Comparative Genomics of Esophageal Adenocarcinoma and Squamous Cell Carcinoma

University of Pittsburgh, Pittsburgh, Pennsylvania, United States
The Annals of thoracic surgery (Impact Factor: 3.85). 04/2012; 93(4):1101-6. DOI: 10.1016/j.athoracsur.2012.01.064
Source: PubMed


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.
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).
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.
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.

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Available from: Tony Godfrey, Apr 27, 2015
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    • "Validation of findings from these targeted studies in independent cohorts has proved difficult, no doubt in part due to methodological differences (Ong et al., 2010). A number of moderate to high density genome-wide CNA studies have also been performed (Walch et al., 2000; Riegman et al., 2001; Varis et al., 2001; Weiss et al., 2003; Albrecht et al., 2004; Nancarrow et al., 2008; Pasello et al., 2009; Paulson et al., 2009; Wiech et al., 2009; Gu et al., 2010; Goh et al., 2011; Bandla et al., 2012), although few of these address prognosis. Pasello et al. (2009) demonstrated that the number of CNAs observed correlates with prognosis, a finding that has been replicated by Goh et al. (2011) (although the number of changes that differentiated survival groups was highly dependent on the resolution of the investigation platform). "
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    ABSTRACT: The incidence of esophageal adenocarcinoma (EAC) has been increasing rapidly for the past 3 decades in Western (Caucasian) populations. Curative treatment is based around esophagectomy, which has a major impact on quality of life. For those suitable for treatment with curative intent, 5-year survival is ∼30%. More accurate prognostic tools are therefore needed, and copy number aberrations (CNAs) may offer the ability to act as prospective biomarkers in this regard. We performed a genome-wide examination of CNAs in 54 samples of EAC using single-nucleotide polymorphism (SNP) arrays. Our aims were to describe frequent regions of CNA, to define driver CNAs, and to identify CNAs that correlated with survival. Regions of frequent amplification included oncogenes such as EGFR, MYC, KLF12, and ERBB2, while frequently deleted regions included tumor suppressor genes such as CDKN2A/B, PTPRD, FHIT, and SMAD4. The genomic identification of significant targets in cancer (GISTIC) algorithm identified 24 regions of gain and 28 regions of loss that were likely to contain driver changes. We discovered 61 genes in five regions that, when stratified by CNA type (gain or loss), correlated with a statistically significant difference in survival. Pathway analysis of the genes residing in both the GISTIC and prognostic regions showed they were significantly enriched for cancer-related networks. Finally, we discovered that copy-neutral loss of heterozygosity is a frequent mechanism of CNA in genes currently targetable by chemotherapy, potentially leading to under-reporting of cases suitable for such treatment. © 2014 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 04/2014; 53(4). DOI:10.1002/gcc.22143 · 4.04 Impact Factor
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    • "By contrast, cigarette smoke is the major risk factor for squamous cell carcinoma, suggesting that there are genetic differences that distinguish these two histologic subtypes. Gene amplification events in basal progenitor cells of stratified epithelium were frequently observed for squamous cell cancer compared to adenocarcinoma at gene loci such as paired homeobox 9 (PAX9) on chromosome 14 and Sry-related HMG box 2 (Sox2) [77] [78]. Downstream regulators of Hh signaling are overexpressed in both adenocarcinoma and squamous esophageal cancers [79]. "
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    ABSTRACT: This review summarizes emerging information regarding the Hedgehog (Hh) signaling pathway during neoplastic transformation in the gastrointestinal tract. Although there is a role for the well-established canonical pathway in which Hedgehog ligands interact with their receptor Patched, there is sufficient evidence that downstream components of the Hh pathway, e.g., Gli1, are hijacked by non-Hh signaling pathways to promote the conversion of the epithelium to dysplasia and carcinoma. We review the canonical pathway and involvement of primary cilia, and then focus on current evidence for Hh signaling in luminal bowel cancers as well as accessory organs, i.e., liver, pancreas and biliary ducts. We conclude that targeting the Hh pathway with small molecules, nutriceuticals and other mechanisms will likely require a combination of inhibitors that target Gli transcription factors in addition to canonical modulators such as Smoothened.
    Cancer Treatment Reviews 08/2013; 40(1). DOI:10.1016/j.ctrv.2013.08.003 · 7.59 Impact Factor
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    • "It is present in 77% of noncardia gastric cancers [10] and in 90% of all chronic gastritis patients, so has been associated with increased risk of cancer up to nine times [11] [12]. Although different genetic and epigenetic alteration involving oncogenes activation, tumor suppressor genes mutations, DNA repair genes, microsatellite instability, loss of heterozygosity (LOH) have been reported in both esophageal and gastric cancers [2] [3] [13] [14], genetic alterations in TP53 tumor suppressor gene are fundamental events related in both early stage and advanced tumor. "
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    ABSTRACT: TP53 genes is one of more important tumor suppressor gene, which acts as a potent transcription factor with fundamental role in the maintenance of genetic stability. The development of esophageal and gastric cancers is a multistep process resulting in successive accumulation of genetic alterations that culminates in the malignant transformation. Thus, this study highlights the participation of the main genetic alterations of the TP53 gene in esophageal and gastric carcinogenesis. Among these changes, high frequency of TP53 mutations, loss of heterozygosity (LOH), overexpression of the p53 protein, and consequently loss of p53 function, which would be early events in esophageal and gastric cancers, as well as an important biomarker of the prognosis and treatment response. Furthermore, Single Nucleotide Polymorphisms (SNPs) of TP53 have been implicated in the development and prognosis of several cancers, mainly TP53 codon 72 polymorphism whose role has been extensively studied in relation to susceptibility for esophageal and gastric cancer development.
    BioMed Research International 08/2012; 2012(2):891961. DOI:10.1155/2012/891961 · 2.71 Impact Factor
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