Considering gemcitabine-based combination chemotherapy as a potential treatment for advanced oesophageal cancer: A meta-analysis of randomised trials.

BACKGROUND: Gemcitabine has been proved to be effective in many advanced cancer. However, almost all trials failed to demonstrate the response rate of gemcitabine-based combination schedules on oesophageal cancer (EC). METHODS: A systematic meta-analysis of randomised clinical trials (RCTs) was performed to investigate the efficacy of gemcitabine-based combination chemotherapy in EC treatment. Clinical trials were collected during the period ranging from January 2000 to November 2018 by searching different databases. Odds-ratios (ORs) of response rate (RR), disease control rate (DCR) and grade 3-4 toxicity rates (TRs) were extracted as presented in retrieved studies. RESULTS: Fourteen trials (1024 patients) were selected for the final analysis. The results showed that RR and DCR of gemcitabine-based combination chemotherapy demonstrated a significant advantage for non-gemcitabine therapy (OR for RR: 1.51; 95% CI: 1.16-1.96; P = .002; OR for DCR: 1.66; 95% CI: 1.19-2.32, P = .003). Toxicities of gemcitabine-based combination chemotherapy on gastrointestinal tract (OR, 0.39; 95% CI: 0.24-0.63, P = .0001) were less frequent compared to that of the non-gemcitabine therapy. CONCLUSION: The improvements of gemcitabine-based combination chemotherapy on RR, CDR and reduction of gastrointestinal tract, hepatic and renal for EC patients suggests that the combined chemotherapy based on gemcitabine could be a potential treatment options for advanced EC.

Whole-Genome Sequencing Reveals Diverse Models of Structural Variations in Esophageal Squamous Cell Carcinoma.

Comprehensive identification of somatic structural variations (SVs) and understanding their mutational mechanisms in cancer might contribute to understanding biological differences and help to identify new therapeutic targets. Unfortunately, characterization of complex SVs across the whole genome and the mutational mechanisms underlying esophageal squamous cell carcinoma (ESCC) is largely unclear. To define a comprehensive catalog of somatic SVs, affected target genes, and their underlying mechanisms in ESCC, we re-analyzed whole-genome sequencing (WGS) data from 31 ESCCs using Meerkat algorithm to predict somatic SVs and Patchwork to determine copy-number changes. We found deletions and translocations with NHEJ and alt-EJ signature as the dominant SV types, and 16% of deletions were complex deletions. SVs frequently led to disruption of cancer-associated genes (e.g., CDKN2A and NOTCH1) with different mutational mechanisms. Moreover, chromothripsis, kataegis, and breakage-fusion-bridge (BFB) were identified as contributing to locally mis-arranged chromosomes that occurred in 55% of ESCCs. These genomic catastrophes led to amplification of oncogene through chromothripsis-derived double-minute chromosome formation (e.g., FGFR1 and LETM2) or BFB-affected chromosomes (e.g., CCND1, EGFR, ERBB2, MMPs, and MYC), with approximately 30% of ESCCs harboring BFB-derived CCND1 amplification. Furthermore, analyses of copy-number alterations reveal high frequency of whole-genome duplication (WGD) and recurrent focal amplification of CDCA7 that might act as a potential oncogene in ESCC. Our findings reveal molecular defects such as chromothripsis and BFB in malignant transformation of ESCCs and demonstrate diverse models of SVs-derived target genes in ESCCs. These genome-wide SV profiles and their underlying mechanisms provide preventive, diagnostic, and therapeutic implications for ESCCs.

Genomic analyses reveal mutational signatures and frequently altered genes in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC-mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC-signature tumors, and no smoking-associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8. In our combined cohort, we identified frequent inactivating mutations in AJUBA, ZNF750, and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1, in addition to known mutations. Functional analyses suggest roles for several genes (CBX4, CBX8, AJUBA, and ZNF750) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets.

[Study of negative feedback between wild-type BRAF or RAFV600E and Mps1 in melanoma].

OBJECTIVE: To study the effect of Mps1 on BRAFWT/MEK/ERK pathway in the presence of wild type BRAF or BRAFV600E in melanoma. METHODS: Melanoma cells harboring BRAFWT genotype were transfected either with pBabe-puro-GST-BRAF-WT and/or pBabe-puro-GFP-Mps1-WT or pBabe-puro-GST-BRAFV600E and/or pBabe-puro-GFP-Mps1-WT, followed by Western blot to detect Mps1 and p-ERK expression. The melanoma cells harboring BRAFWT and BRAFV600E genotype were infected with pSUPER-Mps1 retrovirus to knockdown the endogenous Mps1 protein, followed by Western blot to detect Mps1 and p-ERK expression. Meanwhile, melanoma cells harboring BRAFV600E genotype were infected with pBabe-puro-GFP-Mps1 and Western blot was performed to detect Mps1 and p-ERK expression. RESULTS: In melanoma cells harboring BRAFWT genotype and transfected with pBabe-puro-GST-BRAF-WT and pBabe-puro-GFP-Mps1-WT, phospho-ERK levels were notably reduced as compared to either negative control or empty vector. However, cells transfected with pBabe-puro-GST-BRAFV600E and pBabe-puro-GFP-Mps1-WT, phospho-ERK levels did not change significantly compared with either negative control or empty vector. Knockout of Mps1 in BRAF wild-type cell lines led to an increased ERK activity. However, there was no significant change of ERK activity in BRAFV600E cell lines in the absence of Mps1. The expression of p-ERK in BRAFV600E mutant cell lines infected with pBabe-puro-GFP-Mps1-WT did not show any significant difference from either negative control or empty vector. CONCLUSIONS: Based on these findings, it suggests that there exists an auto-regulatory negative feedback loop between the Mps1 kinase and BRAFWT/ERK signaling. Oncogenic BRAFV600E abrogates the regulatory negative feedback loop of Mps1 on the MAPK pathway.

Mps1 is associated with the BRAFV600E mutation but does not rely on the classic RAS/RAF/MEK/ERK signaling pathway in thyroid carcinoma.

In previous studies, the B-Raf proto-oncogene, serine/threonine kinase (BRAF)V600E mutation has been identified in multiple malignant tumors. BRAFV600E has been revealed to contribute to tumorigenesis by the activation of phospho-mitogen-activated protein kinases (MAPKs) and their downstream Monopolar spindle 1 (Mps1), leading to chromosome euploidy and tumor development. In the present study, the presence of phospho-MAPK and Mps1 in 161 thyroid carcinoma cases with complete clinical parameters was analyzed by immunohistochemistry, and the BRAF mutation was detected by polymerase chain reaction-direct sequencing. It was revealed that BRAFV600E was present in ~34% of thyroid cancer cases and was associated with age, clinical tumor stage and lymph node stage. However, the association of BRAFV600E with overall survival was not statistically significant. The expression of Mps1 was significantly increased in tumor tissues with BRAFV600E, however, this did not affect the expression of phospho-MAPK in thyroid carcinomas. Collectively, the results of the present study suggested that BRAFV600E may regulate the expression of Mps1 in MAP kinase independent ways in thyroid carcinoma. Therefore, Mps1 expression is associated with BRAFV600E while the upstream signaling of phospho-MAPK has no relevance. The specific mechanisms of BRAFV600E and the unknown pathway associated with Mps1 exhibit potential for further study, and provide a theoretical basis for the molecular treatment of thyroid carcinoma.

High TSTA3 Expression as a Candidate Biomarker for Poor Prognosis of Patients With ESCC.

Esophageal squamous cell carcinoma is the sixth most lethal cancer worldwide and the fourth most lethal cancer in China. Tissue-specific transplantation antigen P35B codifies the enzyme GDP-d-mannose-4,6-dehydratase, which participates in the biosynthesis of GDP-l-fucose. GDP-l-fucose is an important substrate involved in the biosynthesis of many glycoproteins. Cancer cells are often accompanied by the changes in glycoprotein structure, which affects the adhesion, invasion, and metastasis of cells. It is not clear whether tissue-specific transplantation antigen P35B has any effect on the development of esophageal squamous cell carcinoma. We used an immunohistochemical method to assess the expression of tissue-specific transplantation antigen P35B in 104 esophageal squamous cell carcinoma samples. The results showed tissue-specific transplantation antigen P35B expression was associated with some clinical features in patients, such as age ( P = .017), clinical stage ( P = .010), and lymph node metastasis ( P = .043). Kaplan-Meier analysis and log-rank test showed that patients with esophageal squamous cell carcinoma having high tissue-specific transplantation antigen P35B expression had a worse prognosis compared to the patients with low expression ( P = .048). Multivariate Cox proportional hazards regression model showed that high expression of tissue-specific transplantation antigen P35B could predict poor prognosis for patients with esophageal squamous cell carcinoma independently. In conclusion, abnormal fucosylation might participate in the progress of esophageal squamous cell carcinoma and tissue-specific transplantation antigen P35B may serve as a novel biomarker for prognosis of patients with esophageal squamous cell carcinoma.

FAT1 prevents epithelial mesenchymal transition (EMT) via MAPK/ERK signaling pathway in esophageal squamous cell cancer.

FAT1 regulates cell-cell adhesion, cell growth, cell migration, and actin dynamics as either oncogene or tumor suppressor in human cancers. We previously identified FAT1 was one of significant mutant genes in esophageal squamous cell carcinoma (ESCC). However, the function and underlying mechanism of FAT1 in ESCC have not been explored. In this study, we report that FAT1 expression was significantly lower in ESCC tumor tissues. Exogenous expression of FAT1 led to inhibition of cell proliferation and colony formation, as well as cell migration and invasion whereas FAT1 knockdown showed the opponent trends in vitro and in vivo. Moreover, FAT1 knockdown led to a statistically decrease of E-cadherin expression and a dramatically increase expression of N-cadherin, Vimentin, and Snail in a MAPK/ERK pathway-dependent manner. Meanwhile, over-expression of FAT1 resulted in the opposite trends. These alterations were abrogated in the presence of U0126, a MEK specific inhibitor. Collectively, our studies identified a novel role for FAT1 in inhibiting tumor growth and EMT occurrence in ESCC. We proposed that disruption of MAPK/ERK pathway by FAT1 contributes the EMT in ESCC and has important implications for understanding ESCC development.

The macro-evolutionary events in esophageal squamous cell carcinoma.

Understanding the evolutionary processes operative in cancer genome may provide insights into clinical outcome and drug-resistance. However, studies focus on genomic signatures, especially for macro-evolutionary events, in esophageal squamous cell carcinoma (ESCC) are limited. Here, we integrated published genomic sequencing data to investigate underlying evolutionary characteristics in ESCC. We found most of ESCC genomes were polyploidy with high genomic instability. Whole genome doubling that acts as one of mechanisms for polyploidy was predicted as a late event in the majority of ESCC genome. Moreover, loss of heterozygosity events were more likely to occur in chromosomes harboring tumor suppressor genes in ESCC. The 40% of neutral loss of heterozygosity events was not a result of genome doubling, suggesting an alternative mechanism for neutral loss of heterozygosity formation. Importantly, deconstruction of copy number alterations extending to telomere revealed that telomere-bounded copy number alterations play a critical role for amplification/deletion of oncogenes/suppressor genes. For well-known genes SOX2, PIK3CA and TERT, nearly all of their amplifications were telomere bounded, which was further confirmed in a Japanese ESCC cohort. Furthermore, we provide evidence that karyotype evolution was mostly punctuated in ESCC. Collectively, our data reveal the potential biological role of whole genome doubling, neutral loss of heterozygosity and telomere-bounded copy number alterations, and highlight mecro-evolution in ESCC tumorigenesis.