading to severe outcome with low prevalence were found in the ORF3A and in NSP7 proteins. Four out of 22 of the most significant mutations mapped onto a 10 amino acid long phosphorylated stretch of N indicating that in spite of obvious sampling restrictions the approach can find functionally relevant sites in the viral genome.

Conclusions: We demonstrate that mutations in the viral genes may have a direct correlation to clinical outcome. Our results help to quickly identify SARS-CoV-2 infections harboring mutations related to severe outcome.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755579PMC
February 2021

GAS2L1 Is a Potential Biomarker of Circulating Tumor Cells in Pancreatic Cancer.

Cancers (Basel) 2020 Dec 15;12(12). Epub 2020 Dec 15.

Junior Clinical Cooperation Unit Translational Surgical Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Pancreatic cancer is a malignant disease with high mortality and a dismal prognosis. Circulating tumor cell (CTC) detection and characterization have emerged as essential techniques for early detection, prognostication, and liquid biopsy in many solid malignancies. Unfortunately, due to the low EPCAM expression in pancreatic cancer CTCs, no specific marker is available to identify and isolate this rare cell population. This study analyzed single-cell RNA sequencing profiles of pancreatic CTCs from a genetically engineered mouse model (GEMM) and pancreatic cancer patients. Through dimensionality reduction analysis, murine pancreatic CTCs were grouped into three clusters with different biological functions. and were shown to be overexpressed in pancreatic CTCs in comparison with peripheral blood mononuclear cells (PBMCs). Further analyses of PBMCs and RNA-sequencing datasets of enriched pancreatic CTCs were used to validate the overexpression of in pancreatic CTCs. A combinatorial approach using both and expression leads to an increased detection rate of CTCs in PDAC in both GEMM and patient samples. is thus proposed as a novel biomarker of pancreatic cancer CTCs.
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http://dx.doi.org/10.3390/cancers12123774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765300PMC
December 2020

Induction of APOBEC3B expression by chemotherapy drugs is mediated by DNA-PK-directed activation of NF-κB.

Oncogene 2021 Feb 15;40(6):1077-1090. Epub 2020 Dec 15.

Department of Surgery & Cancer, Imperial College London, London, W12 0NN, UK.

The mutagenic APOBEC3B (A3B) cytosine deaminase is frequently over-expressed in cancer and promotes tumour heterogeneity and therapy resistance. Hence, understanding the mechanisms that underlie A3B over-expression is important, especially for developing therapeutic approaches to reducing A3B levels, and consequently limiting cancer mutagenesis. We previously demonstrated that A3B is repressed by p53 and p53 mutation increases A3B expression. Here, we investigate A3B expression upon treatment with chemotherapeutic drugs that activate p53, including 5-fluorouracil, etoposide and cisplatin. Contrary to expectation, these drugs induced A3B expression and concomitant cellular cytosine deaminase activity. A3B induction was p53-independent, as chemotherapy drugs stimulated A3B expression in p53 mutant cells. These drugs commonly activate ATM, ATR and DNA-PKcs. Using specific inhibitors and gene knockdowns, we show that activation of DNA-PKcs and ATM by chemotherapeutic drugs promotes NF-κB activity, with consequent recruitment of NF-κB to the A3B gene promoter to drive A3B expression. Further, we find that A3B knockdown re-sensitises resistant cells to cisplatin, and A3B knockout enhances sensitivity to chemotherapy drugs. Our data highlight a role for A3B in resistance to chemotherapy and indicate that stimulation of A3B expression by activation of DNA repair and NF-κB pathways could promote cancer mutations and expedite chemoresistance.
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http://dx.doi.org/10.1038/s41388-020-01583-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116738PMC
February 2021

Proteomic comparison of different synaptosome preparation procedures.

Amino Acids 2020 Dec 19;52(11-12):1529-1543. Epub 2020 Nov 19.

Laboratory of Proteomics, Institute of Biology, ELTE Eötvös Loránd University, Budapest, 1117, Hungary.

Synaptosomes are frequently used research objects in neurobiology studies focusing on synaptic transmission as they mimic several aspects of the physiological synaptic functions. They contain the whole apparatus for neurotransmission, the presynaptic nerve ending with synaptic vesicles, synaptic mitochondria and often a segment of the postsynaptic membrane along with the postsynaptic density is attached to its outer surface. As being artificial functional organelles, synaptosomes are viable for several hours, retain their activity, membrane potential, and capable to store, release, and reuptake neurotransmitters. Synaptosomes are ideal subjects for proteomic analysis. The recently available separation and protein detection techniques can cope with the reduced complexity of the organelle and enable the simultaneous qualitative and quantitative analysis of thousands of proteins shaping the structural and functional characteristics of the synapse. Synaptosomes are formed during the homogenization of nervous tissue in the isoosmotic milieu and can be isolated from the homogenate by various approaches. Each enrichment method has its own benefits and drawbacks and there is not a single method that is optimal for all research purposes. For a proper proteomic experiment, it is desirable to preserve the native synaptic structure during the isolation procedure and keep the degree of contamination from other organelles or cell types as low as possible. In this article, we examined five synaptosome isolation methods from a proteomic point of view by the means of electron microscopy, Western blot, and liquid chromatography-mass spectrometry to compare their efficiency in the isolation of synaptosomes and depletion of contaminating subcellular structures. In our study, the different isolation procedures led to a largely overlapping pool of proteins with a fairly similar distribution of presynaptic, active zone, synaptic vesicle, and postsynaptic proteins; however, discrete differences were noticeable in individual postsynaptic proteins and in the number of identified transmembrane proteins. Much pronounced variance was observed in the degree of contamination with mitochondrial and glial structures. Therefore, we suggest that in selecting the appropriate isolation method for any neuroproteomics experiment carried out on synaptosomes, the degree and sort/source of contamination should be considered as a primary aspect.
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http://dx.doi.org/10.1007/s00726-020-02912-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695668PMC
December 2020

Genomic and transcriptional changes in IFNγ pathway genes are putative biomarkers of response to ipilimumab immunotherapy in melanoma patients.

Expert Rev Clin Immunol 2020 12 15;16(12):1099-1103. Epub 2020 Nov 15.

Hargadon Laboratory, Department of Biology, Hampden-Sydney College , Hampden-Sydney, VA, USA.

: Gao J, Shi LZ, Zhao H . Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. 167(2), 397-404 (2016). Tumor resistance to immune checkpoint inhibitors limits therapeutic efficacy in many cancer patients. The study by Gao . highlighted herein describes a fundamental mechanism by which melanoma escapes the CTLA-4-targeting drug ipilimumab, the first FDA-approved immune checkpoint inhibitor for cancer. This work describes genomic alterations to IFNγ signaling pathway components as a mechanism of melanoma resistance to ipilimumab and has spawned several studies documenting the significance of this pathway to the efficacy of immunotherapy. The authors highlight new analysis of TCGA RNA-seq data that both support and extend the relevance of the IFNγ pathway to CTLA-4 checkpoint blockade as first introduced by this seminal paper, and the authors discuss the relevance of these collective findings to the future of cancer immunotherapy.
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http://dx.doi.org/10.1080/1744666X.2021.1847644DOI Listing
December 2020

Chronic stepwise cerebral hypoperfusion differentially induces synaptic proteome changes in the frontal cortex, occipital cortex, and hippocampus in rats.

Sci Rep 2020 09 29;10(1):15999. Epub 2020 Sep 29.

Laboratory of Proteomics, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary.

During chronic cerebral hypoperfusion (CCH), the cerebral blood flow gradually decreases, leading to cognitive impairments and neurodegenerative disorders, such as vascular dementia. The reduced oxygenation, energy supply induced metabolic changes, and insufficient neuroplasticity could be reflected in the synaptic proteome. We performed stepwise bilateral common carotid occlusions on rats and studied the synaptic proteome changes of the hippocampus, occipital and frontal cortices. Samples were prepared and separated by 2-D DIGE and significantly altered protein spots were identified by HPLC-MS/MS. We revealed an outstanding amount of protein changes in the occipital cortex compared to the frontal cortex and the hippocampus with 94, 33, and 17 proteins, respectively. The high alterations in the occipital cortex are probably due to the hypoxia-induced retrograde degeneration of the primary visual cortex, which was demonstrated by electrophysiological experiments. Altered proteins have functions related to cytoskeletal organization and energy metabolism. As CCH could also be an important risk factor for Alzheimer's disease (AD), we investigated whether our altered proteins overlap with AD protein databases. We revealed a significant amount of altered proteins associated with AD in the two neocortical areas, suggesting a prominent overlap with the AD pathomechanism.
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http://dx.doi.org/10.1038/s41598-020-72868-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524772PMC
September 2020

Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments.

Elife 2020 09 21;9. Epub 2020 Sep 21.

Genome Metabolism Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary.

Numerous anti-cancer drugs perturb thymidylate biosynthesis and lead to genomic uracil incorporation contributing to their antiproliferative effect. Still, it is not yet characterized if uracil incorporations have any positional preference. Here, we aimed to uncover genome-wide alterations in uracil pattern upon drug treatments in human cancer cell line models derived from HCT116. We developed a straightforward U-DNA sequencing method (U-DNA-Seq) that was combined with in situ super-resolution imaging. Using a novel robust analysis pipeline, we found broad regions with elevated probability of uracil occurrence both in treated and non-treated cells. Correlation with chromatin markers and other genomic features shows that non-treated cells possess uracil in the late replicating constitutive heterochromatic regions, while drug treatment induced a shift of incorporated uracil towards segments that are normally more active/functional. Data were corroborated by colocalization studies dSTORM microscopy. This approach can be applied to study the dynamic nature of genomic uracil.
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http://dx.doi.org/10.7554/eLife.60498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505663PMC
September 2020

muTarget: A platform linking gene expression changes and mutation status in solid tumors.

Int J Cancer 2021 Jan 17;148(2):502-511. Epub 2020 Sep 17.

Department of Bioinformatics, Semmelweis University, Budapest, Hungary.

Large oncology repositories have paired genomic and transcriptomic data for all patients. We used these data to perform two independent analyses: to identify gene expression changes related to a gene mutation and to identify mutations altering the expression of a selected gene. All data processing steps were performed in the R statistical environment. RNA-sequencing and mutation data were acquired from The Cancer Genome Atlas (TCGA). The DESeq2 algorithm was applied for RNA-seq normalization, and transcript variants were annotated with AnnotationDbi. MuTect2-identified somatic mutation data were utilized, and the MAFtools Bioconductor program was used to summarize the data. The Mann-Whitney U test was used for differential expression analysis. The established database contains 7876 solid tumors from 18 different tumor types with both somatic mutation and RNA-seq data. The utility of the approach is presented via three analyses in breast cancer: gene expression changes related to TP53 mutations, gene expression changes related to CDH1 mutations and mutations resulting in altered progesterone receptor (PGR) expression. The breast cancer database was split into equally sized training and test sets, and these data sets were analyzed independently. The highly significant overlap of the results (chi-square statistic = 16 719.7 and P < .00001) validates the presented pipeline. Finally, we set up a portal at http://www.mutarget.com enabling the rapid identification of novel mutational targets. By linking somatic mutations and gene expression, it is possible to identify biomarkers and potential therapeutic targets in different types of solid tumors. The registration-free online platform can increase the speed and reduce the development cost of novel personalized therapies.
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http://dx.doi.org/10.1002/ijc.33283DOI Listing
January 2021

Currently favored sampling practices for tumor sequencing can produce optimal results in the clinical setting.

Sci Rep 2020 09 1;10(1):14403. Epub 2020 Sep 1.

Department of Bioinformatics, Semmelweis University, Budapest, Hungary.

Tumor heterogeneity is a consequence of clonal evolution, resulting in a fractal-like architecture with spatially separated main clones, sub-clones and single-cells. As sequencing an entire tumor is not feasible, we ask the question whether there is an optimal clinical sampling strategy that can handle heterogeneity and hypermutations? Here, we tested the effect of sample size, pooling strategy as well as sequencing depth using whole-exome sequencing of ovarian tumor specimens paired with normal blood samples. Our study has an emphasis on clinical application-hence we compared single biopsy, combined local biopsies and combined multi-regional biopsies. Our results show that sequencing from spatially neighboring regions show similar genetic compositions, with few private mutations. Pooling samples from multiple distinct regions of the primary tumor did not increase the overall number of identified mutations but may increase the robustness of detecting clonal mutations. Hypermutating tumors are a special case, since increasing sample size can easily dilute sub-clonal private mutations below detection thresholds. In summary, we compared the effects of sampling strategies (single biopsy, multiple local samples, pooled global sample) on mutation detection by next generation sequencing. In view of the limitations of present tools and technologies, only one sequencing run per sample combined with high coverage (100-300 ×) sequencing is affordable and practical, regardless of the number of samples taken from the same patient.
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http://dx.doi.org/10.1038/s41598-020-71382-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463012PMC
September 2020

Evidence for Enhanced Exosome Production in Aromatase Inhibitor-Resistant Breast Cancer Cells.

Int J Mol Sci 2020 Aug 14;21(16). Epub 2020 Aug 14.

Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, 87036 Arcavacata di Rende (CS), Italy.

Aromatase inhibitors (AIs) represent the standard anti-hormonal therapy for post-menopausal estrogen receptor-positive breast cancer, but their efficacy is limited by the emergence of AI resistance (AI). Exosomes act as vehicles to engender cancer progression and drug resistance. The goal of this work was to study exosome contribution in AI mechanisms, using estrogen-dependent MCF-7 breast cancer cells as models and MCF-7 LTED (Long-Term Estrogen Deprived) subline, modeling AI. We found that exosome secretion was significantly increased in MCF-7 LTED cells compared to MCF-7 cells. MCF-7 LTED cells also exhibited a higher amount of exosomal RNA and proteins than MCF-7 cells. Proteomic analysis revealed significant alterations in the cellular proteome. Indeed, we showed an enrichment of proteins frequently identified in exosomes in MCF-7 LTED cells. The most up-regulated proteins in MCF-7 LTED cells were represented by Rab GTPases, important vesicle transport-regulators in cancer, that are significantly mapped in "small GTPase-mediated signal transduction", "protein transport" and "vesicle-mediated transport" Gene Ontology categories. Expression of selected Rab GTPases was validated by immunoblotting. Collectively, we evidence, for the first time, that AI breast cancer cells display an increased capability to release exosomes, which may be associated with an enhanced Rab GTPase expression. These data provide the rationale for further studies directed at clarifying exosome's role on endocrine therapy, with the aim to offer relevant markers and druggable therapeutic targets for the management of hormone-resistant breast cancers.
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http://dx.doi.org/10.3390/ijms21165841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461508PMC
August 2020

Genomic Mapping Identifies Mutations in RYR2 and AHNAK as Associated with Favorable Outcome in Basal-Like Breast Tumors Expressing PD1/PD-L1.

Cancers (Basel) 2020 Aug 11;12(8). Epub 2020 Aug 11.

Translational Oncology Laboratory, Centro Regional de Investigaciones Biomedicas, Castilla-La Mancha University (CRIB-UCLM), 02008 Albacete, Spain.

Treatment with anti-PD-L1 antibodies has shown efficacy in basal-like breast cancer. In this context, identification of pre-activated immune tumors is a main goal. Here we explore mutations in PD1 and PD-L1 high-expressing tumors to identify genomic correlates associated with outcome. To do so, RNA-seq and mutation data from 971 breast cancer patients from the TCGA dataset were used to identify most prevalent mutations in patients with high levels of PD1 and PD-L1. Transcriptomic signatures associated with the selected mutations were identified and analyzed in terms of outcome and immune cell infiltration. We identified co-occurrent mutations in RYR2 and AHNAK in 8% and 5% of basal-like tumors respectively, which conferred good prognosis in patients with high expression of PD1 and PD-L1 genes. The transcriptomic signature associated with these mutations, composed of CXCL9, GBP5, C1QA, IL2RG, CSF2RB, IDO1 and LAG3 genes, also conferred good prognosis and correlated with immune infiltrations within the tumors. The joint signature classified patients with favorable relapse-free survival (HR: 0.28; CI: 0.2-0.38; = 1.7 × 10) and overall survival (HR: 0.18; CI: 0.09-0.34; = 6.8 × 10), showing a stronger prediction capacity than previous reported signatures. In conclusion, we describe two novel mutations and their transcriptomic signature, both associated with a favorable outcome and immune infiltrates in PD1 and PD-L1 high-expressing basal-like tumors.
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http://dx.doi.org/10.3390/cancers12082243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464853PMC
August 2020

RNA-binding protein NONO contributes to cancer cell growth and confers drug resistance as a theranostic target in TNBC.

Theranostics 2020 2;10(18):7974-7992. Epub 2020 Jul 2.

Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Korea.

Breast cancer (BC) is one of the most common cancers in women. TNBC (Triple-negative breast cancer) has limited treatment options and still lacks viable molecular targets, leading to poor outcomes. Recently, RNA-binding proteins (RBPs) have been shown to play crucial roles in human cancers, including BC, by modulating a number of oncogenic phenotypes. This suggests that RBPs represent potential molecular targets for BC therapy. We employed genomic data to identify RBPs specifically expressed in TNBC. NONO was silenced in TNBC cell lines to examine cell growth, colony formation, invasion, and migration. Gene expression profiles in NONO-silenced cells were generated and analyzed. A high-throughput screening for NONO-targeted drugs was performed using an FDA-approved library. We found that the NONO RBP is highly expressed in TNBC and is associated with poor patient outcomes. NONO binds to STAT3 mRNA, increasing STAT3 mRNA levels in TNBC. Surprisingly, NONO directly interacts with STAT3 protein increasing its stability and transcriptional activity, thus contributing to its oncogenic function. Importantly, high-throughput drug screening revealed that auranofin is a potential NONO inhibitor and inhibits cell growth in TNBC. NONO is an RBP upstream regulator of both STAT3 RNA and protein levels and function. It represents an important and clinically relevant promoter of growth and resistance of TNBCs. NONO is also therefore a potential therapeutic target in TNBC.
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http://dx.doi.org/10.7150/thno.45037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381744PMC
July 2020

BRD4 regulates key transcription factors that drive epithelial-mesenchymal transition in castration-resistant prostate cancer.

Prostate Cancer Prostatic Dis 2021 Mar 21;24(1):268-277. Epub 2020 Jul 21.

Boston University-Boston Medical Center Cancer Center, Boston, MA, 02118, USA.

Background: Androgen deprivation therapies for the hormone-dependent stages of prostate cancer have become so effective that new forms of chemoresistant tumors are emerging in clinical practice, and require new targeted therapies in the metastatic setting. Yet there are important gaps in our understanding of the relevant transcriptional networks driving this process. Progression from localized to metastatic castration resistant prostate cancer (mCRPC) occurs as a result of accumulated resistance mechanisms that develop upon sustained androgen receptor (AR) suppression. Critical to this progression is the plastic nature by which prostate tumor cells transition from epithelial to mesenchymal states (EMT).

Methods: Here, using prostate cancer cell lines with different AR composition, we systematically manipulated somatic proteins of the Bromodomain and ExtraTerminal (BET) family (BRD2, BRD3, and BRD4) to determine which BET proteins influence EMT. We used the TCGA repository to correlate the expression of individual BET genes with key EMT genes and determined biochemical recurrence in 414 patients and progression free survival in 488 patients.

Results: We found that only BRD4-and not BRD2 or BRD3-regulates the expression of SNAI1 and SNAI2, and that the downregulation of these EMT transcription factors significantly increases E-cadherin expression. Furthermore, of the BET genes, only BRD4 correlates with survival outcomes in prostate cancer patients. Moreover, selective degradation of BRD4 protein with MZ1 ablates EMT (transcriptionally and morphologically) induced by TGFß signaling.

Conclusions: Many relapsed/refractory tumors share a neuroendocrine transcriptional signature that had been relatively rare until highly successful antiandrogen drugs like abiraterone and enzalutamide came into widespread use. New therapeutic targets must therefore be developed. Our results identify key EMT genes regulated by BRD4, and offers a novel druggable target to treat mCRPC. BRD4-selective protein degraders offer a promising next generation approach to treat the emerging forms of chemoresistance in advanced prostate cancer.
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http://dx.doi.org/10.1038/s41391-020-0246-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855805PMC
March 2021

Long-Term Exposure of Early-Transformed Human Mammary Cells to Low Doses of Benzo[a]pyrene and/or Bisphenol A Enhances Their Cancerous Phenotype via an AhR/GPR30 Interplay.

Front Oncol 2020 29;10:712. Epub 2020 May 29.

Université Lyon 1, Lyon, France.

It is of utmost importance to decipher the role of chronic exposure to low doses of environmental carcinogens on breast cancer progression. The early-transformed triple-negative human mammary MCF10AT1 cells were chronically (60 days) exposed to low doses (10 M) of Benzo[a]pyrene (B[a]P), a genotoxic agent, and/or Bisphenol A (BPA), an endocrine disruptor. Our study revealed that exposed MCF10AT1 cells developed, in a time-dependent manner, an acquired phenotype characterized by an increase in cancerous properties (anchorage independent growth and stem-like phenotype). Co-exposure of MCF10AT1 cells to B[a]P and BPA led to a significantly greater aggressive phenotype compared to B[a]P or BPA alone. This study provided new insights into the existence of a functional interplay between the aryl hydrocarbon receptor (AhR) and the G protein-coupled receptor 30 (GPR30) by which chronic and low-dose exposure of B[a]P and/or BPA fosters the progression of MCF10AT1 cells into a more aggressive substage. Experiments using AhR or GPR30 antagonists, siRNA strategies, and RNAseq analysis led us to propose a model in which AhR signaling plays a "driver role" in the AhR/GPR30 cross-talk in mediating long-term and low-dose exposure of B[a]P and/or BPA. Retrospective analysis of two independent breast cancer cohorts revealed that the mRNA expression signature resulted in poor breast cancer prognosis, in particular in the ER-negative and the triple-negative subtypes. Finally, the study identified targeting AhR and/or GPR30 with specific antagonists as a strategy capable of inhibiting carcinogenesis associated with chronic exposure to low doses of B[a]P and BPA in MCF10AT1 cells. Altogether, our results indicate that the engagement of both AhR and GPR30 functions, in particular in an ER-negative/triple-negative context of breast cells, favors tumor progression and leads to poor prognosis.
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http://dx.doi.org/10.3389/fonc.2020.00712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326103PMC
May 2020

A novel mesenchymal-associated transcriptomic signature for risk-stratification and therapeutic response prediction in colorectal cancer.

Int J Cancer 2020 12 13;147(11):3250-3261. Epub 2020 Jul 13.

Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA.

Risk stratification in Stage II and III colorectal cancer (CRC) patients is critical, as it allows patient selection for adjuvant chemotherapy. In view of the inadequacy of current clinicopathological features for risk-stratification, we undertook a systematic and comprehensive biomarker discovery effort to develop a risk-assessment signature in CRC patients. The biomarker discovery phase examined 853 CRC patients, and identified a gene signature for predicting recurrence-free survival (RFS). This signature was validated in a meta-analysis of 1212 patients from nine independent datasets, and its performance was compared against established prognostic signatures and consensus molecular subtypes (CMS). In addition, a risk-prediction model was trained (n = 142), and subsequently validated in an independent clinical cohort (n = 286). As a result, this mesenchymal-associated transcriptomic signature (MATS) identified high-risk CRC patients with poor RFS in the discovery (hazard ratio [HR]: 1.79), and nine validation cohorts (HR: 1.86). In multivariate analysis, MATS was the most significant predictor of RFS compared to established prognostic signatures and CMS subtypes. Intriguingly, MATS robustly identified CMS4-subtype in multiple CRC cohorts (AUC = 0.92-0.99). In the two clinical cohorts, MATS stratified low and high-risk groups with a 5-year RFS in the training (HR: 4.11) and validation cohorts (HR: 2.55), as well as predicted response to adjuvant therapy in Stage II and III CRC patients. We report a novel prognostic and predictive biomarker signature in CRC, which is superior to currently used approaches and have the potential for clinical translation in near future.
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http://dx.doi.org/10.1002/ijc.33129DOI Listing
December 2020

Association of Sperm-Associated Antigen 5 and Treatment Response in Patients With Estrogen Receptor-Positive Breast Cancer.

JAMA Netw Open 2020 07 1;3(7):e209486. Epub 2020 Jul 1.

Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.

Importance: There is no proven test that can guide the optimal treatment, either endocrine therapy or chemotherapy, for estrogen receptor-positive breast cancer.

Objective: To investigate the associations of sperm-associated antigen 5 (SPAG5) transcript and SPAG5 protein expressions with treatment response in systemic therapy for estrogen receptor-positive breast cancer.

Design, Settings, And Participants: This retrospective cohort study included patients with estrogen receptor-positive breast cancer who received 5 years of adjuvant endocrine therapy with or without neoadjuvant anthracycline-based combination chemotherapy (NACT) derived from 11 cohorts from December 1, 1986, to November 28, 2019. The associations of SPAG5 transcript and SPAG5 protein expression with pathological complete response to NACT were evaluated, as was the association of SPAG5 mRNA expression with response to neoadjuvant endocrine therapy. The associations of distal relapse-free survival with SPAG5 transcript or SPAG5 protein expressions were analyzed. Data were analyzed from September 9, 2015, to November 28, 2019.

Main Outcomes And Measures: The primary outcomes were breast cancer-specific survival, distal relapse-free survival, pathological complete response, and clinical response. Outcomes were examined using Kaplan-Meier, multivariable logistic, and Cox regression models.

Results: This study included 12 720 women aged 24 to 78 years (mean [SD] age, 58.46 [12.45] years) with estrogen receptor-positive breast cancer, including 1073 women with SPAG5 transcript expression and 361 women with SPAG5 protein expression of locally advanced disease stage IIA through IIIC. Women with SPAG5 transcript and SPAG5 protein expressions achieved higher pathological complete response compared with those without SPAG5 transcript or SPAG5 protein expressions (transcript: odds ratio, 2.45 [95% CI, 1.71-3.51]; P < .001; protein: odds ratio, 7.32 [95% CI, 3.33-16.22]; P < .001). Adding adjuvant anthracycline chemotherapy to adjuvant endocrine therapy for SPAG5 mRNA expression in estrogen receptor-positive breast cancer was associated with prolonged 5-year distal relapse-free survival in patients without lymph node involvement (hazard ratio, 0.34 [95% CI, 0.14-0.87]; P = .03) and patients with lymph node involvement (hazard ratio, 0.35 [95% CI, 0.18-0.68]; P = .002) compared with receiving 5-year endocrine therapy alone. Mean (SD) SPAG5 transcript was found to be downregulated after 2 weeks of neoadjuvant endocrine therapy compared with pretreatment levels in 68 of 92 patients (74%) (0.23 [0.18] vs 0.34 [0.24]; P < .001).

Conclusions And Relevance: These findings suggest that SPAG5 transcript and SPAG5 protein expressions could be used to guide the optimal therapies for estrogen receptor-positive breast cancer. Retrospective and prospective clinical trials are warranted.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.9486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341179PMC
July 2020

Ribosomal protein S11 influences glioma response to TOP2 poisons.

Oncogene 2020 07 11;39(27):5068-5081. Epub 2020 Jun 11.

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University , Chicago, IL, United States.

Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We and others had shown that a subset of glioblastomas, the most malignant of all primary brain tumors in adults, is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, and 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 led to resistance to etoposide and doxorubicin and impaired the induction of proapoptotic gene APAF1 following treatment. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from gliomas and multiple other cancers.
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http://dx.doi.org/10.1038/s41388-020-1342-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646677PMC
July 2020