Comparative genomic analysis of esophageal squamous cell carcinoma and adenocarcinoma: New opportunities towards molecularly targeted therapy

Abstract

Esophageal cancer is one of the most lethal cancers worldwide because of its rapid progression and poor prognosis. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are two major subtypes of esophageal cancer. ESCC predominantly affects African and Asian populations, which is closely related to chronic smoking and alcohol consumption. EAC typically arises in Barrett's esophagus with a predilection for Western countries. While surgical operation and chemoradiotherapy have been applied to combat this deadly cancer, molecularly targeted therapy is still at the early stages. With the development of large-scale next-generation sequencing, various genomic alterations in ESCC and EAC have been revealed and their potential roles in the initiation and progression of esophageal cancer have been studied. Potential therapeutic targets have been identified and novel approaches have been developed to combat esophageal cancer. In this review, we comprehensively analyze the genomic alterations in EAC and ESCC and summarize the potential role of the genetic alterations in the development of esophageal cancer. Progresses in the therapeutics based on the different tissue types and molecular signatures have also been reviewed and discussed.

Keywords: Copy number variation; Esophageal adenocarcinoma; Esophageal cancer; Esophageal squamous cell carcinoma; Genomic alteration; Molecularly targeted therapy; Next-generation sequencing; Somatic mutation.

Graphical abstract

Figure 1

Frequent genetic alterations in human esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). The data of genetic alterations in human ESCC and EAC were collected from cBioPortal, www.cbioportal.org, accessed in April 2021 (Tables S1–S4). The top 15 cancer-related genes with highest rate in mutation (A) or copy number variation (B) in ESCC and EAC were presented as a Venn diagram. Genes in red have been reported to be associated with esophageal cancer and are or potentially are therapeutic targets. ∗EGFR has been verified as a promising target to treat ESCC though it is not among the top 15 altered genes.

Figure 2

Comparison of genetic alterations between ESCC and EAC. The frequency of alteration of the genes in red presented in Fig. 1 was compared between ESCC and EAC according to the data from cBioPortal. SF: similar frequency. If the frequency of alteration in a gene is greater than 2-fold (≥2) in ESCC compared to that in EAC, the gene is assigned to ‘ESCC > EAC’. If the frequency of alteration in a gene is greater than 2-fold (≥2) in EAC compared to that in ESCC, the gene is assigned to ‘ESCC < EAC’. If the difference in the frequency of alteration in a gene is less than 2-fold, the gene was considered as ‘similar frequency’ in both ESCC and EAC. (A) Frequency of mutations. (B) Frequency of copy number variations.

Figure 3

Significantly dysregulated pathways in human ESCC (A) and EAC (B). The most altered genes were classified into three signaling pathways. The frequency of genetic alterations in ESCC and EAC were retrieved from cBioPortal (www.cbioportal.org, accessed in April 2021.). (a) RTK–MAPK–PI3K signaling. (b) Cell cycle regulation. (c) Epigenetic modulation.

Figure 4

Potential therapeutic targets and drugs for the treatment of ESCC and EAC. Drugs in red have been approved by FDA, drugs in black are at different stages of clinical trials, while drugs in blue are in preclinical studies.