RESUMO
Esophageal squamous cell carcinoma (ESCC) demonstrates high genome instability. Here, we analyze 528 whole genomes to investigate structural variations' mechanisms and biological functions. SVs show multi-mode distributions in size, indicating distinct mutational processes. We develop a tool and define five types of complex rearrangements with templated insertions. We highlight a type of fold-back inversion, which is associated with poor outcomes. Distinct rearrangement signatures demonstrate variable genomic metrics such as replicating time, spatial proximity, and chromatin accessibility. Specifically, fold-back inversion tends to occur near the centrosome; TD-c2 (Tandem duplication-cluster2) is significantly enriched in chromatin-accessibility and early-replication region compared to other signatures. Analyses of TD-c2 signature reveal 9 TD hotspots, of which we identify a hotspot consisting of a super-enhancer of PTHLH. We confirm the oncogenic effect of the PTHLH gene and its interaction with enhancers through functional experiments. Finally, extrachromosomal circular DNAs (ecDNAs) are present in 14% of ESCCs and have strong selective advantages to driver genes.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Cromatina/genética , China , DNA CircularRESUMO
BACKGROUND: SPARC (secreted protein, acidic and rich in cysteine) is closely related with the progress, invasion and metastasis of malignant tumor and angiogenesis. METHODS: Using human colon adenocarcinoma tissues (hereinafter referred to as colon cancer) and their corresponding non-diseased colon from 114 patients' biopsies, the expression of SPARC and vascular endothelial growth factor (VEGF) were investigated by immunohistochemistry staining to assessment the relationship between SPARC and VEGF, as well as their prognostic significance in patients. Evaluation of VEGF expression level with the same tissues was used to establish the antigenic profiles, and the marker of CD34 staining was used as an indicator of microvessel density (MVD). RESULTS: SPARC expression was mainly in the stromal cells surrounding the colon cancer, and was significant difference in those tissues with the lymph node metastasis and differentiation degree of tumor. Expression of SPARC was significantly correlated with the expression of VEGF and MVD in colon cancer tissues. Patients with low or absence expressing SPARC had significantly worse overall survival and disease-free survival in a Single Factor Analysis; Cox Regression Analysis, SPARC emerged as an overall survival and disease-free survival independent prognostic factor for colon cancer. CONCLUSION: The low expression or absence of stromal SPARC was an independent prognostic factor for poor prognosis of colon cancer. SPARC maybe involved in the regulation of anti-angiogenesis by which it may serve as a novel target for colon cancer treatment as well as a novel distinctive marker.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/metabolismo , Osteonectina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adenocarcinoma/patologia , Neoplasias do Colo/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Masculino , Microvasos/metabolismo , Microvasos/patologia , Pessoa de Meia-Idade , Prognóstico , Células Estromais/metabolismo , Células Estromais/patologiaRESUMO
It can sometimes be difficult to distinguish between the 2 main types of uterine mesenchymal neoplasms; uterine smooth muscle tumors (SMTs) and endometrial stromal sarcomas (ESSs), particularly when the ESSs show smooth muscle differentiation or the SMTs are highly cellular. The aim of this study was to investigate myocardin expression in normal uterus myometrium, in SMTs, and in ESSs and to determine whether myocardin can be used as a useful diagnostic tool in the classification of problematic uterine mesenchymal tumors. Immunohistochemical staining was performed in each group. Besides myocardin, all cases were also stained for other smooth muscle markers (h-caldesmon, desmin, smooth muscle actin) and for CD10. All tested markers were analyzed in 21 conventional leiomyomas (LMs), 21 highly cellular leiomyomas (HCLs), 12 leiomyosarcomas (LMSs), 3 endometrial stromal nodules (ESNs), 11 ESSs, and 15 normal uterus myometrium. Myocardin was expressed in all normal uterine myometrium and in SMTs (even in the regions with epithelioid features) moderately or strongly, at least topically, whereas in endometrium, in ESNs and in ESSs, except in the regions of smooth muscle differentiation, it was negative. All ESNs, 11 of 11 ESSs and 14 of 15 endometrium were negative for h-caldesmon, but all SMTs and normal uterine myometrium were positive for h-caldesmon except for 2 LMSs, 2 HCLs, and for the regions with epithelioid features in 2 LMs. Desmin was stained in all normal uterine myometrium and in SMTs (except those of the regions with epithelioid features), but it was negative in 1 HCL and 1 LMS. One of 3 ESNs and 2 of 11 ESSs were expressed in desmin. Smooth muscle actin was negative in all ESNs, 2 LMSs, and 2 HCLs, and positive in all myometriums, LMs (except for the regions with epithelioid features), 1 ESSs, and 1 proliferative phase endometrium. Eight of 11 ESSs and all ESNs were positive for CD10, as was 1 HCL, and 2 LMSs. All uterine myometrium, 3 ESSs, and 3 endometriums were negative for CD10. Our study indicates that the myocardin is expressed in normal and neoplastic uterine smooth muscle cells sensitively and that the evaluation of myocardin expression is useful in distinguishing SMTs from ESSs.