Frequent c-<i>myc</i>Amplification in High-Grade Dysplasia and Adenocarcinoma in Barrett Esophagus

Sarbia, Mario; Arjumand, Jawed; Wolter, Marietta; Reifenberger, Guido; Heep, Hansjörg; Gabbert, Helmut E.

doi:10.1309/mxxh-25n3-ual2-g7xx

Cited by 41 publications

(25 citation statements)

References 15 publications

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“…Previously, c-myc locus amplification has been found in 14% to 25% of esophageal cancers, which corresponds well with our results (21). The c-myc amplification has been also documented in patients with Barrett's esophagus with high-grade dysplasia (19,20,36).…”

Section: Discussionsupporting

confidence: 92%

“…Among the most important genetic changes contributing to Barrett's esophagus progression are mutations and allelic losses involving p16 and p53 tumor suppressor genes and DNA ploidy changes (13,(16)(17)(18). In addition to chromosomal deletions, amplification of oncogenes and growth factors also may play an important role in promoting neoplastic progression (19)(20)(21). A variety of gains and amplifications of chromosomal regions have been detected in esophageal adenocarcinoma specimens and adjacent mucosa by Quantitative-PCR, traditional cytogenetic, and metaphase-based comparative genomic hybridization techniques (19,(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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Gains and Amplifications of c-myc, EGFR, and 20.q13 Loci in the No Dysplasia–Dysplasia–Adenocarcinoma Sequence of Barrett's Esophagus

Rygiel

Milano

Kate

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The progression of Barrett's esophagus to esophageal adenocarcinoma is often characterized by the accumulation of genetic abnormalities. The goal was to evaluate the copy number alterations of several oncogene loci, including 7p12 [epidermal growth factor receptor (EGFR)], 8q24 (c-myc), and 20q13 in the sequence of no dysplasia -dysplasia -adenocarcinoma of Barrett's esophagus. Fluorescence in situ hybridization with DNA probes for the centromeric region of chromosome 7 and the locus-specific regions of 7p12 (EGFR), 8q24 (c-myc), and 20q13 was applied on 99 brush cytology specimens of patients with Barrett's esophagus with different stages of dysplasia or esophageal adenocarcinoma. Gains (3-4 copies) of chromosome 17, 8q24 (c-myc), and 20q.13 loci were found in the low frequencies in nondysplastic Barrett's esophagus. Their frequencies increased with the stage of dysplasia and reached a high incidence in esophageal adenocarcinoma.Amplification (>4 copies) of at least 1 of the loci was observed in 14% of high-grade dysplasia and increased to 50% in esophageal adenocarcinoma (P = 0.015). The most frequently amplified locus was c-myc (18%), followed by 20q13 (13%) and EGFR (11%) in the highgrade dysplasia/esophageal adenocarcinoma cases. High amplification levels (>10 copies) of the loci were more frequent in esophageal adenocarcinoma (72%) compared with high-grade dysplasia (20%; P = 0.049). Amplifications of the c-myc, EGFR, and 20q12 loci may serve as diagnostic markers to identify patients with Barrett's esophagus with high-grade dysplasia or esophageal adenocarcinoma. Gains of the loci might be of value as prognostic markers because they are already present in nondysplasia cases and may precede the later event of the amplification as observed in high-grade dysplasia and esophageal adenocarcinoma. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1380 -5)

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Gains and Amplifications of c-myc, EGFR, and 20.q13 Loci in the No Dysplasia–Dysplasia–Adenocarcinoma Sequence of Barrett's Esophagus

Rygiel

Milano

Kate

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…reporting a MYC amplification in 25% of high-grade dysplasias and 44% of adenocarcinomas. 17 There was no significant correlation of genomic alterations with tumor stage and histological grading. However, this does not exclude an association between genomic instability and tumor progression as the number of investigated cases in this study was limited.…”

Section: Discussionmentioning

confidence: 89%

Genome-wide analysis of genetic alterations in Barrett's adenocarcinoma using single nucleotide polymorphism arrays

Wiech

Nikolopoulos

Weis

et al. 2009

Laboratory Investigation

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We performed genome-wide analysis of copy-number changes and loss of heterozygosity (LOH) in Barrett's esophageal adenocarcinoma by single nucleotide polymorphism (SNP) microarrays to identify associated genomic alterations. DNA from 27 esophageal adenocarcinomas and 14 matching normal tissues was subjected to SNP microarrays. The data were analyzed using dChipSNP software. Copy-number changes occurring in at least 25% of the cases and LOH occurring in at least 19% were regarded as relevant changes. As a validation, fluorescence in situ hybridization (FISH) of 8q24.21 (CMYC) and 8p23.1 (SOX7) was performed. Previously described genomic alterations in esophageal adenocarcinomas could be confirmed by SNP microarrays, such as amplification on 8q (CMYC, confirmed by FISH) and 20q13 or deletion/LOH on 3p (FHIT) and 9p (CDKN2A). Moreover, frequent gains were detected on 2p23.3, 7q11.22, 13q31.1, 14q32.31, 17q23.2 and 20q13.2 harboring several novel candidate genes. The highest copy numbers were seen on 8p23.1, the location of SOX7, which could be demonstrated to be involved in amplification by FISH. A nuclear overexpression of the transcription factor SOX7 could be detected by immunohistochemistry in two amplified tumors. Copy-number losses were seen on 18q21.32 and 20p11.21, harboring interesting candidate genes, such as CDH20 and CST4. Finally, a novel LOH region could be identified on 6p in at least 19% of the cases. In conclusion, SNP microarrays are a valuable tool to detect DNA copynumber changes and LOH at a high resolution. Using this technique, we identified several novel genes and DNA regions associated with esophageal adenocarcinoma. KEYWORDS: Barrett's adenocarcinoma; copy-number changes; esophageal carcinoma; LOH; mapping array; SNP array Genomic alterations, such as amplification, deletion, translocation and loss of heterozygosity (LOH) play an important role in the pathogenesis and progression of cancer due to the activation of oncogenes or inactivation of tumor suppressor genes. Apart from numeric aberrations, such as gene amplification or deletion, which are frequently detected in carcinomas, other genomic changes in carcinogenesis, such as LOH, do not necessarily lead to DNA copy-number gain or loss. Several causes of LOH have been described, including deletion, non-disjunction and reduplication, mitotic recombination and gene conversion. 1 The two-hit model describes a tumor suppressor gene inactivation due to a loss of one allele and mutation of the other allele, resulting in an LOH. 2 Besides detailed investigation of known oncogenes and tumor suppressor genes, screening for novel genomic alterations in different cancers and precursor lesions provides information of molecular mechanisms in carcinogenesis.The incidence of esophageal (Barrett's) adenocarcinoma, mostly arising within the precancerous Barrett's esophagus, with the normal esophageal squamous epithelium changed into intestinal metaplasia, has risen in the past decades in western countries. 3 Screening for chromosomal alterations has bee...

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“…These include inactivation of cell-cycle checkpoint (P16 and P53) genes by multiple mechanisms (allelic loss, mutation and promoter hypermethylation in the case of P16) 21,22,28,40 -44 as well as gains/ amplification at different proto-oncogene loci. 24,[45][46][47] P16 and P53 genes regulate the cell cycle. p16 INK4A (p16) is encoded by the INK4a/CDKN2A gene located on chromosome 9p21.…”

Section: Discussionmentioning

confidence: 99%

Utility of Biomarkers in Prediction of Response to Ablative Therapy in Barrett's Esophagus

et al. 2008

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Background & Aims-Photodynamic therapy (PDT) has been shown to be effective in the treatment of high-grade dysplasia (HGD)/mucosal carcinoma in Barrett's esophagus (BE). Substantial proportions of patients do not respond to PDT or progress to carcinoma despite PDT. The role of biomarkers in predicting response to PDT is unknown. We aimed to determine if biomarkers known to be associated with neoplasia in BE can predict loss of dysplasia in patients treated with ablative therapy for HGD/intramucosal cancer.

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Frequent c-mycAmplification in High-Grade Dysplasia and Adenocarcinoma in Barrett Esophagus

Cited by 41 publications

References 15 publications

Gains and Amplifications of c-myc, EGFR, and 20.q13 Loci in the No Dysplasia–Dysplasia–Adenocarcinoma Sequence of Barrett's Esophagus

Gains and Amplifications of c-myc, EGFR, and 20.q13 Loci in the No Dysplasia–Dysplasia–Adenocarcinoma Sequence of Barrett's Esophagus

Genome-wide analysis of genetic alterations in Barrett's adenocarcinoma using single nucleotide polymorphism arrays

Utility of Biomarkers in Prediction of Response to Ablative Therapy in Barrett's Esophagus

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