KRAS Mutation and Microsatellite Instability: Two Genetic Markers of Early Tumor Development That Influence the Prognosis of Colorectal Cancer

Garrett M. Nash MD, Mark Gimbel MD, Alfred M. Cohen MD, Zhao-Shi Zeng MD, Mackevin I. Ndubuisi PhD, Daniel R. Nathanson MD, Jurg Ott PhD, Francis Barany PhD, Philip B. Paty MD
Gastrointestinal Oncology
Volume 17, Issue 2 / February , 2009

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Abstract

Introduction

We examined two genetic markers established early in colorectal tumor development, microsatellite instability (MSI) and mutation of the KRAS proto-oncogene, to see if these genetic changes influence metastatic disease progression and survival.

Patients and methods

MSI and KRAS mutation status were assessed in 532 primary adenocarcinomas (stage I–IV) from patients treated by colon resection. Median follow-up was 4.1 years (range 0–13.3 years) overall, 5.4 years for survivors.

Results

MSI and KRAS mutation were detected in 12 and 36% of cases, respectively. MSI was more common in early-stage disease (I, 15%; II, 21%; III, 10%; IV, 2%; P = 0.0001). Prevalence of KRAS mutation did not vary with stage (I, 36%; II, 34%; III, 35%; IV, 40%; P = ns). Disease-specific survival was far superior for MSI tumors than for microsatellite stability (MSS) tumors (5-year survival 92 vs. 59%, P < 0.0001). KRAS mutation was a marker of poor survival (5-year survival 55 vs. 68%, P = 0.0002). Using Cox regression analysis MSI, KRAS mutation, and stage were strong independent predictors of survival in the entire patient population. A high-mortality group with MSS/KRAS-mutant tumors was identified within the stage I and II cohort.

Conclusions

MSI and KRAS mutation provide fundamental genetic signatures influencing tumor behavior across patient subsets and stages of tumor development.

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