Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

Dmitri Mouradov, Enric Domingo, Peter Gibbs, Robert N. Jorissen, Shan Li, Pik Ying Soo, Lara Lipton, Jayesh Desai, Havard E. Danielsen, Dahmane Oukrif, Marco Novelli, Christopher Yau, Christopher C. Holmes, Ian T. Jones, Stephen McLaughlin, Peter Molloy, Nicholas J. Hawkins, Robyn Ward, Rachel Midgely, David KerrIan Pm Tomlinson, Oliver M. Sieber

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122 Citations (Scopus)

Abstract

OBJECTIVES:Microsatellite 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.METHODS:We 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).RESULTS:In 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.CONCLUSIONS:MSI 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 languageEnglish
Pages (from-to)1785-1793
Number of pages9
JournalAmerican Journal of Gastroenterology
Volume108
Issue number11
DOIs
Publication statusPublished or Issued - Nov 2013
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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