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Frontiers in Immunology 2023Hypermethylated in Cancer 1 (HIC1) was originally confirmed as a tumor suppressor and has been found to be hypermethylated in human cancers. Although growing evidence...
BACKGROUND
Hypermethylated in Cancer 1 (HIC1) was originally confirmed as a tumor suppressor and has been found to be hypermethylated in human cancers. Although growing evidence has supported the critical roles of HIC1 in cancer initiation and development, its roles in tumor immune microenvironment and immunotherapy are still unclear, and no comprehensive pan-cancer analysis of HIC1 has been conducted.
METHODS
HIC1 expression in pan-cancer, and differential HIC1 expression between tumor and normal samples were investigated. Immunohistochemistry (IHC) was employed to validate HIC1 expression in different cancers by our clinical cohorts, including lung cancer, sarcoma (SARC), breast cancer, and kidney renal clear cell carcinoma (KIRC). The prognostic value of HIC1 was illustrated by Kaplan-Meier curves and univariate Cox analysis, followed by the genetic alteration analysis of HIC1 in pan-cancer. Gene Set Enrichment Analysis (GSEA) was conducted to illustrate the signaling pathways and biological functions of HIC1. The correlations between HIC1 and tumor mutation burden (TMB), microsatellite instability (MSI), and the immunotherapy efficacy of PD-1/PD-L1 inhibitors were analyzed by Spearman correlation analysis. Drug sensitivity analysis of HIC1 was performed by extracting data from the CellMiner™ database.
RESULTS
HIC1 expression was abnormally expressed in most cancers, and remarkable associations between HIC1 expression and prognostic outcomes of patients in pan-cancer were detected. HIC1 was significantly correlated with T cells, macrophages, and mast cell infiltration in different cancers. Moreover, GSEA revealed that HIC1 was significantly involved in immune-related biological functions and signaling pathways. There was a close relationship of HIC1 with TMB and MSI in different cancers. Furthermore, the most exciting finding was that HIC1 expression was significantly correlated with the response to PD-1/PD-L1 inhibitors in cancer treatment. We also found that HIC1 was significantly correlated with the sensitivity of several anti-cancer drugs, such as axitinib, batracylin, and nelarabine. Finally, our clinical cohorts further validated the expression pattern of HIC1 in cancers.
CONCLUSIONS
Our investigation provided an integrative understanding of the clinicopathological significance and functional roles of HIC1 in pan-cancer. Our findings suggested that HIC1 can function as a potential biomarker for predicting the prognosis, immunotherapy efficacy, and drug sensitivity with immunological activity in cancers.
Topics: Humans; Ferroptosis; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Prognosis; Carcinoma, Renal Cell; Kidney Neoplasms; Tumor Microenvironment; Kruppel-Like Transcription Factors
PubMed: 37388742
DOI: 10.3389/fimmu.2023.1182030 -
British Journal of Haematology May 2020
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Humans; Leukemia, Mast-Cell; Mast-Cell Sarcoma; Middle Aged; Young Adult
PubMed: 32242922
DOI: 10.1111/bjh.16581 -
Pathobiology : Journal of... 2020Most cases of mastocytosis are indolent, usually cutaneous mastocytosis or indolent systemic mastocytosis (SM). Aggressive mast cell (MC) diseases are very rare and... (Review)
Review
Most cases of mastocytosis are indolent, usually cutaneous mastocytosis or indolent systemic mastocytosis (SM). Aggressive mast cell (MC) diseases are very rare and often fatal. They can develop de novo or due to progression of indolent forms and can present in different ways; either as MC sarcoma or as advanced SM which includes aggressive SM, MC leukemia, and SM with an associated hematological neoplasm. This review will describe these different aggressive forms of mastocytosis, illustrated by cases submitted to the workshop of the 18th Meeting of the European Association for Haematopathology, Basel 2016, organized by the European Bone Marrow Working Group. In addition, the diagnostic criteria for identifying myelomastocytic leukemia, an aggressive myeloid neoplasm with partial MC differentiation that falls short of the criteria for SM, and disease progression in patients with established mastocytosis are discussed.
Topics: Bone Marrow; Congresses as Topic; Diagnosis, Differential; Disease Progression; Europe; Humans; Leukemia, Mast-Cell; Mastocytosis; Mastocytosis, Systemic; Myeloproliferative Disorders
PubMed: 31802761
DOI: 10.1159/000504099 -
PloS One 2024Ewing's sarcoma (ES) is the second most common bone and soft tissue malignancy in children and adolescents with a poor prognosis. The identification of genes with...
Ewing's sarcoma (ES) is the second most common bone and soft tissue malignancy in children and adolescents with a poor prognosis. The identification of genes with prognostic value may contribute to the prediction and treatment of this disease. The GSE17679, GSE68776, GSE63155, and GSE63156 datasets were downloaded from the Gene Expression Omnibus database and qualified. Prognostic value of differentially expressed genes (DEGs) between the normal and tumor groups and immune cell infiltration were explored by several algorithms. A prognostic model was established and validated. Finally, functional analyses of the DEGs were performed. Proline rich 11 (PRR11) and mast cell infiltration were noted as the key indicators for the prognosis of ES. Kaplan-Meier and scatter plots for the training and two validation sets showed that patients in the low-PRR11 expression group were associated with better outcomes than those in the high-PRR11 expression group. The concordance indices and calibration analyses of the prognostic model indicated good predictive accuracy in the training and validation sets. The area under the curve values obtained through the receiver operating characteristic analysis for 1-, 3-, 5-year prediction were ≥ 0.75 in the three cohorts, suggesting satisfactory sensitivity and specificity of the model. Decision curve analyses suggested that patients could benefit more from the model than the other strategies. Functional analyses suggested that DEGs were mainly clustered in the cell cycle pathway. PRR11 and mast cell infiltration are potential prognostic indicators in ES. PRR11 possibly affects the prognosis of patients with ES through the cell cycle pathway.
Topics: Adolescent; Child; Humans; Algorithms; Calibration; Prognosis; Sarcoma; Sarcoma, Ewing
PubMed: 38427643
DOI: 10.1371/journal.pone.0299720 -
BMC Cancer Jan 2023Mastocytosis is a very rare disorder and is divided into three prognostically distinct variants by World Health Organization: Cutaneous mastocytosis (CM), systemic...
Mastocytosis is a very rare disorder and is divided into three prognostically distinct variants by World Health Organization: Cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma or localized mast cell (MC) tumors. The wide range of complaints may cause patients to consult various clinics, with resulting mis- or underdiagnosis. Therefore, cooperation between different subspecialties is of paramount importance. In this article, we have compiled 104 adult mastocytosis cases diagnosed and followed in our Hematology and other clinics. 86 (82.7%) of 104 patients had systemic mastocytosis. Osteoporosis, disease-related complications, and secondary malignancies are important topics in this group. We know that indolent form has great survival. But smoldering or aggressive mastocytosis has a poor prognosis. CM and indolent SM have a significantly better prognosis compared to aggressive SM (p < 0.001). We found that the presence of more than 25% of mast cells in the bone marrow, the presence of concomitant marrow dysplasia, and the presence of disease-related complications affect survival (p < 0.001). In addition to the WHO classification, the IPSM scoring system is indicative of the prognosis in this rare disease.
Topics: Adult; Humans; Mastocytosis, Systemic; Mastocytosis; Mast Cells; Bone Marrow; Prognosis; Myeloproliferative Disorders
PubMed: 36694141
DOI: 10.1186/s12885-022-10498-3 -
Clinical Cancer Research : An Official... Jun 2024To explore the cellular cross-talk of tumor-resident mast cells (MC) in controlling the activity of cancer-associated fibroblasts (CAF) to overcome tumor...
PURPOSE
To explore the cellular cross-talk of tumor-resident mast cells (MC) in controlling the activity of cancer-associated fibroblasts (CAF) to overcome tumor microenvironment (TME) abnormalities, enhancing the efficacy of immune-checkpoint inhibitors in sarcoma.
EXPERIMENTAL DESIGN
We used a coculture system followed by further validation in mouse models of fibrosarcoma and osteosarcoma with or without administration of the MC stabilizer and antihistamine ketotifen. To evaluate the contribution of ketotifen in sensitizing tumors to therapy, we performed combination studies with doxorubicin chemotherapy and anti-PD-L1 (B7-H1, clone 10F.9G2) treatment. We investigated the ability of ketotifen to modulate the TME in human sarcomas in the context of a repurposed phase II clinical trial.
RESULTS
Inhibition of MC activation with ketotifen successfully suppressed CAF proliferation and stiffness of the extracellular matrix accompanied by an increase in vessel perfusion in fibrosarcoma and osteosarcoma as indicated by ultrasound shear wave elastography imaging. The improved tissue oxygenation increased the efficacy of chemoimmunotherapy, supported by enhanced T-cell infiltration and acquisition of tumor antigen-specific memory. Importantly, the effect of ketotifen in reducing tumor stiffness was further validated in sarcoma patients, highlighting its translational potential.
CONCLUSIONS
Our study suggests the targeting of MCs with clinically administered drugs, such as antihistamines, as a promising approach to overcome resistance to immunotherapy in sarcomas.
Topics: Humans; Mice; Animals; Mast Cells; Tumor Microenvironment; Immune Checkpoint Inhibitors; B7-H1 Antigen; Sarcoma; Ketotifen; Cell Line, Tumor; T-Lymphocytes; Xenograft Model Antitumor Assays; Lymphocytes, Tumor-Infiltrating; Female; Cancer-Associated Fibroblasts; Doxorubicin; Osteosarcoma
PubMed: 38578281
DOI: 10.1158/1078-0432.CCR-24-0246 -
Heliyon Sep 2023The prognostic value of D-glucuronyl C5-epimerase ( and mast cell infiltration in Ewing sarcoma (ES) has not been well specified and highlighted, which may facilitate...
BACKGROUND
The prognostic value of D-glucuronyl C5-epimerase ( and mast cell infiltration in Ewing sarcoma (ES) has not been well specified and highlighted, which may facilitate survival prediction and treatment.
METHODS
Several qualified datasets were downloaded from the GEO website. Common differentially expressed genes between normal subjects and ES patients in GSE17679, GSE45544, and GSE68776 were identified and screened by multiple algorithms to find hub genes with prognostic value. The prognostic value of 64 infiltrating cells was also explored. A prognostic model was established and then validated with GSE63155 and GSE63156. Finally, functional analysis was performed.
RESULTS
and mast cell infiltration were screened as two indicators for a prognostic model. The Kaplan‒Meier analysis showed that patients in the low expression, mast cell infiltration and risk score groups had poorer outcomes than patients in the high expression, mast cell infiltration and risk score groups, both in the training and validation sets. Scatter plots and heatmaps also indicated the same results. The concordance indices and calibration analyses indicated a high prediction accuracy of the model in the training and validation sets. The time-dependent receiver operating characteristic analyses suggested high sensitivity and specificity of the model, with area under the curve values between 0.76 and 0.98. The decision curve analyses suggested a significantly higher net benefit by the model than the treat-all and treat-none strategies. Functional analyses suggested that glycosaminoglycan biosynthesis-heparan sulfate/heparin, the cell cycle and microRNAs in cancer were upregulated in ES patients.
CONCLUSIONS
and mast cell infiltration are potential prognostic indicators in ES. may affect the proliferation, angiogenesis and metastasis of ES by affecting the biosynthesis of heparan sulfate and heparin.
PubMed: 37662777
DOI: 10.1016/j.heliyon.2023.e19357 -
American Journal of Hematology Mar 2023
Topics: Humans; Mast-Cell Sarcoma; Mast Cells
PubMed: 36464921
DOI: 10.1002/ajh.26804 -
Clinical Pathology (Thousand Oaks,... 2022Mastocytosis is a rare disorder affecting both children and adults by gathering of functionally defective mast cells in the body's tissues. The World Health Organization...
Mastocytosis is a rare disorder affecting both children and adults by gathering of functionally defective mast cells in the body's tissues. The World Health Organization (WHO) classified mastocytosis into cutaneous mastocytosis, systemic mastocytosis (SM), and mast cell sarcoma (MCS). We hereby present a case of retroperitoneal MCS with concurrent systemic mastocytosis and an undisclosed associated hematological neoplasm (SM-undisclosed AHN). The diagnosis of MCS and SM was made after the second biopsy over retroperitoneal mass, lymph node, and ovary for rapidly progressive disease with the presentation of unexplained recurrent flushing, palpitation, and shock, in addition to abdominal pain. A clonal myeloid neoplasm was also suspected by the karyotype and hemogram data. Unfortunately, the patient succumbed to the disease quickly. Apart from this unique case, the previously reported cases of SM with MCS in the literature were also reviewed.
PubMed: 36119438
DOI: 10.1177/2632010X221123539 -
Novel prognostic biomarkers, METTL14 and YTHDF2, associated with RNA methylation in Ewing's sarcoma.Scientific Reports Apr 2022Ewing's sarcoma has a poor prognosis and high metastasis rate; thus, it is critical to explore prognostic biomarkers of m6A-related genes. Two datasets were downloaded...
Ewing's sarcoma has a poor prognosis and high metastasis rate; thus, it is critical to explore prognostic biomarkers of m6A-related genes. Two datasets were downloaded from the Gene Expression Omnibus database, m6A-related genes were extracted, and prognostic models were constructed using the least absolute shrinkage and selection operator and multivariate COX regression analyses. Immune cell composition and drug sensitivity analyses were performed, and our analysis was validated using laboratory methods of immunohistochemical specific staining and qRT-PCR. Ewing's sarcoma prognostic model demonstrated that the survival rate of cases in the high-risk group was much lower than that of the low-risk group. Naïve B cells, macrophages M0, macrophages M1, and resting mast cells are closely associated with Ewing's sarcoma. METTL14 and YTHDF2 are strongly associated with multiple drug sensitivity. Immunohistochemical specific staining revealed higher expression of both METTL14 and YTHDF2 in Ewing's sarcoma than in the paraneoplastic tissues. The results of qRT-PCR showed that METTL14 expression was significantly higher in both ES cell lines than in the control cell line. The prognostic model constructed using m6A-related genes METTL14 and TYHDF2, can be a potential prognostic biomarker for Ewing's sarcoma, with the survival rate of cases in the high-risk group being much lower than that of the low-risk group.
Topics: Biomarkers; Humans; Methylation; Methyltransferases; Neuroectodermal Tumors, Primitive, Peripheral; Prognosis; RNA; RNA-Binding Proteins; Sarcoma, Ewing; Transcription Factors
PubMed: 35487915
DOI: 10.1038/s41598-022-06744-0