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Gene expression profiling of 91 hepatocellular carcinomas with hepatitis C virus etiology

ABSTRACT: To characterize the genetic alterations that instigate hepatitis C virus-induced hepatocellular carcinoma (HCC), we conducted an integrative genomic analysis of 103 HCCs. Most tumors harbored 1q gain, 8q gain or 8p loss, with occasional alterations in 13 additional chromosome arms. In addition to amplifications at 11q13 in 6 tumors, 4 tumors harbored focal gains at 6p21 incorporating VEGFA, which were confirmed in 4 of 113 HCC in an independent validation set. Strikingly, this locus overlapped with copy gains in 4 of 371 lung adenocarcinomas. Overexpression of VEGFA via 6p21 gain suggested a cell-nonautonomous mechanism of oncogene activation. Hierarchical clustering of gene expression among 91 tumors identified 5 classes, including ‘Wnt-CTNNB1’, ‘proliferation’ and ‘interferon-related’ gene classes. We also discovered a novel class defined by polysomy of chromosome 7, gains of which were associated with early tumor recurrence after resection. These findings reveal key alterations in HCC pathogenesis and implicate potential therapeutic targets. Keywords: disease state analysis

ORGANISM(S): Homo sapiens

PROVIDER: GSE9843 | GEO | 2008/06/22

SECONDARY ACCESSION(S): PRJNA105125

REPOSITORIES: GEO

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Transcription profiling by array of human hepatocellular carcinomas with hepatitis C virus etiology

Project description:To characterize the genetic alterations that instigate hepatitis C virus-induced hepatocellular carcinoma (HCC), we conducted an integrative genomic analysis of 103 HCCs. Most tumors harbored 1q gain, 8q gain or 8p loss, with occasional alterations in 13 additional chromosome arms. In addition to amplifications at 11q13 in 6 tumors, 4 tumors harbored focal gains at 6p21 incorporating VEGFA, which were confirmed in 4 of 113 HCC in an independent validation set. Strikingly, this locus overlapped with copy gains in 4 of 371 lung adenocarcinomas. Overexpression of VEGFA via 6p21 gain suggested a cell-nonautonomous mechanism of oncogene activation. Hierarchical clustering of gene expression among 91 tumors identified 5 classes, including 'Wnt-CTNNB1', 'proliferation' and 'nterferon-related' gene classes. We also discovered a novel class defined by polysomy of chromosome 7, gains of which were associated with early tumor recurrence after resection. These findings reveal key alterations in HCC pathogenesis and implicate potential therapeutic targets. Experiment Overall Design: 91 hepatocellular carcinomas were obtained at the time of surgical resection or orthotopic transplantation.

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2008-06-21 | E-GEOD-9845 | biostudies-arrayexpress

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2008-04-18 | E-TABM-267 | biostudies-arrayexpress

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Focal gains of VEGFA and molecular classification of hepatocellular carcinoma

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Project description:Fifty-one breast tumors were profiled for copy-number alterations with the high-resolution Affymetrix 500K Mapping Array. Combined analysis of the prevalence and amplitude of copy-number alterations defined regions of recurrent gain or loss. Gains were most frequently observed on chromosomes 1, 8, 10, 11, 13, 15, 17, and 20. Losses were most frequent on chromosomes 3, 6, 11, 13, 14, 16, and 17. Compared with previous lower-resolution data, our analysis provided significantly more precise boundaries for frequently altered regions, greatly reducing the number of potential alteration-driving genes. Keywords: Mapping Array

2008-03-17 | GSE7545 | GEO

HER2 FISH results in breast cancers with increased CEN17 signals using alternative chromosome 17 probes - reclassifying cases in the equivocal category.

Project description:AIMS: HER2 testing of invasive breast cancer by in-situ hybridisation guides therapy decisions. Probing HER2 and cen17 simultaneously is supposed to reveal both a potential HER2 gene amplification and polysomy 17. However, a considerable number of breast cancer patients with quasi polysomy 17 are considered "equivocal" which is diagnostically meaningless. Moreover, patients with equivocal / false polysomic tumours are prevented from a potentially beneficial anti-HER2 treatment. Here we evaluated the RAI1, D17S122, and TP53 hybridisation markers to reliably indicate true polysomy and to accurately reclassify equivocal samples as HER2-positive. METHODS AND RESULTS: Samples with (n = 82) and without (n = 52) increased cen17 copy numbers and 78 evidently HER2-amplified specimens were analysed using dual and triple marker hybridisation probes. Selected putative polysomic samples were subjected to array-based comparative genomic hybridisation. We found that 37.8% samples with putative polysomy 17 did not show any gain in RAI1, D17S122, or TP53. Accordingly, aCGH revealed evidence for the presence of HER2/cen17 coamplification rather than for true polysomy in those cases. Reflex testing using alternate 17p markers reclassified up to 56.3% equivocal cases as HER2-positive and the combined assessment of a 17p and 17q locus allows the differentiation of true vs. false polysomy. CONCLUSIONS: An increased cen17 copy number does not necessarily reflect polysomy and reflex testing facilitates the reclassification of "equivocals". Nevertheless, the prognostic and predictive value of a HER2/cen17 coamplification versus HER2 gene amplification alone must still be prospectively evaluated. This article is protected by copyright. All rights reserved.

2017-01-01 | GSE86305 | GEO

Affymetrix SNP array data for pediatric rhabdomyosarcoma (RMS)

Project description:To elucidate the pathogenesis of rhabdomyosarcoma (RMS), particularly for different subgroups, we performed a SNP array-based copy number analysis of 46 RMS specimens from primary cases with ERMS (N = 21), ARMS (N = 14), unclassified RMS (N = 1), and RMS of unknown histology (N = 3) together with 7 RMS-derived cell lines. The ERMS subtype was characterized by hyperploidy and was significantly associated with gains of chromosomes 2, 8, and 12, whereas majority of ARMS cases exhibited near-diploid copy number profiles. Recurrent loss of heterozygosity (LOH) of chromosomes 3 (28.6%) and 15q (35.7%) was detected in ARMS. Uniparental disomy/polysomy of 11p was commonly found in both tumor types. Focal gains/amplifications were associated mostly with PAX3-FOXO1 (5/10) or PAX7-FOXO1 (6/6) fusions, but novel amplified regions were also found, including the IRS2 in 2 ARMS. Gain of 13q was significantly associated with good patient outcome in ERMS. These findings not only illustrate genetic differences between ARMS and ERMS but also provide novel insights into the pathogenesis of RMS. Copy number analysis of Affymetrix 50K/250K SNP arrays was performed for 46 RMS samples.

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