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BACKGROUND: The appropriate surgical approach for pancreatic ductal adenocarcinoma (PDAC) is determined by the tumor's relation to the porto-mesenteric axis. Although the extent and location of lymphadenectomy is dependent on the type of resection, a pancreatoduodenectomy (PD), distal pancreatectomy (DP), or total pancreatectomy (TP) are considered equivalent oncologic operations for pancreatic neck tumors. Therefore, we aimed to assess differences in histopathological and oncological outcomes for surgical approaches in the treatment of pancreatic neck tumors. METHODS: Patients with resected PDAC located in the pancreatic neck were identified from the National Cancer Database (2004-2020). Patients with metastatic disease were excluded. Furthermore, patients with 90-day mortality and R2-resections were excluded from the multivariable Cox-regression analysis. RESULTS: Among 846 patients, 58% underwent PD, 25% DP, and 17% TP with similar R0-resection rates (p = 0.722). Significant differences were observed in nodal positivity (PD:44%, DP:34%, TP:57%, p < 0.001) and mean-number of examined lymph nodes (PD:17.2 ± 10.4, DP:14.7 ± 10.5, TP:21.2 ± 11.0, p < 0.001). Furthermore, inadequate lymphadenectomy (< 12 nodes) was observed in 30%, 44%, and 19% of patients undergoing PD, DP, and TP, respectively (p < 0.001). Multivariable analysis yielded similar overall survival after DP (HR:0.83, 95%CI:0.63-1.11), while TP was associated with worse survival (HR:1.43, 95%CI:1.08-1.89) compared to PD. CONCLUSION: While R0-rates are similar amongst all approaches, DP is associated with inadequate lymphadenectomy which may result in understaging disease. However, this had no negative influence on survival. In the premise that an oncological resection of the pancreatic neck tumor is feasible with a partial pancreatectomy, no benefit is observed by performing a TP.
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Carcinoma Ductal Pancreático , Pancreatectomía , Neoplasias Pancreáticas , Pancreaticoduodenectomía , Humanos , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Masculino , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Femenino , Estudios Retrospectivos , Pancreatectomía/métodos , Anciano , Persona de Mediana Edad , Pancreaticoduodenectomía/métodos , Pancreaticoduodenectomía/mortalidad , Escisión del Ganglio Linfático , Estudios de CohortesRESUMEN
PURPOSE: Improvement of patient care is associated with increasing publication numbers in biomedical research. However, such increasing numbers of publications make it challenging for physicians and scientists to screen and process the literature of their respective fields. In this study, we present a comprehensive bibliometric analysis of the evolution of gastrointestinal stromal tumor (GIST) research, analyzing the current state of the field and identifying key open questions going beyond the recent advantages for future studies to assess. METHODS: Using the Web of Science Core Collection, 5040 GIST-associated publications in the years 1984-2022 were identified and analyzed regarding key bibliometric variables using the Bibliometrix R package and VOSviewer software. RESULTS: GIST-associated publication numbers substantially increased over time, accentuated from year 2000 onwards, and being characterized by multinational collaborations. The main topic clusters comprise surgical management, tyrosine kinase inhibitor (TKI) development/treatment, diagnostic workup, and molecular pathophysiology. Within all main topic clusters, a significant progress is reflected by the literature over the years. This progress ranges from conventional open surgical techniques over minimally invasive, including robotic and endoscopic, resection techniques to increasing identification of specific functional genetic aberrations sensitizing for newly developed TKIs being extensively investigated in clinical studies and implemented in GIST treatment guidelines. However, especially in locally advanced, recurrent, and metastatic disease stages, surgery-related questions and certain specific questions concerning (further-line) TKI treatment resistance were infrequently addressed. CONCLUSION: Increasing GIST-related publication numbers reflect a continuous progress in the major topic clusters of the GIST research field. Especially in advanced disease stages, questions related to the interplay between surgical approaches and TKI treatment sensitivity should be addressed in future studies.
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Antineoplásicos , Neoplasias Gastrointestinales , Tumores del Estroma Gastrointestinal , Humanos , Tumores del Estroma Gastrointestinal/cirugía , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Gastrointestinales/cirugía , Antineoplásicos/uso terapéuticoRESUMEN
In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2-ERG (T2E)-fusion oncoproteins defining two molecular subtypes (T2E-positive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate gene-signatures associated with metastasis in T2E-positive and T2E-negative PCa independently, we integrated tumor transcriptomes and clinicopathological data of two cohorts (total n = 783), and analyzed metastasis-associated gene-signatures regarding the T2E-status. Here, we show that the prognostic value of biomarkers in PCa critically depends on the T2E-status. Using gene-set enrichment analyses, we uncovered that metastatic T2E-positive and T2E-negative PCa are characterized by distinct gene-signatures. In addition, by testing genes shared by several functional gene-signatures for their association with event-free survival in a validation cohort (n = 272), we identified five genes (ASPN, BGN, COL1A1, RRM2 and TYMS)-three of which are included in commercially available prognostic tests-whose high expression was significantly associated with worse outcome exclusively in T2E-negative PCa. Among these genes, RRM2 and TYMS were validated by immunohistochemistry in another validation cohort (n = 135), and several of them proved to add prognostic information to current clinicopathological predictors, such as Gleason score, exclusively for T2E-negative patients. No prognostic biomarkers were identified exclusively for T2E-positive tumors. Collectively, our study discovers that the T2E-status, which is per se not a strong prognostic biomarker, crucially determines the prognostic value of other biomarkers. Our data suggest that the molecular subtype needs to be considered when applying prognostic biomarkers for outcome prediction in PCa.
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Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Biomarcadores de Tumor , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/mortalidad , Adenocarcinoma/diagnóstico , Biología Computacional , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Neoplasias de la Próstata/diagnósticoRESUMEN
Chronic hepatitis B virus (HBV) infection is a main risk factor for development of liver cirrhosis and hepatocellular carcinoma (HCC). Although HBV vaccination and antiviral therapy lead to substantial risk reduction for HCC development, it is evident that both can reduce, but not completely eliminate the risk. High serum levels of HBV surface antigen (HBsAg) were shown to predict disease progression of chronic HBV infection in patients harboring low viral load, and in line with this, HBV surface proteins were shown to exert oncogenic functions. As HBsAg seroclearance is infrequently achieved in patients who have undergone antiviral therapy, it is necessary to gain further insights into molecular mechanisms of HBsAg seroclearance failure after antiviral therapy and HCC development mediated by HBV surface proteins. A recent study published in this journal has shown that the HBsAg large surface protein (LHBs) contributes to HCC development by inducing cytokinesis failure and consequent aneuploidy via induction of DNA damage and polo-like kinase 1 (PLK1)-mediated G2/M checkpoint failure in hepatocytes. Inhibition of PLK1 by a PLK1-specific small molecule inhibitor was shown to restore G2/M checkpoint in vitro and to reduce tumor burden in vivo. The initial LHBs-induced hepatocyte aneuploidy may give rise to further aneuploidy and thereby lead to self-propagating cycles of chromosomal instability driving intra-tumor heterogeneity and clonal cancer evolution. Thus, LHBs-induced cytokinesis failure may be a priming event for HCC development. In conclusion, the study not only provides further mechanistic insights into the oncogenic role of LHBs, but also identifies a potential target to interfere with the vicious circle of LHBs-induced aneuploidy, which may be especially useful in patients showing failure of HBsAg seroclearance after antiviral therapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Carcinoma Hepatocelular , Hepatitis B Crónica/inmunología , Neoplasias Hepáticas , Aneuploidia , Antígenos de Superficie , Citocinesis , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Hepatocitos , Humanos , Proteínas de la Membrana/genética , Reino UnidoRESUMEN
Soft-tissue sarcomas are rare, heterogeneous, and often aggressive mesenchymal cancers. Many of them are associated with poor outcome, partially because biomarkers that can identify high-risk patients are lacking. Studies on sarcomas are often limited by small sample-sizes rendering the identification of biomarkers difficult when focusing on individual cohorts. However, the increasing number of publicly available 'omics' data opens inroads to overcome this obstacle. Here, we combine transcriptome analyses, immunohistochemistry, and functional assays to show that high adenosine monophosphate deaminase 2 (AMPD2) is a robust prognostic biomarker for worse outcome in undifferentiated pleomorphic sarcoma (UPS). Gene expression and survival data for UPS from two independent studies were subjected to survival association-testing. Genes, whose high expression was significantly correlated with worse outcome in both cohorts, were considered as biomarker candidates. The best candidate, AMPD2, was validated in a tissue microarray. Analysis of DNA copy-number data and matched transcriptomes indicated that high AMPD2 expression is significantly correlated with gains at the AMPD2 locus. Gene set enrichment analyses of AMPD2 co-expressed genes in both transcriptome datasets suggested that AMPD2-high UPS are enriched in tumorigenic signatures. Consistently, knockdown of AMPD2 by RNA interference in an UPS cell line inhibited proliferation in vitro and tumorigenicity in vivo. Collectively, we provide evidence that AMPD2 may serve as a biomarker for outcome prediction in UPS. Our study exemplifies how the integration of 'omics' data, immunohistochemistry, and functional experiments can identify novel biomarkers even in a rare sarcoma, which may serve as a blueprint for biomarker identification for other rare cancers.
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AMP Desaminasa/genética , Biomarcadores de Tumor/genética , Genómica/métodos , Histiocitoma Fibroso Maligno/genética , AMP Desaminasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Histiocitoma Fibroso Maligno/metabolismo , Histiocitoma Fibroso Maligno/patología , Humanos , Estimación de Kaplan-Meier , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Persona de Mediana Edad , Pronóstico , Tratamiento con ARN de Interferencia/métodos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Adulto JovenAsunto(s)
Biomarcadores de Tumor , Neoplasias Óseas/genética , Neoplasias Óseas/mortalidad , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Sarcoma de Ewing/genética , Sarcoma de Ewing/mortalidad , Animales , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Xenoinjertos , Humanos , Ratones , Estadificación de Neoplasias , Pronóstico , Sarcoma de Ewing/patologíaAsunto(s)
Biomarcadores de Tumor , Neoplasias Óseas/etiología , Ribonucleósido Difosfato Reductasa/genética , Sarcoma de Ewing/etiología , Animales , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/terapia , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Terapia Molecular Dirigida , Pronóstico , Piridinas/farmacología , Ribonucleósido Difosfato Reductasa/metabolismo , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/terapia , Tiosemicarbazonas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: Retroperitoneal soft tissue sarcoma (RPS) is characterized by high recurrence rates. Since complete tumor resection, often necessitating multivisceral resection, enables long-term survival in both primary and recurrent disease, health related quality of life (QoL) after RPS resection has attracted increasing interest. However, data regarding this topic is limited. Here, we multidimensionally assessed long-term QoL after RPS resection. METHODS: Five previously validated (1. EORTC QLQ-C30, 2. WEMWBS, 3. FoP-Q-SF, 4. PC-PTSD, 5. Pro-CTCAE) were sent to patients having undergone resection of primary, recurrent and metastasized RPS at Heidelberg University Hospital between 10/2001 and 12/2020. Multivariable linear regression models were used to test associations between clinical/demographic variables and patient reported outcomes (PROs). RESULTS: Questionnaires were answered by 127 patients (71% response rate). The median interval between RPS diagnosis and assessment of PROs was 80 months. The overall Global Health score was 64.1 and comparable to the general German population. RPS patients reported deficits regarding emotional and social functioning, whereas physical limitations were less pronounced. Besides diarrhea, abdominal symptoms were comparable to the overall population. Tumor recurrences, the number of surgeries, multivisceral resections or postoperative complications did not significantly affect long-term QoL ratings. CONCLUSION: RPS patients rate their QoL relatively high, even after multiple and multivisceral resections. Psychosocial well-being should be monitored in follow-up sessions to offer tailored support if necessary, thus improving postoperative care.
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Neoplasias Retroperitoneales , Sarcoma , Humanos , Calidad de Vida , Estudios Retrospectivos , Recurrencia Local de Neoplasia , Sarcoma/patología , Neoplasias Retroperitoneales/patologíaRESUMEN
Introduction: The incidence of early-onset gastric adenocarcinoma (patients <50 years, EOGA) is rising. Tumors in younger patients are associated with prognostically unfavorable features. The impact of EOGA on patient survival, however, remains unclear. The aim of this study is to evaluate early-onset age as a prognostic factor compared to late-onset gastric adenocarcinoma (LOGA, >50years) in a surgical cohort and assess treatment options. Methods: We analyzed 738 patients (129 early-onset/609 late-onset) operated in curative intent from 2002 to 2021. Data was extracted from a prospectively managed database of an academic tertiary referral hospital. Differences in perioperative as well as oncological outcomes were calculated by chi-square test. Cox regression analysis was performed to assess disease-free survival (DFS) and overall survival (OS). Results: EOGA patients were more often treated with neoadjuvant therapy (62.8% vs. 43.7%, p<0.001) and extended surgical resections e.g. through additional resections (36.4% vs. 26.8%, p=0.027). EOGA was more often metastasized into regional lymph nodes (pN+ 67.4% vs. 55.3%, p=0.012) and to distant sites (pM+: 23.3% vs. 12.0%, p=0.001) and was more often poorly differentiated (G3/G4: 91.1% vs. 67.2%, p<0.001). There were no significant differences in overall complication rates (31.0% vs. 36.6%, p=0.227). Survival analysis showed shorter DFS (median DFS 25.6 months vs. not reached, p=0.006) but similar OS (median OS: 50.5 months vs. not reached, p=0.920) in EOGA compared to LOGA. Conclusions: This analysis confirmed that EOGA is associated with more aggressive tumor characteristics. Early-Onset was not a prognostic factor in the multivariate analysis. EOGA patients may be more capable to undergo intensive multimodal therapy including perioperative chemotherapy and extended surgery.
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BACKGROUND: Increasing publication numbers in the biomedical field led to an improvement of patient care in many aspects but are challenging for scientists when integratively processing data of their fields. Using bibliometric analyses, the present study assesses the productivity and predominant topics in retroperitoneal soft-tissue sarcoma (RPS) research across the past 122 years, thereby identifying crucial questions to address in future RPS research. METHODS: Using the Web of Science Core Collection, 1018 RPS-associated publications from 1900 to 2022 were identified and analyzed regarding key bibliometric variables using the Bibliometrix R package and the VOSviewer software. RESULTS: A continuous increase in RPS-associated publication numbers can be noticed over the time, which is strongly pronounced from 2005 onwards, and is characterized by a multinationally driven collaborative clinical research focus. The research primarily reflects progression regarding surgical techniques, histology-based therapy, radiotherapy regimens, and identification of prognostic clinicopathological factors. This progression is accompanied with improved overall survival of RPS patients. However, a paucity of RPS-specific basic/translational research indicates that such research might be additionally needed to better understand the pathophysiology of RPS and with that to enable the development of personalized therapies and to further improve patient outcome. CONCLUSION: Increasing publication numbers of multinationally driven clinical RPS research are accompanied with improved overall survival of RPS patients, highlighting the importance of international collaborations to facilitate future clinical trials. However, this bibliometric analysis reveals a lack of RPS-specific basic/translational research which is needed to further improve patient outcome in the context of precision oncology.
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Neoplasias Retroperitoneales , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Medicina de Precisión , Sarcoma/cirugía , Neoplasias Retroperitoneales/cirugía , Estudios Retrospectivos , Recurrencia Local de Neoplasia/patologíaRESUMEN
Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) encodes the 4EBP1 protein, a negative regulator of mRNA translation and a substrate of the mechanistic target of rapamycin (mTOR), whose function and relevance in cancer is still under debate. Here, we analyzed EIF4EBP1 expression in different glioma patient cohorts and investigated its mode of transcriptional regulation in glioblastoma cells. We verified that EIF4EBP1 mRNA is overexpressed in malignant gliomas, including isocitrate dehydrogenase (IDH)-wildtype glioblastomas, relative to non-neoplastic brain tissue in multiple publically available datasets. Our analyses revealed that EIF4EBP1 overexpression in malignant gliomas is neither due to gene amplification nor to altered DNA methylation, but rather results from aberrant transcriptional activation by distinct transcription factors. We found seven transcription factor candidates co-expressed with EIF4EBP1 in gliomas and bound to the EIF4EBP1 promoter, as revealed by chromatin immunoprecipitation (ChIP)-sequencing data. We investigated the ability of these candidates to activate the EIF4EBP1 promoter using luciferase reporter assays, which supported four transcription factors as candidate EIF4EBP1 regulators, namely MYBL2, ETS1, HIF-1A, and E2F6. Finally, by employing transient knock-down experiments to repress either of these transcription factors, we identified MYBL2 and ETS1 as the relevant transcriptional drivers of enhanced EIF4EBP1 expression in malignant glioma cells. Taken together, our findings confirm enhanced expression of EIF4EBP1 in malignant gliomas relative to non-neoplastic brain tissue and characterize the underlying molecular pathomechanisms.
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Cell proliferation is broadly defined as a process leading to an increase of cell number, essentially depending on a balance between cell cycle progression/cell division, cell death, and cellular senescence. Deregulation of cell proliferation is a key feature of cancer cells, making assessment of proliferation a central methodological issue in cancer research. Especially in Ewing sarcoma (EwS) that exhibit a high proliferative capacity, experimental assessment of proliferation in preclinical research plays an important role. Among the variety of applicable methods, trypan blue exclusion is described here as a robust, easy-to-perform, and cost-effective method to assess cell proliferation in an experimental setting.
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Neoplasias Óseas/patología , Proliferación Celular , Supervivencia Celular , Sarcoma de Ewing/patología , Azul de Tripano , Muerte Celular , División Celular , Línea Celular Tumoral , Senescencia Celular , HumanosRESUMEN
In Ewing sarcoma (EwS), development of new therapeutic strategies is crucial in order to refine treatment and improve patient survival, especially in metastatic or recurrent disease stages. Thus, preclinical drug screening is a key issue in EwS research. As especially in such drug screening assays, the cell viability aspect of cell proliferation is important, resazurin colorimetry shall be reviewed here as a fast, high-throughput method with automated readout to efficiently screen for potency of drugs via measurement of cell viability.
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Colorimetría/métodos , Evaluación Preclínica de Medicamentos/métodos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Oxazinas , Xantenos , Antineoplásicos/farmacología , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Sarcoma de EwingRESUMEN
INTRODUCTION: Local recurrences (LR) and distant metastases (DM) are common in retroperitoneal soft tissue sarcoma (RPS). Longer time to recurrence and resection of the recurrent lesion have been identified as beneficial prognostic factors for overall survival (OS) upon first tumor relapse. However, prognostic factors concerning OS upon subsequent recurrences are scarcely defined. In this study, we aimed to identify prognostic factors for post-relapse outcome in multiple recurrent RPS. METHODS: Patients undergoing resection of primary and recurrent RPS at the University Hospital Heidelberg were retrospectively analyzed. Multivariable Cox regression analyses were performed to identify predictors of overall, LR- and DM-free survival. Subgroup analyses were performed for liposarcoma and leiomyosarcoma patients. RESULTS: 201 patients with primary disease, 101 patients with first, 66 patients with second and 43 patients with third LR as well as 75 patients with DM were analyzed. More than 12 months to recurrence and resection of recurrence were associated with improved OS after resection of first and second LR (5-year OS for first/second LR; resection: 64%/62%, no resection: 20%/46%). Gross macroscopic incomplete resection of first (p < 0.001), second (p = 0.001), and third recurrences (p < 0.001) was an independent prognostic factor for poor OS. CONCLUSION: Development of LR and DM is frequent in RPS. Once a tumor relapsed, patients benefit from tumor resection not only in case of first, but also in case of subsequent recurrences.
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Leiomiosarcoma/cirugía , Liposarcoma/cirugía , Recurrencia Local de Neoplasia/cirugía , Neoplasias Retroperitoneales/cirugía , Sarcoma/cirugía , Tasa de Supervivencia , Anciano , Femenino , Humanos , Leiomiosarcoma/patología , Liposarcoma/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/patología , Modelos de Riesgos Proporcionales , Neoplasias Retroperitoneales/patología , Estudios Retrospectivos , Sarcoma/patologíaRESUMEN
Chromosomal instability (CIN) is a hallmark of cancer1. Yet, many childhood cancers, such as Ewing sarcoma (EwS), feature remarkably 'silent' genomes with minimal CIN2. Here, we show in the EwS model how uncoupling of mitosis and cytokinesis via targeting protein regulator of cytokinesis 1 (PRC1) or its activating polo-like kinase 1 (PLK1) can be employed to induce fatal genomic instability and tumor regression. We find that the EwS-specific oncogenic transcription factor EWSR1-FLI1 hijacks PRC1, which physiologically safeguards controlled cell division, through binding to a proximal enhancer-like GGAA-microsatellite, thereby promoting tumor growth and poor clinical outcome. Via integration of transcriptome-profiling and functional in vitro and in vivo experiments including CRISPR-mediated enhancer editing, we discover that high PRC1 expression creates a therapeutic vulnerability toward PLK1 inhibition that can repress even chemo-resistant EwS cells by triggering mitotic catastrophe.Collectively, our results exemplify how aberrant PRC1 activation by a dominant oncogene can confer malignancy but provide opportunities for targeted therapy, and identify PRC1 expression as an important determinant to predict the efficacy of PLK1 inhibitors being used in clinical trials.
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Apoptosis/genética , Proteínas de Ciclo Celular/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Sarcoma de Ewing/genética , Animales , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Niño , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Estimación de Kaplan-Meier , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Interferencia de ARN , Tratamiento con ARN de Interferencia/métodos , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/terapia , Transducción de Señal/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Quinasa Tipo Polo 1RESUMEN
Deciphering principles of inter-tumoral heterogeneity is crucial for refinement of precision oncology. We have recently demonstrated that 'oncogenic cooperation' between somatic mutations and regulatory germline variants can serve as a major cause for inter-tumoral heterogeneity, suggesting the requirement of integrating the regulatory genome into 'omics'-based precision oncology.
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A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20017-2.
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Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 - a physiological driver of proliferation of osteo-chondrogenic progenitors - by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol.Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.
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Regulación Neoplásica de la Expresión Génica , Proteínas de Fusión Oncogénica/metabolismo , Estrés Oxidativo , Sarcoma de Ewing/patología , Adulto , Animales , Neoplasias Óseas/patología , Línea Celular Tumoral , Proliferación Celular , Niño , Condrocitos/metabolismo , Metilación de ADN , Elementos de Facilitación Genéticos , Perfilación de la Expresión Génica , Células HEK293 , Humanos , Hidrazinas/química , Células Madre Mesenquimatosas/metabolismo , Ratones , Repeticiones de Microsatélite , Mitocondrias/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Oncogenes , Interferencia de ARN , Factores de Transcripción SOXD/metabolismo , Sarcoma/genéticaRESUMEN
Ewing sarcoma (EwS) is an aggressive cancer displaying an undifferentiated small-round-cell histomorphology that can be easily confused with a broad spectrum of differential diagnoses. Using comparative transcriptomics and immunohistochemistry (IHC), we previously identified BCL11B and GLG1 as potential specific auxiliary IHC markers for EWSR1-FLI1-positive EwS. Herein, we aimed at validating the specificity of both markers in a far larger and independent cohort of EwS (including EWSR1-ERG-positive cases) and differential diagnoses. Furthermore, we evaluated their intra-tumoral expression heterogeneity. Thus, we stained tissue microarrays from 133 molecularly confirmed EwS cases and 320 samples from morphological mimics, as well as a series of patient-derived xenograft (PDX) models for BCL11B, GLG1, and CD99, and systematically assessed the immunoreactivity and optimal cut-offs for each marker. These analyses demonstrated that high BCL11B and/or GLG1 immunoreactivity in CD99-positive cases had a specificity of 97.5% and an accuracy of 87.4% for diagnosing EwS solely by IHC, and that the markers were expressed by EWSR1-ERG-positive EwS. Only little intra-tumoral heterogeneity in immunoreactivity was observed for differential diagnoses. These results indicate that BCL11B and GLG1 may help as specific auxiliary IHC markers in diagnosing EwS in conjunction with CD99, especially if confirmatory molecular diagnostics are not available.
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Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.