Array comparative genomic hybridisation analysis of colorectal cancer shows prognostically relevant differential patterns of DNA copy number alterations in microsatellite stable and unstable tumours


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George Poulogiannis1, Koichi Ichimura1, Suet Y Leung2, Siu T Yuen2, Rifat Hamoudi1, Feijun Luo1, David Harrison3, V Peter Collins1, Andrew Wyllie1, Mark Arends1

1University of Cambridge, UK, 2University of Hong Kong, Hong Kong, 3University of Edinburgh, UK

Abstract

Background
Many, but not all, studies of colorectal cancer (CRC) have found that tumours with microsatellite instability have a better prognosis than microsatellite stable (MSS) cancers. To explore the basis of this, we analysed a series of CRC by array comparative genomic hybridisation (aCGH) at high resolution to identify DNA copy number changes with prognostic relevance.

Results
DNA copy number changes were studied in 109 CRC including 13 with microsatellite instability at high frequency (MSI-H) and 96 MSS tumours, using aCGH at ~1Mbase resolution with a 2,904 element pan-genomic array. The frequency of copy number change was compared between tumours grouped according to microsatellite status, presence or absence of lymph node metastasis, recurrence, and long-term survival. The most significant differences (p<0.05) in DNA copy number changes between MSS and MSI-H CRCs were losses within chromosomes 8p, 17p and 18q and gains within 13q and 20q. Unsupervised hierarchical clustering of the genomic microarray data identified four groups I-IV, one of which (group II) was associated with significantly better prognosis than the other three, as previously reported. Further analysis of the prognostically relevant copy number changes identified a set of 23 clone loci, copy number changes of which were associated with aggressive growth behaviour including poor survival. Fourteen of these 23 clone loci showed significantly different copy number changes between MSS and MSI-H tumours, while the MSI-H tumours that do acquire changes to these clone loci have a poorer prognosis compared to those that do not, similar to the MSS group.

Conclusion
Prognostic information is provided by DNA copy number analysis of colorectal cancers. The controversial relationship of MSI-H with better prognosis than MSS tumours may be explained by differential association with copy number change at particular loci.

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