Original article
General thoracic
Comparative Genomics of Esophageal Adenocarcinoma and Squamous Cell Carcinoma

Presented at the Basic Science Forum of the Fifty-eighth Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 9–12, 2011.
https://doi.org/10.1016/j.athoracsur.2012.01.064Get rights and content

Background

Esophageal cancer consists of two major histologic types: esophageal squamous cell carcinoma (ESCC), predominant globally, and esophageal adenocarcinoma (EAC), which has a higher incidence in westernized countries. Five-year overall survival is 15%. Clinical trials frequently combine histologic types 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 in 70 ESCCs with publicly available array data and 189 EACs from our group. All data was from single nucleotide polymorphism arrays. Analysis was performed using a 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

The ESCC and EAC genomes showed some copy number abnormalities with similar frequencies (eg, CDKN2A, EGFR, KRAS, MYC, CDK6, MET) but also many copy number abnormalities with different frequencies between histologic types, most of which were amplification events. Some of these regions harbor genes for which targeted therapies are currently available (VEGFA, ERBB2) or for which agents are in clinical trials (PIK3CA, FGFR1). Other regions contain putative oncogenes that may be targeted in the future.

Conclusions

Using single nucleotide polymorphism arrays we compared genomic abnormalities in a large cohort of EACs and ESCCs. We report here the similar and different frequencies of copy number abnormalities in ESCC and EAC. These results may allow development of histology-specific therapeutic agents for esophageal cancer.

Section snippets

Esophageal Adenocarcinoma Copy Number Data

We obtained Affymetrix 250K Sty GeneChip data from 73 patients with EAC originally published as part of a study by Berouhkim and associates [8] from the authors. Tumor data were normalized to a baseline reference file that was created from matched normal subjects. Additionally, we included our own Affymetrix 6.0 SNP array data from 116 EACs from patients treated at the University of Pittsburgh Medical Center from 2002 through 2008. The baseline reference file for this population was created

Common Regions of Aberrations

Analyses of CN data from 70 ESCC and 189 EAC samples resulted in at least 18 regions of gain and 14 regions of loss that occur in both ESCC and EAC at similar frequencies (p < 0.05 by Fisher's exact test; Table 1). These changes include previously reported cancer loci including gains (VEGFA [6p], EGFR [7p], CDK6 [7q21], MET [7q31], KRAS [12p], ERBB2 [17q12]) and losses (FHIT [3p], CSMDI [8p], and SMAD4 [18q]). We also observed other regions of gain, such as on 1p, 1q, 6p, 7q22, 8p, 10q, 11q,

Comment

We have performed a comparative genomic analysis of the largest cohort of EAC and ESCC samples and at the highest resolution to date. We found considerable similarity between these two tumor types but also many focal regions of DNA amplification or loss that are more frequent in one histologic type than in the other. This confirms some findings from smaller studies reported previously [11, 12], but our considerably larger sample size allows us to more precisely define regions, accurately

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