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ObjectivesMicrosatellite instability (MSI) is an established marker of good prognosis in colorectal cancer (CRC). Chromosomal instability (CIN) is strongly negatively associated with MSI and has been shown to be a marker of poor prognosis in a small number of studies. However, a substantial group of "double-negative" (MSI-/CIN-) CRCs exists. The prognosis of these patients is unclear. Furthermore, MSI and CIN are each associated with specific molecular changes, such as mutations in KRAS and BRAF, that have been associated with prognosis. It is not known which of MSI, CIN, and the specific gene mutations are primary predictors of survival.MethodsWe evaluated the prognostic value (disease-free survival, DFS) of CIN, MSI, mutations in KRAS, NRAS, BRAF, PIK3CA, FBXW7, and TP53, and chromosome 18q loss-of-heterozygosity (LOH) in 822 patients from the VICTOR trial of stage II/III CRC. We followed up promising associations in an Australian community-based cohort (N=375).ResultsIn the VICTOR patients, no specific mutation was associated with DFS, but individually MSI and CIN showed significant associations after adjusting for stage, age, gender, tumor location, and therapy. A combined analysis of the VICTOR and community-based cohorts showed that MSI and CIN were independent predictors of DFS (for MSI, hazard ratio (HR)=0.58, 95% confidence interval (CI) 0.36-0.93, and P=0.021; for CIN, HR=1.54, 95% CI 1.14-2.08, and P=0.005), and joint CIN/MSI testing significantly improved the prognostic prediction of MSI alone (P=0.028). Higher levels of CIN were monotonically associated with progressively poorer DFS, and a semi-quantitative measure of CIN was a better predictor of outcome than a simple CIN+/- variable. All measures of CIN predicted DFS better than the recently described Watanabe LOH ratio.ConclusionsMSI and CIN are independent predictors of DFS for stage II/III CRC. Prognostic molecular tests for CRC relapse should currently use MSI and a quantitative measure of CIN rather than specific gene mutations.

Original publication

DOI

10.1038/ajg.2013.292

Type

Journal article

Journal

The American journal of gastroenterology

Publication Date

11/2013

Volume

108

Pages

1785 - 1793

Addresses

1] Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, Parkville, Victoria, Australia [2] Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia.

Keywords

Humans, Colorectal Neoplasms, Chromosome Aberrations, GTP Phosphohydrolases, ras Proteins, Ubiquitin-Protein Ligases, Proto-Oncogene Proteins B-raf, F-Box Proteins, Cell Cycle Proteins, Membrane Proteins, Proto-Oncogene Proteins, Neoplasm Staging, Prognosis, Disease-Free Survival, Survival Rate, DNA Mutational Analysis, Mutation, Loss of Heterozygosity, Aged, Aged, 80 and over, Middle Aged, Female, Male, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Microsatellite Instability, Phosphatidylinositol 3-Kinases, Class I Phosphatidylinositol 3-Kinases, F-Box-WD Repeat-Containing Protein 7