Development Of Sarcoma Research Articles

Prospects for Epigenetic Targeted Therapies of Bone and Soft-Tissue Sarcomas.

Targeted therapies have revolutionized cancer treatment. It is well established that alterations of chromatin configuration and modifications affect tumorigenesis of some, possibly most, bone and soft-tissue sarcomas. As epigenetic regulators play a major role in the development of bone and soft-tissue sarcomas, epigenetic drugs provide a novel potential avenue for rational targeted therapies for these aggressive cancers. The present review summarizes the application of epigenetic drugs for clinical utilization in bone and soft-tissue sarcomas and provides an overview of clinical trials currently evaluating epigenetic therapies in this space.

Identification of prognostic alternative splicing events in sarcoma

Sarcoma is a rare malignancy with unfavorable prognoses. Accumulating evidence indicates that aberrant alternative splicing (AS) events are generally involved in cancer pathogenesis. The aim of this study was to identify the prognostic value of AS-related survival genes as potential biomarkers, and highlight the functional roles of AS events in sarcoma. RNA-sequencing and AS-event datasets were downloaded from The Cancer Genome Atlas (TCGA) sarcoma cohort and TCGA SpliceSeq, respectively. Survival-related AS events were further assessed using a univariate analysis. A multivariate Cox regression analysis was also performed to establish a survival-gene signature to predict patient survival, and the area-under-the-curve method was used to evaluate prognostic reliability. KOBAS 3.0 and Cytoscape were used to functionally annotate AS-related genes and to assess their network interactions. We detected 9674 AS events in 40,184 genes from 236 sarcoma samples, and the 15 most significant genes were then used to construct a survival regression model. We further validated the involvement of ten potential survival-related genes (TUBB3, TRIM69, ZNFX1, VAV1, KCNN2, VGLL3, AK7, ARMC4, LRRC1, and CRIP1) in the occurrence and development of sarcoma. Multivariate survival model analyses were also performed, and validated that a model using these ten genes provided good classifications for predicting patient outcomes. The present study has increased our understanding of AS events in sarcoma, and the gene-based model using AS-related events may serve as a potential predictor to determine the survival of sarcoma patients.

Abstract 2714: Development of a phenotypically diverse model of sarcoma formation to identify key drivers of tumorigenesis across subtypes

Abstract Approximately 13,000 people this year in the United States alone will be diagnosed with sarcoma and nearly 5,000 will lose their lives to this devastating disease. Soft tissue sarcomas are a clinically and biologically heterogeneous group of tumors made up of approximately fifty subtypes that are classified by their presumed mesenchymal origin. The development of novel therapies for sarcoma has been hampered by the considerable heterogeneity of the disease and the limited understanding of the molecular mechanisms driving sarcoma formation and evolution. Due to this, clinically, the majority of patients with aggressive soft tissue sarcoma subtypes are treated similarly despite evidence these subtypes are unique. Our lab has focused on the development of a new model for the study of sarcoma subtypes using a primary human transformation system. Based on TCGA data, one characteristic that is shared between sarcoma subtypes is the loss or silencing of p53 and Rb1. We have started with immortalized mesenchymal stem cells (MSC), the presumed cell of origin for sarcoma and introduced lentiviral constructs targeting p53 and Rb1 by CRISPR technology to delete these genes. Following this, we have added a barcoded oncogene library with genes implicated in sarcoma specific biology or across cancer subtypes. Using this system, we have successfully transformed these MSCs into high grade soft tissue sarcomas. The current goal is to continue to manipulate this system to develop multiple soft tissue sarcoma subtypes. By starting with the same cell of origin and arriving at different sarcoma subtypes, we can begin to understand the relationship between these subtypes which will inform clinical trial design. Using this system, we can investigate the development of sarcoma, understand subtype heterogeneity, and utilize this tool to develop novel therapies for our patients. Citation Format: Janai Carr-Ascher. Development of a phenotypically diverse model of sarcoma formation to identify key drivers of tumorigenesis across subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2714.

Late Events in Adult Patients with ALK-Positive Anaplastic Large Cell Lymphoma

ALK-positive anaplastic large cell lymphoma is a lymphoproliferative disorder of “young age”; its incidence among all non-Hodgkin lymphomas in adult patient cohort is 2-15%. Cytogenetic aberrations associated with ALK rearrangements mainly include t(2;5)(p23;q32) and the chimeric fusion gene NPM-ALK, while less than 10-15% of cases are associated with variant translocations involving 2p23 and resulting in formation of rare oncogenes.Favorable prognosis in patients with this type of the disorder who receive high-dose chemotherapy regimens (NHL BFM-90) is associated with 75%-92% overall and event-free survival rates, including in adult patients. Therapy failures are generally diagnosed during the first 1.5-2 years of follow-up. The risk of development of secondary tumor lesions following high-dose chemotherapy does not exceed 10% (in children).The goal of the study was to evaluate the development of late events (relapse, secondary tumors) in 52 adult patients (median age 33 years) with ALK-positive anaplastic large cell lymphoma who had received unified program of high-dose chemotherapy according to NHL BFM-90 protocol.The results: this therapy program was associated with 83% and 79% overall and event-free survival rates, respectively (median follow-up - 83 months), early relapses (median time to development 12 months) were verified in 3 patients (6%), disease progression - in 3 (6%) cases. Three patients developed late events (>5.5 years following the end of treatment). In two cases, a tumor relapse was diagnosed: in one patient who initially had stage IV disease and extranodal lesions in the skin and soft tissues - after 5.5 years of follow-up; and in another patient - after 7 years of follow-up. Peculiar features of the first clinical case - minimal disseminated disease was revealed at the moment of diagnosis verification, with the ATIC-ALK chimeric transcript detected in peripheral blood and bone marrow (which was consistent with a variant translocation, inv (2)(p23;q35)); no chimeric oncogene has been detected after the courses of induction therapy and during subsequent years of follow-up. In the second case, at the moment of the relapse verification, the ATIC-ALK transcript was detected again in the specimens of bone marrow and peripheral blood, indicating the development of a distant relapse from the identical primary tumor clone.The third late event (diagnosed in >11 years after the end of chemotherapy) was the development of epithelioid sarcoma with primary spleen involvement.Thus, high-dose first-line chemotherapy in adult patients with ALK+ ALGL has proven to be highly effective. Early relapses and progressions were verified not more than in 6% of cases. The characteristics of these late events are of special interest: a relapse in the form of development of new skin lesions (as was observed at the time of the disease manifestation); in the second case - relapse from the identical tumor cell clone in 7 years, and, finally, the development of a rare secondary tumor (epithelioid sarcoma) together with non-conventional clinical course (tumor nodes in the spleen and retroperitoneal lymphadenopathy). DisclosuresNo relevant conflicts of interest to declare.

The FLI portion of EWS/FLI contributes a transcriptional regulatory function that is distinct and separable from its DNA-binding function in Ewing sarcoma

Ewing sarcoma is an aggressive bone cancer of children and young adults defined by the presence of a chromosomal translocation: t(11;22)(q24;q12). The encoded protein, EWS/FLI, fuses the amino-terminal domain of EWS to the carboxyl-terminus of FLI. The EWS portion is an intrinsically disordered transcriptional regulatory domain, while the FLI portion contains an ETS DNA-binding domain and two flanking regions of unknown function. Early studies using non-Ewing sarcoma models provided conflicting information on the roles of each domain of FLI in EWS/FLI oncogenic function. We therefore sought to define the specific contributions of each FLI domain to EWS/FLI activity in a well-validated Ewing sarcoma model and, in doing so, to better understand Ewing sarcoma development mediated by the fusion protein. We analyzed a series of engineered EWS/FLI mutants with alterations in the FLI portion using a variety of assays. Fluorescence anisotropy, CUT&RUN, and ATAC-sequencing experiments revealed that the isolated ETS domain is sufficient to maintain the normal DNA-binding and chromatin accessibility function of EWS/FLI. In contrast, RNA-sequencing and soft agar colony formation assays revealed that the ETS domain alone was insufficient for transcriptional regulatory and oncogenic transformation functions of the fusion protein. We found that an additional alpha-helix immediately downstream of the ETS domain is required for full transcriptional regulation and EWS/FLI-mediated oncogenesis. These data demonstrate a previously unknown role for FLI in transcriptional regulation that is distinct from its DNA-binding activity. This activity is critical for the cancer-causing function of EWS/FLI and may lead to novel therapeutic approaches.

Levels of the IGF system components in malignant lesions of the lungs with preventive effect of 1,3-diethylbenzimidazolium triiodide in the experiment.

e15095 Background: The system of insulin-like growth factors (IGF) is involved in carcinogenesis, since it promotes proliferation and survival of tumor cells. The purpose of the study was an analysis of the dynamics of the IGF system components in the lungs of rats with antitumor effect of 1,3-diethylbenzimidazolium triiodide. Methods: The main group included male (n=27) and female (n=27) white outbred rats with sarcoma 45 inoculated into the subclavian vein (2×106 cells in 0.5 mL saline) but not developed in the lungs due to administration of 1,3-diethylbenzimidazolium triiodide (intragastrically, 0.4 mg/kg once a day according to the regimen: administration for 5 days with a 2-day interval). Control group included males (n=14) and females (n=14) with sarcoma 45 growing in the lungs without treatment. Intact groups included 5 males and 5 females. After 4, 5 and 8 weeks of the experiment animals were decapitated, and levels of IGFI, IGFII, IGFBP1, IGFBP2 and IGFBP3 were measured by ELISA in 10% lung homogenates (CUSABIO BIOTECH Co., Ltd., China). Results: The sarcoma development in the lung was accompanied by the IGFI increase by 2.4-3.0 times in males and by 4.3 times in females, and the opposite IGFII dynamics: an increase in males (by 4.6 times) and decrease in females (by 4.3 times), together with the IGFBP decline. 1,3-diethylbenzimidazolium triiodide upregulated IGFI levels in the lungs of all rats on average by 1.3 times (p<0.05) and normalized IGFII in males, while increasing it in females by 1.6 times (p<0.05), together with higher (compared to controls) IGFBP levels. Conclusions: Preventive antitumor effect of 1.3-diethylbenzimidazolium triiodide is based on the stabilization of the IGF system grossly altered during the malignant process development in the lung.

Phase 1 expansion trial of the LSD1 inhibitor seclidemstat (SP-2577) with and without topotecan and cyclophosphamide (TC) in patients (pts) with relapsed or refractory Ewing sarcoma (ES) and select sarcomas.

TPS11577 Background: Several sarcomas possess chromosomal translocations in FET family members ( FUS, EWSR1, and TAF15) responsible for cancer development. Sarcomas caused by FET family gene rearrangements include ES, desmoplastic round cell small tumors (DSRCT), myxoid liposarcoma (ML), and several others. Lysine specific demethylase 1 (LSD1) is a critical protein for sarcoma development and progression through its colocalization and/or association with several FET family oncogenic transcription factors. This suggests that pharmacologic inhibition of LSD1 may be a therapeutic strategy. Seclidemstat (SP-2577, Salarius Pharmaceuticals) is an oral, first-in-class, small molecule with reversible, noncompetitive inhibition of LSD1 (IC50: 25–50 nM). In vitro and in vivo data demonstrate seclidemstat, or analogs, modulate EWS/ETS transcriptional activity, down-regulating oncogene expression and up-regulating tumor-suppressor gene expression, leading to significant tumor growth inhibition in ES mouse xenograft studies. Seclidemstat has shown in in vitro ES cell lines near additivity efficacy when added to TC. In in vitro studies of other FET-translocated sarcomas, including ML (FUS/DDIT3 fusion) and clear cell sarcoma (EWS/ATF1 fusion), seclidemstat showed anti-proliferative activity. In an ongoing Phase 1 trial investigating single agent seclidemstat in advanced solid tumors (NCT03895684), three pts with metastatic FET-translocated sarcomas had a median progression-free survival of 5.7 months (range: 4.3–7.2) with a best response of stable disease despite having a median of 5 (range: 1–7) prior therapies. Methods: This dose expansion Phase 1 study (NCT03600649) assesses seclidemstat at 900 mg PO BID, the recommended Phase 2 dose, in two expansion cohorts: a single agent expansion in select sarcoma pts (n = 30) and a safety lead-in dose escalation and expansion (n = 24) of seclidemstat combined with TC in pts with ES. Pts must be ≥12 years old, have ECOG performance status of 0 or 1, with a life expectancy > 4 months. In the select sarcoma cohort, pts must have ML (n = 15) or other sarcomas with FET family translocations (n = 15) including DSRCT. One to 3 prior lines of therapy are allowed. In the ES combination cohort, up to 2 lines of prior therapy are allowed. Primary objective is safety/tolerability and secondary objective is efficacy. The trial is currently recruiting across 8 locations in the United States. Clinical trial information: NCT03600649.

Have Duchenne Muscular Dystrophy Patients an Increased Cancer Risk?

Increasing evidence suggests that Duchenne muscular dystrophy (DMD) gene is involved in the occurrence of different types of cancer. Moreover, development of sarcomas was reported in mdx mice, the murine model of DMD, in older age. So far, nine isolated DMD patients were reported with concomitant cancer, four of whom with rhabdomyosarcoma (RMS), but no systematic investigation was performed about the true incidence of cancer in DMD. All members of the Italian Association of Myology were asked about the occurrence of cancer in their DMD patients in the last 30 years. Four DMD patients with cancer were reported after checking 2455 medical records. One developed brain tumour at the age of 35 years. Two patients had alveolar RMS at 14 and 17 years of age. The fourth patient had a benign enchondroma when 11-year-old. Prevalence of cancer in general in the Italian DMD patients does not seem to be different from that in the general population with the same age range. Although the small numbers herein presented do not allow definitive conclusion, the frequent occurrence of RMS in DMD patients raises an alert for basic researchers and clinicians. The role of DMD gene in cancer merits further investigations.

Lifetime radiation-induced sarcoma risk in patients subjected to IMRT or VMAT for uterine cervix carcinoma.

This study was conducted to estimate the lifetime radiation-induced bone and soft tissue sarcoma risks from intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) for uterine cervix carcinoma. 13 cervical cancer patients were included. The bone and soft tissue structures were defined on patients' treatment planning computed tomography (CT) scans. Both CT-based IMRT and VMAT plans with 6 MV photons delivering 45Gy to the target site were designed for each patient. The organ equivalent dose (OED) and the lifetime attributable risk (LAR) for developing bone or soft tissue sarcoma were estimated using treatment planning data and a non-linear mechanistic model. The estimation method did not consider the survival rates following radiotherapy and the use of brachytherapy treatments. The patient-specific OEDs of the bone structure from IMRT and VMAT were 2.33-2.83 and 2.34-2.82Gy, respectively. The corresponding values for the soft tissue structure were 1.27-1.70 and 1.32-1.73Gy. An insignificant difference was found between the patient-specific OEDs and the directly proportional sarcoma risks (bone: P = 0.07; soft tissue: P = 0.38). The LAR for the development of a bone sarcoma varied from 0.05 to 0.16% by the patient's age during irradiation and the applied treatment delivery technique. The corresponding LAR range for radiation-induced soft-tissue sarcoma was 0.08-0.27%. The above LARs resulted in a relative risk of more than 1.20 indicating that IMRT or VMAT may lead to a considerable risk increase of developing bone or soft tissue sarcoma exceeding 20% in respect to the current incidence of these malignancies in unexposed population.

PLCG2 as a potential indicator of tumor microenvironment remodeling in soft tissue sarcoma.

The tumor microenvironment (TME) plays an important role in the occurrence and development of soft tissue sarcoma (STS). A number of studies have shown that to inhibit tumor growth, the TME can be remodeled into an environment unsuitable for tumor proliferation. However, a lack of understanding exists regarding the dynamic regulation of TME.In this study, we used CIBERSORT and ESTIMATE calculation methods from the Cancer Genome Atlas (TCGA) database to calculate the proportion of tumor infiltrating immune cells (TICs) and the number of immune and stromal components in 263 STS samples. Differential expression genes (DEGs) shared by Immune Score and Stromal Score were obtained via difference analysis. Univariate Cox regression analysis and construction of protein–protein interaction (PPI) networks were applied to the DEGs.Through intersection analysis of univariate COX and PPI, PLCG2 was determined as the indicator. Further analysis showed that PLCG2 expression was positively correlated with the survival of STS patients. Gene set enrichment analysis (GSEA) showed that genes in the highly expressed PLCG2 group were enriched in immune-related activities. In the low-expression PLCG2 group, genes were enriched in the E2F, G2M, and MYC pathways. Difference analysis and correlation analysis showed that CD8+ T cells, gamma delta T cells, monocytes, and M1 macrophages were positively correlated with PLCG2 expression, indicating that PLCG2 may represent the immune status of TME.Therefore, the level of PLCG2 may aid in determining the prognosis of STS patients, especially the status of TME. These data provide additional insights into the remodeling of TME.

Magic box – not only flesh but also with a fatal bone: A rare case of extraskeletal intra-abdominal osteogenic sarcoma

Extraskeletal osteogenic sarcoma is a rare tumor with a poor prognosis. It is histologically characterized by the formation of malignant osteoid, however, there is no association with the axial or appendicular skeleton. It comprises less than 2% of the soft-tissue sarcomas. Postulated risk factors for the development of extraskeletal osteogenic sarcoma are middle and elderly aged patients, history of radiation in the past, and trauma. Here, we report a rare case of extraskeletal intra-abdominal osteogenic sarcoma in a 56-year-old female who presented with a complaint of on and off abdominal pain for the past month. The patient presented with a large retroperitoneal soft-tissue mass with areas of calcifications on CT. Positron emission tomography-CT revealed a large mass with diffuse fluorodeoxyglucose uptake with no other lesion elsewhere in the body. A CT-guided tru-cut biopsy was taken and immunohistochemistry was done on the same. This was proven as osteogenic sarcoma on immunohistochemistry. The patient was started on palliative chemotherapy as the mass was not resectable.

Current Status of Management and Outcome for Patients with Ewing Sarcoma.

Simple SummaryEwing sarcoma is a highly aggressive malignancy affecting primarily children and adolescents. It is the second most common bone sarcoma among children, affecting between 1 and 3 persons per million inhabitants. The tumor typically carries a pathognomonic chromosomal translocation resulting in a fusion transcript (EWSR1-FLI1), which plays an orchestral role in tumor development. While the fusion transcript has been known for decades, targeted treatment has been disappointing. However, new molecular techniques such as next-generation sequencing have significantly increased our understanding of this rare disease. Moreover, new closely related tumors with similar morphology but different characteristics have evolved. Treatment today consists of multiagent chemotherapy, radiation treatment, and surgery, all of which are associated with significant short- and long-term side effects. In this review article, we describe the currently existing diagnostic- and treatment-related challenges as well as the most important ongoing or recently conducted studies.Ewing sarcoma is the second most common bone sarcoma in children after osteosarcoma. It is a very aggressive malignancy for which systemic treatment has greatly improved outcome for patients with localized disease, who now see survival rates of over 70%. However, for the quarter of patients presenting with metastatic disease, survival is still dismal with less than 30% of patients surviving past 5 years. Patients with disease relapse, local or distant, face an even poorer prognosis with an event-free 5-year survival rate of only 10%. Unfortunately, Ewing sarcoma patients have not yet seen the benefit of recent years’ technical achievements such as next-generation sequencing, which have enabled researchers to study biological systems at a level never seen before. In spite of large multinational studies, treatment of Ewing sarcoma relies entirely on chemotherapeutic agents that have been largely unchanged for decades. As many promising modern therapies, including monoclonal antibodies, small molecules, and immunotherapy, have been disappointing to date, there is no clear candidate as to which drug should be investigated in the next large-scale clinical trial. However, the mechanisms driving tumor development in Ewing sarcoma are slowly unfolding. New entities of Ewing-like tumors, with fusion transcripts that are related to the oncogenic EWSR1-FLI1 fusion seen in the majority of Ewing tumors, are being mapped. These tumors, although sharing much of the same morphologic features as classic Ewing sarcoma, behave differently and may require a different treatment. There are also controversies regarding local treatment of Ewing sarcoma. The radiosensitive nature of the disease and the tendency for Ewing sarcoma to arise in the axial skeleton make local treatment very challenging. Surgical treatment and radiotherapy have their pros and cons, which may give rise to different treatment strategies in different centers around the world. This review article discusses some of these controversies and reproduces the highlights from recent publications with regard to diagnostics, systemic treatment, and surgical treatment of Ewing sarcoma.

Integrated case-control and somatic-germline interaction analyses of soft-tissue sarcoma

PurposeThe contribution of rare genetic variation in the development of soft-tissue sarcoma (STS) remains underexplored. To address this gap, we conducted a whole-exome case-control and somatic-germline interaction study to identify...

Development and validation of prognostic markers in sarcomas base on a multi-omics analysis

BackgroundIn sarcomas, the DNA copy number and DNA methylation exhibit genomic aberrations. Transcriptome imbalances play a driving role in the heterogeneous progression of sarcomas. However, it is still unclear whether abnormalities of DNA copy numbers are systematically related to epigenetic DNA methylation, thus, a comprehensive analysis of sarcoma occurrence and development from the perspective of epigenetic and genomics is required.MethodsRNASeq, copy number variation (CNV), methylation data, clinical follow-up information were obtained from The Cancer Genome Atlas (TCGA) and GEO database. The association between methylation and CNV was analyzed to further identify methylation-related genes (MET-Gs) and CNV abnormality-related genes (CNV-Gs). Subsequently DNA copy number, methylation, and gene expression data associated with the MET-Gs and CNV-Gs were integrated to determine molecular subtypes and clinical and molecular characteristics of molecular subtypes. Finally, key biomarkers were determined and validated in independent validation sets.ResultsA total of 5354 CNV-Gs and 4042 MET-Gs were screened and showed a high degree of consistency. Four molecular subtypes (iC1, iC2, iC3, and iC4) with different prognostic significances were identified by multiomics cluster analysis, specifically, iC2 had the worst prognosis and iC4 indicated an immune-enhancing state. Three potential prognostic markers (ENO1, ACVRL1 and APBB1IP) were determined after comparing the molecular characteristics of the four molecular subtypes. The expression of ENO1 gene was significantly correlated with CNV, and was noticeably higher in iC2 subtype with the worst prognosis than any other subtypes. The expressions of ACVRL1 and APBB1IP were negatively correlated with methylation, and were high-expressed in the iC4 subtype with the most favorable prognosis. In addition, the number of silent/nonsilent mutations and neoantigens in iC2 subtype were significantly more than those in iC1/iC3/iC4 subtype, and the same trend was also observed in CNV Gain/Loss.ConclusionThe current comprehensive analysis of genomic and epigenomic regulation provides new insights into multilayered pathobiology of sarcomas. Four molecular subtypes and three prognostic markers developed in this study improve the current understanding of the molecular mechanisms underlying sarcoma.

Targeted therapies and checkpoint inhibitors in sarcoma.

Sarcomas are defined as a group of mesenchymal malignancies with over 100 heterogeneous subtypes. As a rare and difficult to diagnose entity, micrometastasis is already present at the time of diagnosis in many cases. Current treatment practice of sarcomas consists mainly of surgery, (neo)adjuvant chemo- and/or radiotherapy. Although the past decade has shown that particular genetic abnormalities can promote the development of sarcomas, such as translocations, gain-of-function mutations, amplifications or tumor suppressor gene losses, these insights have not led to established alternative treatment strategies so far. Novel therapeutic concepts with immunotherapy at its forefront have experienced some remarkable success in different solid tumors while their impact in sarcoma remains limited. In this review, the most common immunotherapy strategies in sarcomas, such as immune checkpoint inhibitors, targeted therapy and cytokine therapy are concisely discussed. The programmed cell death (PD)-1/PD-1L axis and apoptosis-inducing cytokines, such as TNF-related apoptosis-inducing ligand (TRAIL), have not yielded the same success like in other solid tumors. However, in certain sarcoma subtypes, e.g. liposarcoma or undifferentiated pleomorphic sarcoma, encouraging results in some cases when employing immune checkpoint inhibitors in combination with other treatment options were found. Moreover, newer strategies such as the targeted therapy against the ancient cytokine macrophage migration inhibitory factor (MIF) may represent an interesting approach worth investigation in the future.

SWI/SNF-deficient thoraco-pulmonary neoplasms.

The SWI/SNF complexes are major regulators of gene expression and their alterations occur in a large array of cancers both of epithelial and mesenchymal lineages. Malignant rhabdoid tumors were the first malignancies linked to deregulation of these complexes with the involvement of SMARCB1 in their development but genetic alterations affect all subunits in other malignancies. In the chest and lung regions, SMARCA4 (BRG1) is the most frequently altered subunit and is involved in the pathogenesis of two subtypes of tumors, including bona fide carcinomas (SMARCA4-deficient non-small cell lung cancers) but also undifferentiated tumors that harbor an undifferentiated phenotype close to those of malignant rhabdoid tumors (SMARCA4-undifferentiated tumors). Although their histogenesis is yet to be fully understood, these tumors are associated with distinct clinical and pathological features even though some overlapping features have been reported in rare cases. SMARCA4 deficiency is easily asserted by immunohistochemistry that show the loss of nuclear expression of the protein in the nuclei of tumor cells. These tumors are commonly associated with high-grade cytological features, rhabdoid cytomorphology, solid architecture and extensive necrosis. The typical immunohistochemical signature of SMARCA4-UT combines co-inactivation of SMARCA2 (BRM) and the overexpression of SOX2 and SALL4. No specific therapeutic strategies have been so far developed for SMARCA4-deficient neoplasms. SMARCB1 subunit is involved in the development of several SMARCB1-deficient sarcomas on top of malignant rhabdoid tumors that may develop in the thorax. Malignant rhabdoid tumors affect mostly children of less than 5y. The differential diagnosis includes epithelioid sarcomas, malignant myoepithelial tumors or myoepithelial carcinomas, extra-skeletal myxoid chondrosarcomas and synovial sarcomas.

Overexpression of EWSR1 (Ewing sarcoma breakpoint region 1/EWS RNA binding protein 1) predicts poor survival in patients with hepatocellular carcinoma

ABSTRACT Hepatocellular carcinoma (HCC) is one of the most prevalent malignant neoplasms with high relapse and mortality rate. It is of great importance to identify novel and effective molecular markers to predict prognosis for the treatment of HCC. The Ewing sarcoma breakpoint region 1 (EWSR1) gene is well known to fuse with various partner genes and involved in promoting the development of multiple sarcomas, especially the Ewing sarcoma family of tumors. Nevertheless, seldom studies have focused on the role of EWSR1 in cancers of epithelial origin, let alone in HCC. In the current study, the transcriptional and clinical data of EWSR1 in HCC patients were obtained from TCGA and GEO databases, as well as 124 cases from the department of Pathology of Sichuan Jianyang People’s Hospital. Kaplan-Meier and Cox regression analysis were used to assess patient prognosis. EWSR1 mRNA levels were significantly upregulated in HCC tissues than in normal liver tissues (P < 0.001). The TCGA database analysis showed upregulation of EWSR1 was associated with histological grade, pathologic T stage and death, in addition to that, the T staging, N staging, TNM staging, Ki67, AFP expression were extremely higher in the EWSR1 over-expression group in our cohort. Univariate and multivariate Cox hazard regression analysis results revealed that EWSR1 was an independent prognostic factor for OS in HCC, and bioinformatics analysis showed RNA splicing process represented the major function and pathway. In conclusion, our data showed EWSR1 could serve as a novel promising prognostic biomarker for HCC patients. Abbreviations: AFP, Alpha-fetoprotein; CCL14, C-C motif chemokine ligand 14; CK19, Cytokeratin 19; CI, coefficient interval; COL1A1, Collagen 1A1; DFS, Disease-free Survival; EWSR1, Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1; FLI1, Friend leukemia virus integration 1; GEO, Gene Expression Omnibus; GO, Gene Ontology; HCC, Hepatocellular carcinoma; HR, Hazard ratio; KEGG, Kyoto Encyclopedia of Genes and Genomes; mRNA, messenger Ribonucleic Acid; N, nodule; OS, Overall survival; PPI, Protein-Protein Interaction analysis; RNA, Ribonucleic Acid; SD, Standard Deviation; TCGA, The Cancer Genome Atlas; T, tumor; TNM, tumor-nodule-metastasis.

Oral Kaposi sarcoma development is associated with HIV viral load, CD4+ count and CD4+/CD8+ ratio.

Background Kaposi’s sarcoma (KS) is an uncommon, multifocal and angioproliferative lesion, which demonstrates a poor prognosis. The aim of the present research was to explore the association of HIV viral load, CD4+ and CD8+ counts and the CD4+/CD8+ ratio on the risk of oral Kaposi’s sarcoma (KS) development.Material and Methods A total of 62 patients were retrieved from March 2008 to October 2020 from the files of two oral pathology centres. Clinical, laboratory and follow-up data were retrieved from their medical files. Poisson regression was used to explore the role of history of immunosuppression and its association with oral KS development. A P-value <0.05 was considered significant.Results Sixty-two patients were included in the present study (32 with oral KS and 30 with no presentation of lesions anywhere on the body). Patients with oral KS presented a mean age of 32.6 years, and male patients were more affected. The hard palate (15 cases; 46.8%) was the main anatomical site affected. The lesions were mostly presented as swellings (13 cases; 40.6%) and nodules (12 cases; 37.5%). Systemic manifestations were also observed, including candidiasis (4 cases; 12.5%), bacterial infection (3 cases; 9.3%), tuberculosis (3 cases; 9.3%), herpes simplex (3 cases; 9.3%) and pneumonia (3 cases; 9.3%). A significant correlation was observed between HIV viral load, CD4+ count and the CD4+/CD8+ ratio with oral KS development.Conclusions HIV viral load, CD4+ count and the CD4+/CD8+ ratio are associated with oral KS development. Key words:Cancer, oral, Kaposi’s sarcoma, diagnostic.

Prevalence of Human Herpes Virus 8 Infection and Pattern of TLR4 rs4986791 Polymorphism in Women with Breast Cancer

Background: Breast cancer is a major cause of female death worldwide. Several factors contribute to cancer development, one of the most important of which is viruses identified by the host immune system and Toll-like receptors (TLRs). Human herpes virus 8 (HHV-8) is one of the viruses with a proven role in Kaposi’s sarcoma development. Objectives: This study aimed to investigate the correlation between HHV-8 infection and breast cancer, as well as the role of rs4986791 polymorphism in women’s health. Methods: Blood samples of 80 healthy subjects and 80 patients suffering from breast cancer were collected (from May-September 2018). The presence of HHV-8 in the samples was examined by PCR. Also, the rs4986791 polymorphism was evaluated by nested PCR-RFLP. Results: The results showed a significant relationship between age and breast cancer. Of 80 cancer patients and 80 healthy subjects, 17 (21.3%) and 15 (18.8%) were carriers of HHV-8, respectively. Also, there was no significant relationship between HHV-8 infection and breast cancer (P = 0.693). We found no significant relationship between the presence of virus and cancer grade (P = 0.618). Conclusions: The results of rs498679 polymorphism analysis indicated that the T allele was associated with increased health phenotype and decreased risk of cancer development. Also, women with TT genotype exhibited significantly lower HHV-8 infection than the other genotypes.

The Tat Protein of Human Immunodeficiency Virus Type-1 Promotes Vascular Cell Growth and Locomotion by Engaging the α5β1 and αvβ3 Integrins and by Mobilizing Sequestered Basic Fibroblast Growth Factor

AbstractThe Tat protein of human immunodeficiency virus type-1 (HIV-1) has been shown to be released during acute infection of T cells by HIV-1 and to promote angiogenesis and Kaposi's sarcoma (KS) development in infected individuals. In this study, we investigated the molecular mechanisms responsible for the angiogenic effects of Tat. The results shown herein indicate that two different Tat domains cooperate to induce these effects by different pathways. The arginine-glycine-aspartic acid (RGD) sequence present at the carboxyterminal of Tat mediates vascular cell migration and invasion by binding to the α5β1 and αvβ3 integrins. This interaction also provides endothelial cells with the adhesion signal they require to grow in response to mitogens. At the same time, the Tat basic sequence retrieves into a soluble form extracellular basic fibroblast growth factor (bFGF) bound to heparan sulfate proteoglycans by competing for heparin-binding sites. This soluble bFGF mediates Tat-induced vascular cell growth. These effects resemble those of extracellular matrix proteins, suggesting that Tat enhances angiogenesis and promotes KS progression by a molecular mimicry of these molecules.