ColoGuideEx: a robust gene classifier specific for stage II colorectal cancer prognosis
- Trude H Ågesen1,2,
- Anita Sveen1,2,
- Marianne A Merok1,2,3,
- Guro E Lind1,2,
- Arild Nesbakken2,3,
- Rolf I Skotheim1,2,
- Ragnhild A Lothe1,2
- 1Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- 2Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- 3Department of Gastrointestinal Surgery, Aker, Oslo University Hospital, Oslo, Norway
- Correspondence to Professor Ragnhild A Lothe, Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, PO Box 4953 Nydalen, NO-0424 Oslo, Norway;
Contributors THÅ and AS performed the experimental and statistical analyses, THÅ drafted the manuscript, MAM and AN provided the biobank material and update of clinical data, GEL participated in evaluation of results, RIS and RAL were responsible for the study design and participated in evaluation of results, and all authors contributed to manuscript preparation.
- Revised 23 November 2011
- Accepted 1 December 2011
- Published Online First 2 January 2012
Background and aims Several clinical factors have an impact on prognosis in stage II colorectal cancer (CRC), but as yet they are inadequate for risk assessment. The present study aimed to develop a gene expression classifier for improved risk stratification of patients with stage II CRC.
Methods 315 CRC samples were included in the study. Gene expression measurements from 207 CRC samples (stage I–IV) from two independent Norwegian clinical series were obtained using Affymetrix exon-level microarrays. Differentially expressed genes between stage I and stage IV samples from the test series were identified and used as input for L1 (lasso) penalised Cox proportional hazards analyses of patients with stage II CRC from the same series. A second validation was performed in 108 stage II CRC samples from other populations (USA and Australia).
Results An optimal 13-gene expression classifier (PIGR, CXCL13, MMP3, TUBA1B, SESN1, AZGP1, KLK6, EPHA7, SEMA3A, DSC3, CXCL10, ENPP3, BNIP3) for prediction of relapse among patients with stage II CRC was developed using a consecutive Norwegian test series from patients treated according to current standard protocols (n=44, p<0.001, HR=18.2), and its predictive value was successfully validated for patients with stage II CRC in a second Norwegian CRC series collected two decades previously (n=52, p=0.02, HR=3.6). Further validation of the classifier was obtained in a recent external dataset of patients with stage II CRC from other populations (n=108, p=0.001, HR=6.5). Multivariate Cox regression analyses, including all three sample series and various clinicopathological variables, confirmed the independent prognostic value of the classifier (p≤0.004). The classifier was shown to be specific to stage II CRC and does not provide prognostic stratification of patients with stage III CRC.
Conclusion This study presents the development and validation of a 13-gene expression classifier, ColoGuideEx, for prognosis prediction specific to patients with stage II CRC. The robustness was shown across patient series, populations and different microarray versions.
THÅ and AS contributed equally to this work.
Funding The study has been financed by grants from the Norwegian Cancer Society (PR-2006-0442 (RAL), including a PhD grant to THÅ, and PR-2007-0166 (RIS)) and by a grant from the Research Council at Rikshospitalet-Radiumhospitalet Health Enterprise (RAL), including a PhD grant to AS.
Competing interests None.
Ethics approval The Regional Committee for Medical and Health Research Ethics, South-Eastern Norway. The research conformed to the Declaration of Helsinki and the research biobanks have been registered according to national legislation (numbers 2781 and 236-2005-16141). This study (amendment number 2010/1805) is part of a project approved by the Regional Committee for Medical and Health Research Ethics (numbers 1.2005.1629 and S-09282c 2009/4958) which requires that informed consent is obtained from patients being enrolled to the study.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Raw data are publicly available in the Gene Expression Omnibus (GEO) database (accession number GSE24550, GSE29638, and GSE30378).