Gene expression signatures for colorectal cancer microsatellite status and HNPCC

• 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
• DOI: 10.1038/sj.bjc.6602621
• EISSN: 1532-1827
• ISSN: 0007-0920

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.