Comparative Genomics of Esophageal Adenocarcinoma and Squamous Cell Carcinoma

Abstract

Background Esophageal cancer consists of two major histologic types: esophageal squamous cell carcinoma (ESCC) predominant globally and esophageal adenocarcinoma (EAC) with a higher incidence in westernized countries. Five-year overall survival is 15%. Clinical trials frequently combine histologies although they are different diseases with distinct origins. In the evolving era of personalized medicine and targeted therapies, we hypothesized that ESCC and EAC have genomic differences important for developing new therapeutic strategies for esophageal cancer. Methods We explored DNA copy number abnormalities (CNAs) in 70 ESCCs with publicly available array data and 189 EAC from our group. All data was from Affymetrix single nucleotide polymorphism (SNP) arrays. Analysis was performed with Nexus 5.0 Copy number software using a SNPRank segmentation algorithm. Log ratio thresholds for copy number gain and loss were set at +/− 0.2 (approximately 2.3 and 1.7 copies respectively). Results ESCC and EAC genomes showed some CNAs with similar frequencies (e.g., CDKN2A, EGFR, KRAS, MYC, CDK6, MET) but also many CNAs with different frequencies between histologies, most of which were amplification events. Some of these regions harbor genes to which targeted therapies are currently available (VEGFA, ERBB2) or where agents are in clinical trials (PIK3CA, FGFR1). Other regions contain putative oncogenes that may be targeted in the future. Conclusions Using SNP arrays we compared genomic abnormalities in a large cohort of EAC and ESCC. We report here the similar and different frequencies of CNAs in ESCC and EAC. These results may allow development of histology-specific therapeutic agents for esophageal cancer.

LINE-1 Hypomethylation, DNA Copy Number Alterations, and CDK6 Amplification in Esophageal Squamous Cell Carcinoma

“…Amplification of 7q21-22 containing a candidate oncogene CDK6 was observed in all LINE-1-hypomethylated tumors, whereas this locus was not amplified in all LINE-1-hypermethylated tumors. Previous studies have shown that CDK6 amplification is associated with CDK6 overexpression and poor survival in esophageal cancer, supporting that CDK6 might mark malignant esophageal cancer (32,33). From these findings, we further hypothesize that global DNA hypomethylation in ESCC contributes to aggressive phenotype by genomic gain of oncogenes such as CDK6.…”

Beyond HER2: recent advances and future directions in targeted therapies in esophagogastric cancers

“…As these profiles were derived from a mixed population of patients, that was primarily non-metastatic gastric adenocarcinoma, how well these classifications will reflect patients with metastatic EGCa remains uncertain. However, others have categorized gastric cancers from different study populations, and esophageal adenocarcinomas and squamous cell carcinoma, and have also reported noting a distinct population with MSI-high gastric, again representing about 15-20% of patients, but also noting some differences (7)(8)(9). Interestingly, none of these classifications specify that the HER2 amplified gastric cancers represent a distinct group of patients.…”

Identification of a Novel Fusion Gene (HLA-E and HLA-B) by RNA-seq Analysis in Esophageal Squamous Cell Carcinoma

“…Transcriptome sequencing (RNA-Seq) has become 1 , Jian-Qiang Zhao 2 , Jun-Ji Lv 2 a revolutionary tool for comprehensive study of the whole transcripts and with the merits to identify the gene structure variation, such as gene fusion, splicing variants (Wang et al, 2009). Recently limited study has performed in ESCC (Bandla et al, 2012;Ma et al, 2012;Zhang et al, 2013), which has elucidated some basis of the tumorigenesis and development in ESCC. A major goal for cancer research was to find the tumor specific causal genetic aberrations.…”