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Exploiting gene expression profiling to identify novel minimal residual disease markers of neuroblastoma.

ABSTRACT: Minimal residual disease (MRD) presents a significant hurdle to curing metastatic neuroblastoma. Biological therapies directed against MRD can improve outcome. Evaluating treatment efficacy requires MRD measurement, which serves as surrogate endpoint. Because of tumor heterogeneity, no single marker will likely be adequate. Genome-wide expression profiling can uncover potential MRD markers differentially expressed in tumors over normal marrow/blood.Gene expression array was carried out on 48 stage 4 tumors and 9 remission marrows using the Affymetrix U95 gene chip. Thirty-four genes with a tumor-to-marrow expression ratio higher than tyrosine hydroxylase were identified. Quantitative reverse transcription-PCR was done on all 34 genes to study the dynamic range of tumor cell detection and the expression of these genes in normal marrow/blood samples and in stage 4 neuroblastoma tumors. Top ranking markers were then tested for prognostic significance in the marrows of stage 4 patients collected from the same treatment protocol after two cycles of immunotherapy.Based on sensitivity assays, 8 top-ranking markers were identified: CCND1, CRMP1, DDC, GABRB3, ISL1, KIF1A, PHOX2B, and TACC2. They were abundantly expressed in stage IV neuroblastoma tumors (n=20) and had low to no detection in normal marrow/blood samples (n=20). Moreover, expression of CCND1, DDC, GABRB3, ISL1, KIF1A, and PHOX2B in 116 marrows sampled after two treatment cycles was highly prognostic of progression-free and overall survival (P<0.001).Marker discovery based on differential gene expression profiling, stringent sensitivity and specificity assays, and well-annotated patient samples can rapidly prioritize and identify potential MRD markers of neuroblastoma.

SUBMITTER: Cheung IY

PROVIDER: S-EPMC2670609 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Exploiting gene expression profiling to identify novel minimal residual disease markers of neuroblastoma.

Cheung Irene Y IY Feng Yi Y Gerald William W Cheung Nai-Kong V NK

Clinical cancer research : an official journal of the American Association for Cancer Research 20081101 21

<h4>Purpose</h4>Minimal residual disease (MRD) presents a significant hurdle to curing metastatic neuroblastoma. Biological therapies directed against MRD can improve outcome. Evaluating treatment efficacy requires MRD measurement, which serves as surrogate endpoint. Because of tumor heterogeneity, no single marker will likely be adequate. Genome-wide expression profiling can uncover potential MRD markers differentially expressed in tumors over normal marrow/blood.<h4>Experimental design</h4>Gen ...[more]

PMID: 18980998

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Project description:(This section will be revisited in good time prior to publication, for final approval) Research within the field of functional genomics provides a more profound understanding of living organisms, by elucidating the interaction between genes and gene products. This is of increasing importance in many fields, and especially within cancer research. With the use of microarray technology, the gene expression of a vast number of genes can be measured simultaneously. This allows us insight into tumor biology, and an opportunity to obtain knowledge of diagnostic and prognostic value, as well as hints towards the causes of cancer. In this study the gene expression in a selection of human neuroendocrine (NE) and non-neuroendocrine tumor cell lines were compared. Both qualitative and quantitative methods were applied to get an insight into the NE tumor biology. NE cells are found in practically every organ and tissue in the body and are assigned to synthesize peptide hormones and take up amino acids and transform these into biogenic amines by carboxylation. NE tumors arise after malignant transformation of neuroendocrine cells and are usually highly differentiated and have a low growth rate, which makes this a high prevalence tumor type. These rather rare tumors characteristically express NE markers, such as chromogranin A, and contains characteristic dense-secretory core granules. By using cDNA microarray analysis, the gene expression profiles of various NE tumor cell lines (e. g. carcinoid, neuroblastoma, medullary thyroid carcinoma and endocrine pancreatic tumor) were compared with those of non-NE tumor cells. As a reference the commercially available Universal human RNA reference (Stratagene) was used. Verification of the results were done by real time RT-PCR analysis after the NE nature of the cell lines was stated by immunohistochemical, electron microscopic and light microscopic examinations. A large number of genes were differentially expressed in NE cell lines vs. the non-NE cell lines, and were found to be of interest in NE tumor biology. Some of these genes were previously known in NE tumor biology, whereas the vast majority of the specified genes are novel in the context of NE tumor biology. Genes with little previous information were also identified and thought to be an asset in the search of new NE markers. A feasible prospective of the study would be expansion with additional samples cell lines and a more thorough verification with real time RT-PCR analysis. This would enhance the credibility and thus the utility of the findings. Future studies on the biological functions of the candidate genes and the mechanisms of their regulation, will hopefully enable suggestions of new NE markers of prognostic or diagnostic value, and eventually new drug targets. Keywords: neuroendocrine, neuroendocrine markers, gene expression profiling, cDNA microarray The hybridisation was performed by an experienced laboratory technician Eli Helge, (Dept. of Laboratory Medicine, Children`s and Women`s health, NTNU) at the microarray core facility. Three separate runs with 10, 11 and 3 slides was needed to obtain the 20 hybridisations (dyeswap x 10 cell lines) planned for this study. Of the 10 cell lines 6 were neuroendocrine and 4 were non-neuroendocrine. For comparison between these two groups the universal human reference RNA (Stratagene) was used as the "control" on each slide. An adapted version of the 3DNA Array 350 protocol (Genisphere) was used. The slides were scanned with a ScanArrayTMExpressHT (Packard BioScience) twice immediately after the hybridisation was completed to avoid photo bleaching of the fluorescent dyes.

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Exploiting gene expression profiling to identify novel minimal residual disease markers of neuroblastoma.

Publications

Exploiting gene expression profiling to identify novel minimal residual disease markers of neuroblastoma.

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