A multi‐omics study delineates new molecular features and therapeutic targets for esophageal squamous cell carcinoma

The incidence and histological type of esophageal cancer are highly variable depending on geographic location and race/ethnicity. Here we want to determine if racial difference exists in the molecular features of esophageal cancer. We firstly confirmed that the incidence rate of esophagus adenocarcinoma (EA) was higher in Whites than in Asians and Blacks, while the incidence of esophageal squamous cell carcinoma (ESCC) was highest in Asians. Then we compared the genome-wide somatic mutations, methylation, and gene expression to identify differential genes by race. The mutation frequencies of some genes in the same pathway showed opposite difference between Asian and White patients, but their functional effects to the pathway may be consistent. The global patterns of methylation and expression were similar, which reflected the common characteristics of ESCC tumors from different populations. A small number of genes had significant differences between Asians and Whites. More interesting, the racial differences of COL11A1 were consistent across multiple molecular levels, with higher mutation frequency, higher methylation, and lower expression in White patients. This indicated that COL11A1 might play important roles in ESCC, especially in White population. Additional studies are needed to further explore their functions in esophageal cancer.

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Potential Role of Targeting KDR and Proteasome Inhibitors in the Therapy of Esophageal Squamous Cell Carcinoma

Technology in Cancer Research & Treatment ◽

10.1177/1533033820948060 ◽

2020 ◽

Vol 19 ◽

pp. 153303382094806

Author(s):

Ling Zhang ◽

Xia Niu ◽

Yanghui Bi ◽

Heyang Cui ◽

Hongyi Li ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Zinc Finger Protein ◽

Cancer Genomics ◽

Therapeutic Targets ◽

Specific Inhibitor ◽

Genomic Variation ◽

Tumor Xenograft

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancer types in China. In recent years, progress has been made in various types of cancer genomics including ESCC. However, the clinical significance of genomic variation of ESCC remains poorly defined. In the present study, genomic sequencing data from 469 ESCC cases were analyzed and potential therapeutic targets in the Druggable Genome Interaction Database (DGIdb) were screened. A series of potential therapeutic target genes and pathways were identified, of which treatment of ESCC with bortezomib (a specific inhibitor targeting proteasome) potently inhibited the proliferation of 5 ESCC cell lines and administration of bortezomib led to significant tumor xenograft regression in SCID mice. It was also identified that kinase insert domain receptor (KDR), which had drug recommendations from all 6 sources integrated by the DGldb and harbored significant amplification in ESCC, might be a downstream target of zinc finger protein 750 (ZNF750). ZNF750 acts as a transcription factor and has been demonstrated to harbor frequently inactivating mutations in ESCC by previous independent studies. In the present study, KDR was upregulated upon ZNF750 knockdown and the rescue of ZNF750 also led to marked restoration of KDR. KDR knockdown in stable ZNF750-knockdown KYSE150 and KYSE140 ESCC cells significantly attenuated the promotion of cell growth, colony formation, invasion and migration induced by ZNF750 knockdown. Further experiments found that apatinib treatment, a potent inhibitor of KDR, resulted in profound inhibition of cell proliferation and invasion. Collectively, the present study provided insight for genomic alterations as potential therapeutic targets in ESCC and supported the possibility of a therapeutic strategy targeting the proteasome in ESCC. The present results also suggested that targeting KDR may be an effective way to treat ESCC, not only in KDR variant cases, but also in individuals with ZNF750 mutations and deletions.

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689 MMS22L EXPRESSION AS A PREDICTIVE BIOMARKER FOR THE EFFICACY OF NEOADJUVANT CHEMORADIOTHERAPY IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Diseases of the Esophagus ◽

10.1093/dote/doab052.689 ◽

2021 ◽

Vol 34 (Supplement_1) ◽

Author(s):

Xue-feng Leng ◽

Wenwu He ◽

Tianqin Mao ◽

Yongtao Han

Keyword(s):

Gene Expression ◽

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Roc Curve ◽

Neoadjuvant Chemoradiotherapy ◽

Predictive Biomarker ◽

Term Survival ◽

Molecular Features

Abstract Long-term survival in esophageal squamous cell carcinoma (ESCC) is related with pathological response after neoadjuvant chemoradiation therapy (NCRT) followed by surgery. However, effective biomarkers for prediction of pathologic response is still lacking. Therefore, a systematic analysis focusing on genes associated with efficacy of chemoradiotherapy in ESCC will provide valuable insights to understand the molecular features. Methods We collected genes associated with efficacy of chemoradiotherapy by screening publications deposited in PubMed. A specific subnetwork was constructed using Steiner minimum tree algorithm. Then the correlations between gene expression and prognosis of ESCC patients was analyzed using Kaplan–Meier Plotter online resources. The key gene expression was evaluated by quantitative real-time polymerase chain reaction, western blotting analysis and immunohistochemical staining. The predictive performance of biomarkers was estimated using receiver operating characteristic (ROC) curve analysis. Results We identified 101 genes associated with efficacy of chemoradiotherapy. Moreover, specific molecular network included some potential related genes, such as CUL3, MUC13, MMS22L, MME, UBC, VAPA, CYP1B1 and UGDH. MMS22L mRNA expression level had most significant association with the ESCC patient outcome (P < 0.01). Furthermore, MMS22L was downregulated at both the mRNA (P < 0.01) and protein levels in tumor compared with normal tissues. Lymph node metastasis was significantly associated with low MMS22L expression (P < 0.001). MMS22L levels were inversely correlated with NCRT response in ESCC (P < 0.01). MMS22L yielded an area under the ROC curve (AUC) of 0.847 (P < 0.01). Conclusion Low MMS22L expression could be an effective predictive biomarker for resistance to NCRT in ESCC.

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