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Integrating chromosomal aberrations and gene expression profiles to dissect rectal cancer

ABSTRACT: Accurate staging of rectal tumors is essential for making the correct treatment choice. In a previous study, we found that loss of 17p, 18q and gain of 8q, 13q and 20q could distinguish adenoma from carcinoma tissue and that loss of 1q was related to lymph node metastasis. In order to find markers for tumor staging, we searched for candidate genes on these specific chromosomes. We performed gene expression microarray analysis on 79 rectal tumors and integrated these data with genomic data from the same sample series (Series GSE7946, Samples GSM194994-GSM195028). We performed supervised analysis to find candidate genes on affected chromosomes and validated the results with qRT-PCR and immunohistochemistry. Approximately 8% of the genes were significantly different between adenomas and carcinomas; the most differently expressed genes were involved in cell adhesion and cell cycle processes. Integration of gene expression and chromosomal instability data revealed a significant genome-wide correlation between these two data types. Supervised analysis identified up-regulation of EFNA1 in cases with 1q gain, and EFNA1 expression was correlated with the expression of a target gene (VEGF). The BOP1 gene, involved in ribosome biogenesis and related to chromosomal instability, was over-expressed in cases with 8q gain. SMAD2 was the most down-regulated gene on 18q, and on 20q, STMN3 and TGIF2 were highly up-regulated. Immunohistochemistry for SMAD4 correlated with SMAD2 gene expression and 18q loss. This study showed a good correlation between chromosomal aberrations and gene expression data. In the near future, specific genes identified by such integrative methods could be of additional value for explaining rectal tumorigenesis. Keywords: disease state analysis

ORGANISM(S): Homo sapiens

PROVIDER: GSE12225 | GEO | 2008/10/21

SECONDARY ACCESSION(S): PRJNA113681

REPOSITORIES: GEO

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Project description:Accurate staging of rectal tumors is essential for making the correct treatment choice. In a previous study, we found that loss of 17p, 18q and gain of 8q, 13q and 20q could distinguish adenoma from carcinoma tissue and that loss of 1q was related to lymph node metastasis. In order to find markers for tumor staging, we searched for candidate genes on these specific chromosomes. We performed gene expression microarray analysis on 79 rectal tumors and integrated these data with genomic data from the same sample series (Series GSE7946, Samples GSM194994-GSM195028). We performed supervised analysis to find candidate genes on affected chromosomes and validated the results with qRT-PCR and immunohistochemistry. Approximately 8% of the genes were significantly different between adenomas and carcinomas; the most differently expressed genes were involved in cell adhesion and cell cycle processes. Integration of gene expression and chromosomal instability data revealed a significant genome-wide correlation between these two data types. Supervised analysis identified up-regulation of EFNA1 in cases with 1q gain, and EFNA1 expression was correlated with the expression of a target gene (VEGF). The BOP1 gene, involved in ribosome biogenesis and related to chromosomal instability, was over-expressed in cases with 8q gain. SMAD2 was the most down-regulated gene on 18q, and on 20q, STMN3 and TGIF2 were highly up-regulated. Immunohistochemistry for SMAD4 correlated with SMAD2 gene expression and 18q loss. This study showed a good correlation between chromosomal aberrations and gene expression data. In the near future, specific genes identified by such integrative methods could be of additional value for explaining rectal tumorigenesis. Keywords: disease state analysis Samples GSM307294-GSM307372: 79 Tumor RNAs were hybridised, all against a common reference sample, consisting of a mixture of cell line and normal colon RNA. 9 replicates (primarily duplicates) were performed (tumor samples: 217, 544, 608, 609, TME1344, TME625, TME884, TME947).

Project description:Background: The high incidence of recurrence and unpredictable clinical outcome for paediatric ependymoma reflect the imprecision of current therapeutic staging and need for novel risk stratification markers. Gain of chromosome 1q has been reported as a frequent aberration and correlate of adverse outcome in ependymoma. We therefore evaluated a prognostic role for 1q25 gain across three age-defined European clinical trial cohorts of paediatric intracranial ependymoma. Methods: The frequency of 1q gain in paediatric ependymoma was assessed across 51 tumours (42 primary, 9 recurrent) using Affymetrix® 500K SNP arrays. Gain of 1q25 was evaluated by interphase FISH (iFISH) across 189 primary intracranial ependymomas from children treated on the CCLG/SIOP CNS9204 (n = 60) and BBSFOP (n = 65) adjuvant chemotherapy trials, or with primary post-operative radiotherapy (SIOP CNS9904/RT group, n = 64). Results were correlated with clinical, histological and survival data. Findings: Gain of 1q was the most frequent imbalance in primary (7/42, 17 %) and recurrent ependymomas (3/9, 33 %). Gain of 1q25 was the strongest independent predictor of tumour progression in both CNS9204 (HR 3·36, p = 0·0009) and BBSFOP (HR 4·10, p = 0·0009) trial cohorts. In contrast, 1q25 gain was not prognostic for the older CNS9904/RT only group (PFS: p = 0·37, OS: p = 0·95). Clinical variables implicated in adverse outcome amongst cohorts included incomplete tumour resection and posterior fossa location. Interpretation: This is the first study to prospectively identify then validate a prognostic genomic marker for childhood ependymoma across independent prospective trial groups. 1q25 gain predicts progression in primary chemotherapy cohorts but not those treated by post-operative radiotherapy. We propose 1q25 gain is incorporated as an adverse marker into future European chemotherapeutic clinical trial design. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from flash frozen tumour specimens and patient-matched peripheral blood Copy number analysis of Affymetrix 500K SNP arrays was performed for DNA from 51 ependymomas and 40 constitutional DNA samples. Analysing broad genomic aberrations in 51 paediatric ependymomas, looking particularly at 1q gain.

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Integrating chromosomal aberrations and gene expression profiles to dissect rectal cancer

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