Gene expression signatures for colorectal cancer microsatellite status and HNPCC

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 i...

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Bibliographic Details
Published in:	British journal of cancer Vol. 92; no. 12; pp. 2240 - 2248
Main Authors:	KRUHEFFER, M, JENSEN, J. L, MECKLIN, J.-P, JÄRVINEN, H, THYKJAER, T, WIKMAN, F. P, BECH-KNUDSEN, F, JUHOLA, M, NUPPONEN, N. N, LAURBERG, S, ANDERSEN, C. L, AALTONEN, L. A, LAIHO, P, ØRNTOFT, T. F, DYRSKJØT, L, SALOVAARA, R, ARANGO, D, BIRKENKAMP -DEMTRODER, K, SØRENSEN, F. B, CHRISTENSEN, L. L, BUHL, L
Format:	Journal Article
Language:	English
Published:	Basingstoke Nature Publishing Group 20-06-2005
Subjects:	Adenocarcinoma - genetics Adult Aged Aged, 80 and over Base Pair Mismatch - genetics Biological and medical sciences Cancer research Chemotherapy Chromosomal Instability - genetics Colonic Neoplasms - genetics Colorectal cancer Colorectal Neoplasms, Hereditary Nonpolyposis - genetics DNA Repair - genetics Gastroenterology. Liver. Pancreas. Abdomen Gene expression Gene Expression - genetics Gene Expression Profiling Genetics and Genomics Humans Medical research Medical sciences Microsatellite Repeats - genetics Middle Aged Mutation Oligonucleotide Array Sequence Analysis Predictive Value of Tests Research parks Stomach. Duodenum. Small intestine. Colon. Rectum. Anus Tumors Yeast Denmark Aarhus Denmark Finland microsatellite instability Rectal disease Colorectal cancer Malignant tumor Gene expression Colonic disease HNPCC Colon cancer Cancerology Microsatellite DNA Digestive diseases Intestinal disease Instability
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-3 content type line 23 ObjectType-Undefined-2
ISSN:	0007-0920 1532-1827
DOI:	10.1038/sj.bjc.6602621