Transcriptional oncogenomic hot spots in Barrett's adenocarcinomas: Serial analysis of gene expression

Razvi, Mohammad; Peng, Dunfa; Dar, Altaf A.; Powell, Steven M.; Frierson, Henry F.; Moskaluk, Christopher A.; Washington, Kay; El–Rifai, Wael

doi:10.1002/gcc.20479

Cited by 18 publications

(17 citation statements)

References 56 publications

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“…We noted a reduced activity in gene ontology groups that relate to metabolic and xenobiotic activities (HPGD, LIPF, SULT1C2, ADH1B, ADH1C, ALDH3A1, AKR1C1, AKR1C2, AKR1B10) within EACs, as have other profiling studies [13], [15], [18], [19], [36]. These changes may signify dedifferentiation, a feature of cancer, and perhaps indicate that EAC cancer cells maybe more susceptible to the DNA damaging effects of smoking and reflux, although we could not find literature to support this.…”

Section: Resultssupporting

confidence: 65%

Whole Genome Expression Array Profiling Highlights Differences in Mucosal Defense Genes in Barrett's Esophagus and Esophageal Adenocarcinoma

et al. 2011

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Esophageal adenocarcinoma (EAC) has become a major concern in Western countries due to rapid rises in incidence coupled with very poor survival rates. One of the key risk factors for the development of this cancer is the presence of Barrett's esophagus (BE), which is believed to form in response to repeated gastro-esophageal reflux. In this study we performed comparative, genome-wide expression profiling (using Illumina whole-genome Beadarrays) on total RNA extracted from esophageal biopsy tissues from individuals with EAC, BE (in the absence of EAC) and those with normal squamous epithelium. We combined these data with publically accessible raw data from three similar studies to investigate key gene and ontology differences between these three tissue states. The results support the deduction that BE is a tissue with enhanced glycoprotein synthesis machinery (DPP4, ATP2A3, AGR2) designed to provide strong mucosal defenses aimed at resisting gastro-esophageal reflux. EAC exhibits the enhanced extracellular matrix remodeling (collagens, IGFBP7, PLAU) effects expected in an aggressive form of cancer, as well as evidence of reduced expression of genes associated with mucosal (MUC6, CA2, TFF1) and xenobiotic (AKR1C2, AKR1B10) defenses. When our results are compared to previous whole-genome expression profiling studies keratin, mucin, annexin and trefoil factor gene groups are the most frequently represented differentially expressed gene families. Eleven genes identified here are also represented in at least 3 other profiling studies. We used these genes to discriminate between squamous epithelium, BE and EAC within the two largest cohorts using a support vector machine leave one out cross validation (LOOCV) analysis. While this method was satisfactory for discriminating squamous epithelium and BE, it demonstrates the need for more detailed investigations into profiling changes between BE and EAC.

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Section: Resultssupporting

confidence: 65%

Whole Genome Expression Array Profiling Highlights Differences in Mucosal Defense Genes in Barrett's Esophagus and Esophageal Adenocarcinoma

et al. 2011

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“…Ours is not the first report of generating SAGE libraries in either Barrett esophagus or EAC;27–29 nevertheless, there are several unique facets to our study design that deserve comment. To the best of our knowledge, this is the first study to create SAGE profiles from non-invasive dysplastic lesions (LGD and HGD) that precede invasive EAC.…”

Section: Discussionmentioning

confidence: 93%

The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma

Alvarez

Montgomery

Karikari

et al. 2010

Cancer Biology & Therapy

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Esophageal adenocarcinoma (EAC) arises in the backdrop of reflux-induced metaplastic phenomenon known as Barrett esophagus. The prognosis of advanced EAC is dismal, and there is an urgent need for identifying molecular targets for therapy. Serial Analysis of Gene Expression (SAGE) was performed on metachronous mucosal biopsies from a patient who underwent progression to EAC during endoscopic surveillance. SAGE confirmed significant upregulation of Axl “tags” during the multistep progression of Barrett esophagus to EAC. In a cohort of 92 surgically resected EACs, Axl overexpression was associated with shortened median survival on both univariate (p < 0.004) and multivariate (p < 0.036) analysis. Genetic knockdown of Axl receptor tyrosine kinase (RTK) function was enabled in two EAC lines (OE33 and JH-EsoAd1) using lentiviral short hairpin RNA (shRNA). Genetic knockdown of Axl in EAC cell lines inhibited invasion, migration and in vivo engraftment, which was accompanied by downregulation in the activity of the Ral GTPase proteins (RalA and RalB). Restoration of Ral activation rescued the transformed phenotype of EAC cell lines, suggesting a novel effector mechanism for Axl in cancer cells. Pharmacological inhibition of Axl was enabled using a small molecule antagonist, R428 (Rigel Pharmaceuticals). Pharmacological inhibition of Axl with R428 in EAC cell lines significantly reduced anchorage-independent growth, invasion and migration. Blockade of Axl function abrogated phosphorylation of ERBB2 (Her-2/neu) at the Tyr877 residue, indicative of receptor crosstalk. Axl RTK is an adverse prognostic factor in EAC. The availability of small molecule inhibitors of Axl function provides a tractable strategy for molecular therapy of established EAC.

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“…Prlh modulates secretion of prolactin [28], a hormone that has been shown to be a risk factor for human breast cancer [28], [29]. Notably, for Mts-2 QTL on chromosome-1, the marker at the QTL-peak, D1Rat350, is located within the Anpep [alanyl (membrane) aminopeptidase] transcription unit, an enzyme that might be a candidate gene because it has been associated with invasive colorectal cancer [30] and prostate cancer [31], and Barrett’s adenocarcinoma [32]. Another candidate gene on chromosome 1, Blm localizes at 136.2 Mb also within the Mts-2 QTL interval (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, the candidate genes for Mts-2 QTL, Anpep or Blm are both implicated in breast cancer. Anpep is increased in breast cancer effusions [43], and its down regulation is associated with invasive colorectal cancer [30] and prostate cancer [31], while over expression of Anpep has been linked to Barrett’s adenocarcinomas [32]. Blm , the gene for Bloom syndrome, is a DNA repair gene which may play a role in breast cancer occurrence as its loss may contribute to somatic mutations and loss of heterozygosis, chromosomal instability, aneuploidy, and sensitivity to DNA damaging agents [44].…”

Section: Discussionmentioning

confidence: 99%

Multiple Susceptibility Loci for Radiation-Induced Mammary Tumorigenesis in F2[Dahl S x R]-Intercross Rats

2013

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Although two major breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified accounting for 20% of breast cancer genetic risk, identification of other susceptibility genes accounting for 80% risk remains a challenge due to the complex, multi-factorial nature of breast cancer. Complexity derives from multiple genetic determinants, permutations of gene-environment interactions, along with presumptive low-penetrance of breast cancer predisposing genes, and genetic heterogeneity of human populations. As with other complex diseases, dissection of genetic determinants in animal models provides key insight since genetic heterogeneity and environmental factors can be experimentally controlled, thus facilitating the detection of quantitative trait loci (QTL). We therefore, performed the first genome-wide scan for loci contributing to radiation-induced mammary tumorigenesis in female F2-(Dahl S x R)-intercross rats. Tumorigenesis was measured as tumor burden index (TBI) after induction of rat mammary tumors at forty days of age via 127Cs-radiation. We observed a spectrum of tumor latency, size-progression, and pathology from poorly differentiated ductal adenocarcinoma to fibroadenoma, indicating major effects of gene-environment interactions. We identified two mammary tumorigenesis susceptibility quantitative trait loci (Mts-QTLs) with significant linkage: Mts-1 on chromosome-9 (LOD-2.98) and Mts-2 on chromosome-1 (LOD-2.61), as well as two Mts-QTLs with suggestive linkage: Mts-3 on chromosome-5 (LOD-1.93) and Mts-4 on chromosome-18 (LOD-1.54). Interestingly, Chr9-Mts-1, Chr5-Mts-3 and Chr18-Mts-4 QTLs are unique to irradiation-induced mammary tumorigenesis, while Chr1-Mts-2 QTL overlaps with a mammary cancer susceptibility QTL (Mcs 3) reported for 7,12-dimethylbenz-[α]antracene (DMBA)-induced mammary tumorigenesis in F2[COP x Wistar-Furth]-intercross rats. Altogether, our results suggest at least three distinct susceptibility QTLs for irradiation-induced mammary tumorigenesis not detected in genetic studies of chemically-induced and hormone-induced mammary tumorigenesis. While more study is needed to identify the specific Mts-gene variants, elucidation of specific variant(s) could establish causal gene pathways involved in mammary tumorigenesis in humans, and hence novel pathways for therapy.

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Transcriptional oncogenomic hot spots in Barrett's adenocarcinomas: Serial analysis of gene expression

Cited by 18 publications

References 56 publications

Whole Genome Expression Array Profiling Highlights Differences in Mucosal Defense Genes in Barrett's Esophagus and Esophageal Adenocarcinoma

Whole Genome Expression Array Profiling Highlights Differences in Mucosal Defense Genes in Barrett's Esophagus and Esophageal Adenocarcinoma

The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma

Multiple Susceptibility Loci for Radiation-Induced Mammary Tumorigenesis in F2[Dahl S x R]-Intercross Rats

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