Dataset Information

Gene expression signatures for colorectal cancer microsatellite status and HNPCC.

ABSTRACT: The majority of microsatellite instable (MSI) colorectal cancers are sporadic, but a subset belongs to the syndrome hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability is caused by dysfunction of the mismatch repair (MMR) system that leads to a mutator phenotype, and MSI is correlated to prognosis and response to chemotherapy. Gene expression signatures as predictive markers are being developed for many cancers, and the identification of a signature for MMR deficiency would be of interest both clinically and biologically. To address this issue, we profiled the gene expression of 101 stage II and III colorectal cancers (34 MSI, 67 microsatellite stable (MSS)) using high-density oligonucleotide microarrays. From these data, we constructed a nine-gene signature capable of separating the mismatch repair proficient and deficient tumours. Subsequently, we demonstrated the robustness of the signature by transferring it to a real-time RT-PCR platform. Using this platform, the signature was validated on an independent test set consisting of 47 tumours (10 MSI, 37 MSS), of which 45 were correctly classified. In a second step, we constructed a signature capable of separating MMR-deficient tumours into sporadic MSI and HNPCC cases, and validated this by a mathematical cross-validation approach. The demonstration that this two-step classification approach can identify MSI as well as HNPCC cases merits further gene expression studies to identify prognostic signatures.

SUBMITTER: Kruhoffer M

PROVIDER: S-EPMC2361815 | biostudies-other | 2005 Jun

REPOSITORIES: biostudies-other

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Gene expression signatures for colorectal cancer microsatellite status and HNPCC.

Kruhøffer M M Jensen J L JL Laiho P P Dyrskjøt L L Salovaara R R Arango D D Birkenkamp-Demtroder K K Sørensen F B FB Christensen L L LL Buhl L L Mecklin J-P JP Järvinen H H Thykjaer T T Wikman F P FP Bech-Knudsen F F Juhola M M Nupponen N N NN Laurberg S S Andersen C L CL Aaltonen L A LA Ørntoft T F TF

British journal of cancer 20050601 12

The majority of microsatellite instable (MSI) colorectal cancers are sporadic, but a subset belongs to the syndrome hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability is caused by dysfunction of the mismatch repair (MMR) system that leads to a mutator phenotype, and MSI is correlated to prognosis and response to chemotherapy. Gene expression signatures as predictive markers are being developed for many cancers, and the identification of a signature for MMR deficiency ...[more]

PMID: 15956967

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Project description:The immune system is crucial in regulating colorectal cancer (CRC) tumorigenesis. Identification of immune-related transcriptomic signatures derived from the peripheral blood of patients with CRC would provide insights into CRC pathogenesis, and suggest novel clues to potential immunotherapy strategies for the disease. The present study collected blood samples from 59 patients with CRC and 62 healthy control patients and performed whole blood gene expression profiling using microarray hybridization. Immune-related gene expression signatures for CRC were identified from immune gene datasets, and an algorithmic predictive model was constructed for distinguishing CRC from controls. Model performance was characterized using an area under the receiver operating characteristic curve (ROC AUC). Functional categories for CRC-specific gene expression signatures were determined using gene set enrichment analyses. A Kaplan-Meier plotter survival analysis was also performed for CRC-specific immune genes in order to characterize the association between gene expression and CRC prognosis. The present study identified five CRC-specific immune genes [protein phosphatase 3 regulatory subunit Bα (PPP3R1), amyloid β precursor protein, cathepsin H, proteasome activator subunit 4 and DEAD-Box Helicase 3 X-Linked]. A predictive model based on this five-gene panel showed good discriminatory power (independent test set sensitivity, 83.3%; specificity, 94.7%, accuracy, 89.2%; ROC AUC, 0.96). The candidate genes were involved in pathways associated with 'adaptive immune responses', 'innate immune responses' and 'cytokine signaling'. The survival analysis found that a high level of PPP3R1 expression was associated with a poor CRC prognosis. The present study identified five CRC-specific immune genes that were potential diagnostic biomarkers for CRC. The biological function analysis indicated a close association between CRC pathogenesis and the immune system, and may reveal more information about the immunogenic and pathogenic mechanisms driving CRC in the future. Overall, the association between PPP3R1 expression and survival of patients with CRC revealed potential new targets for CRC immunotherapy.

Dataset Information

Gene expression signatures for colorectal cancer microsatellite status and HNPCC.

Publications

Gene expression signatures for colorectal cancer microsatellite status and HNPCC.

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