KRAS mutation and microsatellite instability: two genetic markers of early tumor development that influence the prognosis of colorectal cancer

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.

FIG. 1

a Stage distribution of MSI (P < 0.0001) and KRAS. b Chisquare table of MSI and KRAS prevalence

FIG. 2

Disease-specific survival for stage I–IV patients: a MSI versus MSS, b KRAS mutant versus wild type

FIG. 3

Disease-specific survival by stage: a MSI versus MSS, b KRAS mutant (mut) versus Wild type (wt)

FIG. 4

Disease-specific survival stratified by both genetic markers

FIG. 5

Early-stage cancer stratified by MSS and mutant KRAS