Immune-tumor interaction dictates spatially directed evolution of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a poor-prognostic cancer type with extensive intra- and inter-patient heterogeneity in both genomic variations and tumor microenvironment (TME). However, the patterns and drivers of spatial genomic and microenvironmental heterogeneity of ESCC remain largely unknown. Here, we generated a spatial multi-omic atlas by whole-exome, transcriptome, and methylome sequencing of 507 tumor samples from 103 patients. We identified a novel tumor suppressor PREX2, accounting for 22% of ESCCs with frequent somatic mutations or hyper-methylation, which promoted migration and invasion of ESCC cells in vitro. Analysis of the TME and quantification of subclonal expansion indicated that ESCCs undergo spatially directed evolution, where subclones mostly originated from the tumor center but had a biased clonal expansion to the upper direction of the esophagus. Interestingly, we found upper regions of ESCCs often underwent stronger immunoediting with increased selective fitness, suggesting more stringent immune selection. In addition, distinct TMEs were associated with variable genomic and clinical outcomes. Among them, hot TME was associated with high immune evasion and subclonal heterogeneity. We also found that immunoediting, instead of CD8+ T cell abundance, acts as an independent prognostic factor of ESCCs. Importantly, we found significant heterogeneity in previously considered potential therapeutic targets, as well as BRCAness characteristics in a subset of patients, emphasizing the importance of focusing on heterogeneity in ESCC targeted therapy. Collectively, these findings provide novel insights into the mechanisms of the spatial evolution of ESCC and inform precision therapeutic strategies.

MBIP promotes ESCC metastasis by activating MAPK pathway.

MBIP is a component of the Ada2A containing complex (ATAC) and has been identified as a susceptibility gene in several cancers. However, the role and molecular mechanism of MBIP in esophageal squamous cell carcinoma (ESCC) remain unclear. Our finding indicated that the expression level of MBIP in ESCC was higher than that in normal tissue (P < 0.05) based on the data from the Cancer Gene Atlas (TCGA) and Gene Expression Omnibus (GEO). Kaplan-Meier analysis showed that high MBIP expression was closely associated with deeper invasion and worse prognosis. Transwell assay and mouse xenograft assay demonstrated that MBIP overexpression promoted migration and invasion in vitro and in vivo, while MBIP knockdown played the opposite role. Furthermore, the results of RNA-seq, qRT-PCR, western blotting and rescue experiments revealed that MBIP promoted epithelial-mesenchymal transition (EMT) via the phosphorylation JNK/p38 in ESCC. Our study indicates that MBIP plays a significant role in the prognosis and metastasis of ESCC, suggesting that MBIP might serve as an ESCC prognostic biomarker.

TSTA3 overexpression promotes malignant characteristics in LUSC by regulating LAMP2-mediated autophagy and tumor microenvironment.

BACKGROUND: TSTA3 gene encoding GDP-L-fucose synthase has recently been proved to be closely related to the prognosis of patients with various tumors. However, its role in lung cancer is still unclear. The purpose of this study is to explore the expression level, prognostic effect, potential function and mechanism of TSTA3 in lung cancer. METHODS: Based on TCGA database, Kaplan-Meier and COX regression was used to analyze the relationship between TSTA3 expression and prognosis of lung cancer patients. Immunohistochemistry was used to determine the TSTA3 protein expression in lung cancer and normal tissues. The function of TSTA3 in lung squamous cell carcinoma (LUSC) cell was determined by CCK8, colony formation, transwell assay in vitro and subcutaneous xenografts in vivo. Transcriptome analysis, Lyso-Tracker Red staining and rescue experiment were used to explore the possible underlying mechanism. RESULTS: The expression of TSTA3 was significantly increased in lung cancer, especially in LUSC, and was significantly correlated with the malignant characteristics of LUSC. COX regression analysis showed that the high expression of TSTA3 was an independent prognostic factor in LUSC patients. This was also confirmed by immunohistochemical staining. Compared with the control group, the proliferation, colony formation, invasion and migration ability of LUSC cells with TSTA3 overexpression was enhanced. Similarly, the ability of cell proliferation, colony formation, invasion and migration were weakened after transient knockdown of TSTA3. In vivo experiment showed that compared with control group, TSTA3 overexpression significantly promoted the growth of tumor and shortened survival time. In addition, transcriptome sequencing analysis showed that the differentially expressed genes between TSTA3 overexpression and control group was mainly concentrated in the lysosome pathway. Further study found that TSTA3 might affect the proliferation, invasion and migration of LUSC by regulating the expression of lysosome-associated membrane protein 2 (LAMP2) in LUSC. CONCLUSION: The expression level of TSTA3 in LUSC is significantly higher than that in normal tissues. High expression of TSTA3 is associated with poor prognosis of LUSC patients. TSTA3 may affect the proliferation, invasion and migration of LUSC by regulating LAMP2.

Integrated multi-omics profiling yields a clinically relevant molecular classification for esophageal squamous cell carcinoma.

Integrated molecular analysis of human cancer has yielded molecular classification for precise management of cancer patients. Here, we analyzed the whole genomic, epigenomic, transcriptomic, and proteomic data of 155 esophageal squamous cell carcinomas (ESCCs). Multi-omics analysis led to the classification of ESCCs into four subtypes: cell cycle pathway activation, NRF2 oncogenic activation, immune suppression (IS), and immune modulation (IM). IS and IM cases were highly immune infiltrated but differed in the type and distribution of immune cells. IM cases showed better response to immune checkpoint blockade therapy than other subtypes in a clinical trial. We further developed a classifier with 28 features to identify the IM subtype, which predicted anti-PD-1 therapy response with 85.7% sensitivity and 90% specificity. These results emphasize the clinical value of unbiased molecular classification based on multi-omics data and have the potential to further improve the understanding and treatment of ESCC.

Subclassifying triple-negative breast cancers and its potential clinical utility.

The molecular subtyping of triple-negative breast cancer (TNBC) is critical to guiding individualized patient treatment. In this study, we sought to characterize the clinicopathologic features of TNBC subtypes and to identify correlates of patient survival in an effort to provide a robust foundation for treatment planning. We additionally assessed PD-L1 expression in Chinese TNBC patients and evaluated the relationship between such expression and immunotherapeutic treatment outcomes. Based on analyses of histologic characteristics including apocrine differentiation, tumor-infiltrating lymphocytes, and metaplastic features, we selected immunohistochemical (IHC) markers including CD8, FOXC1, and AR for use in classifying TNBC cases. Associations between these subtypes and a range of clinicopathologic characteristics were evaluated. We classified a cohort of 93 TNBC patients into individuals with luminal androgen receptor (LAR), immunomodulatory (IM), basal-like immune-suppressed (BLIS), and mesenchymal (MES) tumor subtypes (23, 24, 39, and 7 cases, respectively). PD-L1 positivity was observed in 49.6% of cases and was more common in individuals with IM subtype disease. Mismatch repair deficiency (dMMR) was observed in just one patient. Significant differences in histologic grade, pT stage, lymphocyte distribution patterns, large scarring areas without cells in tumor of central (central scar), and PD-L1, P53, and Rb status were observed among these TNBC subtypes, whereas no such differences were observed with respect to age, invasion pattern, or pN stage. Rates of disease progression were higher at the 40-50 month follow-up time point, but there were no significant differences in recurrence-free survival or breast cancer-specific survival among these subtypes. IHC markers associated with clinicopathologic characteristics represent a powerful approach to TNBC molecular typing, providing a foundation for precision patient treatment. PD-L1 expression may represent a relevant factor in TNBC patient immunotherapeutic treatment planning, whereas dMMR is not likely to be of substantial value when evaluating immunotherapeutic efficacy in these patients.

Extracellular vesicles mediated proinflammatory macrophage phenotype induced by radiotherapy in cervical cancer.

BACKGROUND: Radiotherapy is a highly effective treatment for cervical cancer. Recent studies focused on the radiotherapy induced anti-tumor immunity. Whether tumor-derived extracellular vesicles (EVs) play roles in radiotherapy induced tumor associated macrophage (TAM) polarization remains unclear. MATERIALS AND METHODS: This study analysed the phenotype of macrophages in cancer tissue and peripheral blood of cervical cancer patients using flow cytometry analysis. The role of EVs from plasma of post-irradiated patients on M2-like transformed macrophages was assessed. The M1- and M2-like macrophages were assessed by expression of cell surface markers (CCR7, CD163) and intracellular cytokines (IL-10, TNFα and iNOS). The capacity of phagocytosis was assessed by PD-1 expression and phagocytosis of pHrodo Red E. coli bioparticles. RESULTS: Our results demonstrated that radiotherapy of cervical cancer induced an increase in the number of TAMs and a change in their subtype from the M2-like to the M1-like phenotype (increased expression of CCR7 and decreased expression of CD163). The EVs from plasma of post-irradiated patients facilitated the M2-like to the M1-like phenotype transition (increased expression of CCR7, TNFα and iNOS, and decreased expression of CD163 and IL-10) and increased capacity of phagocytosis (decreased PD-1 expression and increased phagocytosis of pHrodo Red E. coli bioparticles). CONCLUSIONS: Our data demonstrated that irradiation in cervical cancer patients facilitated a proinflammatory macrophage phenotype which could eventually able to mediate anti-tumor immune responses. Our findings highlight the importance of EV in the crosstalk of tumor cells and TAM upon irradiation, which potentially leading to an increased inflammatory response to cancer lesions.

Two cases report of secretory carcinoma of the salivary gland in the lung: one primary and one metastatic after many years.

Background: Secretory carcinoma of the salivary gland (SCSG) is a recently discovered salivary gland tumor that occurs mostly in the major salivary glands and occasionally in the skin, cervix, trachea, etc. Secretory carcinoma of the lung is extremely rare. To our knowledge, this is the third report of SCSG arising as a primary pulmonary tumor. The two SCSG cases reported in this paper are unique in that one was primary and the other was metastasized to the lung. Case Description: Case 1 is a primary endobronchial tumor in a 66-year-old man. He went to the doctor complaining of fever, cough and yellow phlegm, and his body weight was significantly reduced by 3 kg. The bronchoscope showed the growth of new organisms in the right upper lobe of the lung. Immunohistochemistry of his biopsy specimen was positive for AE1/AE3, Keratin7 (CK7), S-100, mammaglobin, and pan-TRK, but negative for thyroid transcription factor-1 (TTF-1), napsin-A, synaptophysin (SYN), chromogranin A (CGA), and discovered on GIST-1 (Dog-1), and the MKI-67 (Ki-67) proliferation index was 2%. This case lacked the typical ETV-6 gene rearrangement. After one cycle of chemotherapy, the tumor was significantly reduced, and surgical excision was planned. Case 2 was a metastatic secretory carcinoma with a history of parotid pleomorphic adenoma resection 30 years ago and malignant pleomorphic adenoma resection 16 years ago before the study, respectively. He presented with a complaint of a parotid gland mass. Chest CT examination revealed a mass in the upper lobe of the left lung. The biopsy tissue of him exhibited a typical histological appearance under the microscope. Immunohistochemistry was positive for AE1/AE3, CK7, S-100, and mammaglobin; partially positive for estrogen receptor (ER) and pan-TRK; and negative for TTF-1, Napsin-A, SYN, CGA, P63, P40, and Dog-1. The Ki-67 proliferation index was approximately 3%. Fluorescence in situ hybridization (FISH) revealed ETV-6 gene rearrangement. After the diagnosis of SCSG, the patient underwent resection of the lung mass, and there was no recurrence of the lung after 1 month's follow-up. Conclusions: By examining these two cases, we have a better understanding of the clinicopathological features of secretory carcinoma, which will help to improve the accuracy of pathological diagnosis.

CDCA7 Facilitates Tumor Progression by Directly Regulating CCNA2 Expression in Esophageal Squamous Cell Carcinoma.

BACKGROUND: CDCA7 is a copy number amplified gene identified not only in esophageal squamous cell carcinoma (ESCC) but also in various cancer types. Its clinical relevance and underlying mechanisms in ESCC have remained unknown. METHODS: Tissue microarray data was used to analyze its expression in 179 ESCC samples. The effects of CDCA7 on proliferation, colony formation, and cell cycle were tested in ESCC cells. Real-time PCR and Western blot were used to detect the expression of its target genes. Correlation of CDCA7 with its target genes in ESCC and various SCC types was analyzed using GSE53625 and TCGA data. The mechanism of CDCA7 was studied by chromatin immunoprecipitation (ChIP), luciferase reporter assays, and rescue assay. RESULTS: The overexpression of CDCA7 promoted proliferation, colony formation, and cell cycle in ESCC cells. CDCA7 affected the expression of cyclins in different cell phases. GSE53625 and TCGA data showed CCNA2 expression was positively correlated with CDCA7. The knockdown of CCNA2 reversed the malignant phenotype induced by CDCA7 overexpression. Furthermore, CDCA7 was found to directly bind to CCNA2, thus promoting its expression. CONCLUSIONS: Our results reveal a novel mechanism of CDCA7 that it may act as an oncogene by directly upregulating CCNA2 to facilitate tumor progression in ESCC.

Identification of miRNA-34a and miRNA-155 as prognostic markers for mantle cell lymphoma.

OBJECTIVE: MicroRNAs (miRNAs) with functional relevance have not been previously identified in mantle cell lymphoma (MCL). Here, we aimed to evaluate the relationships between miR-34a and miR-155-5p and MCL clinicopathology and prognosis. METHODS: Seventy-five paraffin-embedded tissue samples from patients with MCL who completed at least four cycles of chemotherapy from January 2006 to October 2016, and 27 samples from control patients with reactive lymphoid hyperplasia (RLH), were collected. MiRNA expression levels were measured by qRT-PCR. RESULTS: The miR-155-5p levels were significantly higher in patients with MCL than in the controls. The Eastern Cooperative Oncology Group (ECOG) ≥ 2 and Sex-Determining Region Y-Box transcription factor 11 (SOX11) < median value (M) groups presented lower miR-34a expression than the ECOG < 2 and SOX11 ≥ M groups, respectively. MiR-155-5p expression differed between low, intermediate, and high MCL International Prognostic Index risk groups. The AUCs of miR-34a and miR-155-5p were 0.5819 and 0.7784, respectively. The median survival times of the miR-34a ≤ 0.2150 and miR-155-5p > 2.11 groups were shorter than those of the miR-34a > 0.2150 and miR-155-5p ≤ 2.11 groups, respectively. CONCLUSIONS: Low miR-34a and elevated miR-155-5p levels may be correlated with poor prognosis in MCL.

Burkitt-like lymphoma with 11q aberration in a patient with AIDS and a patient without AIDS: Two cases reports and literature review.

OBJECTIVE: The aim of this study is to evaluate the clinicopathological features and the treatment of the Burkitt-like lymphoma with 11q aberration. METHODS: We reported two patients with Burkitt-like lymphoma with 11q aberration: a 56-year-old man with AIDS (case 1) and a 37-year-old woman (case 2) without AIDS. The biopsy of cervical lymph nodes showed Burkitt-like morphologic and immunophenotypic features. But both of them lack MYC rearrangement and carry an 11q-arm aberration with proximal gains and/or telomeric losses. The diagnosis was confirmed by pathological morphology, immunohistochemistry, and fluorescence in situ hybridization. RESULT: After a cycle of R-CTOEP (rituximab, cyclophosphamide, pirarubicin, vincristine, and prednisone) chemotherapy, case 1 refused to chemotherapy and radiotherapy and was followed up for 34 months without recurrence and new focus. Case 2 received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) for two cycles and achieved PR (partial response). Then, the patient in case 2 received EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) for three cycles, and the right cervical mass disappeared. She achieved complete response and was followed up for 16 months without recurrence and new focus. CONCLUSION: Burkitt-like lymphoma with 11q abnormalities resembles Burkitt lymphoma morphologically but lacks MYC rearrangement and may have a better prognosis.

A standardized pathological proposal for evaluating microvascular invasion of hepatocellular carcinoma: a multicenter study by LCPGC.

BACKGROUND AND AIMS: Microvascular invasion (MVI) is a key pathological factor that severely affects the postoperative prognosis of patients with hepatocellular carcinoma (HCC). However, no MVI classification schemes based on standardized gross sampling protocols of HCC are available at present. METHODS: 119 HCC specimens were sampled at multiple sites (3-, 7-, and 13 points) for the optimum MVI detection rate. 16,144 resected HCCs were graded as M0, M1 or M2 by adopting three-tiered MVI grading (MVI-TTG) scheme based on the seven-point sampling protocol (SPSP). Survival analyses were performed on 2573 patients to explore the advantages of MVI-TTG. RESULTS: The MVI detection rate determined by SPSP was significantly higher than that determined by the 3-point sampling method (34.5% vs. 47.1%, p = 0.048), but was similar to that determined by the 13-point sampling method (47.1% vs. 51.3%, p = 0.517). Among 16,144 resected HCCs, the proportions of M0, M1 and M2 specimens according to SPSP were 53.4%, 26.2% and 20.4%, respectively. Postoperative survival analysis in 2573 HCC patients showed that the 3-year recurrence rates in M0, M1 and M2 MVI groups were 62.5%, 71.6% and 86.1%, respectively (p < 0.001), and the corresponding 3-year overall survival (OS) rates were 94.1%, 87.5% and 67.0%, respectively (p < 0.001). M1 grade was associated with early recurrence, while M2 grade was associated with both early and late recurrence. MVI-TTG had a larger area under the curve and net benefit rate than the two-tiered MVI grading scheme for predicting time to recurrence and OS. CONCLUSIONS: SPSP is a practical method to balance the efficacy of sampling numbers and MVI detection rates. MVI-TTG based on SPSP is a better prognostic predictor than the two-tiered MVI scheme. The combined use of SPSP and MVI-TTG is recommended for the routine pathological diagnosis of HCC.

Author Correction: Multi-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Clinical-Pathologic Analysis of Breast Cancer With PIK3CA Mutations in Chinese Women.

PURPOSE: Mutations of PIK3CA have recently been shown to play an important role in the pathogenesis and progression of breast neoplasms. The prevalence of PIK3CA in Chinese breast cancer patients may be underestimated. Therefore, we investigated the distribution of somatic PIK3CA mutation in Chinese breast cancer patients and explored their role in tumor phenotypes. METHODS: Mutational analysis of PIK3CA was done in 113 primary breast cancers of Chinese women used Amplification refractory mutation system (ARMS). The relationship of PIK3CA mutations with several clinicopathologic characteristics was analyzed. RESULTS: PIK3CA gene mutation was identified in 43(38.05%) cases and has a more significant difference between exon 9 and 20. HER2 gene amplification was 32.6% in 43 cases of PIK3CA mutation, but 37.1% in 70 cases of non-mutation (χ2 = 0.245, P > 0.05). There was no significant correlation of the age distribution, lymph node status, histological tumor grading, ER and/or PR and P53 between 2 groups (P > 0.05). CONCLUSION: A high frequency of somatic PIK3CA mutation was detected in Chinese breast cancer patients, especially in exon 20. The relationship between PIK3CA gene mutation and clinical pathological features of breast cancer needs to be further studied in a large series of patients. PIK3CA mutations seem to have the potential to be used in target treatment and as an indicator of prognosis.

Whole-genome sequencing of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a poor-prognosis cancer type with limited understanding of its molecular etiology. Using 508 ESCC genomes, we identified five novel significantly mutated genes and uncovered mutational signature clusters associated with metastasis and patients' outcomes. Several functional assays implicated that NFE2L2 may act as a tumor suppressor in ESCC and that mutations in NFE2L2 probably impaired its tumor-suppressive function, or even conferred oncogenic activities. Additionally, we found that the NFE2L2 mutations were significantly associated with worse prognosis of ESCC. We also identified potential noncoding driver mutations including hotspot mutations in the promoter region of SLC35E2 that were correlated with worse survival. Approximately 5.9% and 15.2% of patients had high tumor mutation burden or actionable mutations, respectively, and may benefit from immunotherapy or targeted therapies. We found clinically relevant coding and noncoding genomic alterations and revealed three major subtypes that robustly predicted patients' outcomes. Collectively, we report the largest dataset of genomic profiling of ESCC useful for developing ESCC-specific biomarkers for diagnosis and treatment.

Decreased ZNF750 promotes angiogenesis in a paracrine manner via activating DANCR/miR-4707-3p/FOXC2 axis in esophageal squamous cell carcinoma.

ZNF750 is one novel significantly mutated gene identified in esophageal squamous cell carcinoma (ESCC) using next-generation sequencing. However, its clinically relevant and potential mechanisms have remained elusive. Using genomic sequencing of 612 ESCC patients, we analyzed the associations of ZNF750 mutations with clinicopathologic features and its prognostic value. We further investigated the function and underlying mechanism of ZNF750 in angiogenesis. The results showed ZNF750 mutations/deletions are significantly associated with malignant progression and poor prognosis of ESCC patients. Decreased ZNF750 in ESCC cells induces enhanced angiogenesis of human umbilical vein endothelial cells (HUVECs) and human arterial endothelial cells (HAECs), and the effect may be indirectly mediated by FOXC2. RNA-seq and ChIP shows lncRNA DANCR is a direct downstream target of ZNF750. Furtherly, knockdown ZNF750 evokes DANCR expression, which prevents miR-4707-3p to interact with FOXC2 as a microRNA sponge in a ceRNA manner, leading to enhanced FOXC2 signaling and angiogenesis. In contrast, ZNF750 expression reverses the effect. Our study reveals a novel mechanism of ZNF750, highlights a significance of ZNF750 as a metastatic and prognostic biomarker, and offers potential therapeutic targets for ESCC patients harboring ZNF750 mutations.

Tumor infiltrative growth pattern correlates with the immune microenvironment and is an independent factor for lymph node metastasis and prognosis in stage T1 esophageal squamous cell carcinoma.

In this retrospective study, we analyzed the association between the tumor infiltrative growth pattern (INF) and tumor immune environment and its predictive value for lymph node metastasis and overall survival (OS) in stage T1 esophageal squamous cell carcinoma (ESCC). In total, 593 patients with a diagnosis of stage T1 ESCC who underwent esophagectomy and regional lymphadenectomy between 2009 and 2018 were included. The INF type and elements of the tumor immune microenvironment, including tumor infiltrative lymphocytes (TILs) and tertiary lymphoid structures (TLSs), were microscopically evaluated within the tumor invasive margin with hematoxylin and eosin (HE)-stained slices. The infiltrative-type INF (INFc) was associated with low-grade TILs and the absence of TLSs, deep tumor invasion, poorly differentiated phenotype. Multivariate logistic regression identified INFc as one of the independent risk factors for lymph node metastasis. INFc and low-grade TILs were independent inferior predictive factors for OS. A novel histologic risk stratification model was classified as INFa/b and high-grade TILs, INFa/b and low-grade TILs, INFc and high-grade TILs, and INFc and low-grade TILs. The Kaplan-Meier curves showed that INFa/b and high-grade TILs were associated with the best prognosis, and INFc and low-grade TILs were associated with the worst prognosis, and there was significant difference between groups. In conclusion, INFc is an independent risk factor for lymph node metastasis and an independent inferior prognostic factor for stage T1 ESCC. Furthermore, INFc is associated with immunosuppression, and the combination of the INF and TILs is useful for the risk stratification of prognosis.

Novel ESCC-related gene ZNF750 as potential Prognostic biomarker and inhibits Epithelial-Mesenchymal Transition through directly depressing SNAI1 promoter in ESCC.

Background: Cancer genomic studies have identified Zinc Finger Protein 750 (ZNF750) was a novel significantly mutated gene in esophageal squamous cell carcinoma (ESCC). This study was designed to determine the clinical value and molecular mechanisms of ZNF750 in the development of ESCC. Methods: Genomic data from 4 reported ESCC cohorts were used to analyze the mutation profile of ZNF750. Tissue microarrays were used to detect its expression in 308 ESCC samples. Furtherly, the effects of ZNF750 on proliferation, colony formation, migration and invasion were tested in ESCC cells. PCR-array, chromatin immunoprecipitation (ChIP), luciferase reporter assays, and rescue assay were used to explore the mechanism of ZNF750. Correlation of ZNF750 with its target genes was analyzed in TCGA data from various SCC types. Results: ZNF750 was frequently mutated in ESCC and the most common type was nonsense mutation. Its nucleus/cytoplasm ratio in ESCC was significantly lower than that in paired non-tumor tissues; it was an independent and potential predictor for survival in ESCC patients. Furtherly, ZNF750 knockdown significantly promoted proliferation, colony formation, migration and invasion in ESCC cells. PCR-array showed epithelial-to-mesenchymal transition (EMT) was the main biologic process affected by ZNF750. Moreover, ZNF750 directly bound to the promoter region of SNAI1 and depressed its activity. Decreased ZNF750 up-regulated SNAI1 expression and promoted EMT phenotype. SNAI1 knockdown partially reversed the malignant phenotype induced by ZNF750 knockdown. Further TCGA data analyses showed ZNF750 expression was positively correlated with E-cadherin and negatively correlated with SNAI1, N-cadherin and Vimentin in ESCC and other SCC samples. Conclusion: Our results suggest that ZNF750 may act as a tumor suppressor by directly repressing SNAI1 and inhibiting EMT process in ESCC and other types of SCC.

Hormone Receptor and Human Epidermal Growth Factor Receptor 2 Detection in Invasive Breast Carcinoma: A Retrospective Study of 12,467 Patients From 19 Chinese Representative Clinical Centers.

INTRODUCTION: We evaluated the current status of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) detection in invasive breast carcinoma (IBC) in various laboratories across China. MATERIALS AND METHODS: The Breast Pathology Study Group of the Chinese Society of Pathologists collected HR and HER2 data from 12,467 IBC cases from 19 representative clinical centers in China. The data from every center were compared with the pooled data from the other centers. RESULTS: The assessment of HR status showed that the overall positive estrogen receptor (ER) and progesterone receptor (PR) rates were 71.7% and 63.7% (range, 60.9%-87.9% and 43.9%-84.8%), respectively. The ER results in 3 centers and the PR results in 6 centers were outside the 99.5% confidence interval and were considered to be outliers (P < .0005). Of the 12,467 cases, 62.4% were ER+/PR+, 9.3% were ER+/PR-, 1.3% were ER-/PR+, and 27.0% were ER-/PR-. The assessment of HER2 status showed that the overall positive rate of HER2 (with a definition of immunohistochemistry [IHC] 3+ or IHC2+/ in situ hybridization-positive) was 24.7% (range, 13.7%-35.7%) in each center. Three centers were outside the 99.5% confidence interval and were considered to be outliers (P < .0005). The proportion of HER2 IHC3+ was 21.1%. The positive rates of HER2 gene amplification in IHC 0/1+, 2+, 3+ cases were 2.0%, 17.6%, and 85.9%, respectively. CONCLUSIONS: As the largest study of HR and HER2 status in Chinese patients with IBC, the data from the present study have indicated that the overall rates of HR and HER2 were comparable to those reported in previous studies. However, the rates varied among the laboratories. Individual centers had not met the target values, and they need to improve the detection.