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K-ras and p16 Aberrations Confer Poor Prognosis in Human Colorectal Cancer

From the Johns Hopkins Oncology Center, Baltimore, MD; Laboratori d’Investigacio Gastrointestinal, and S. Oncología Médica, Hospital de la Santa Creu i Sant Pau; Institut Català d’Oncologia and Institut de Recerca Oncològica, Hospital Duran i Reynals, Barcelona, Spain.

Address reprint requests to Gabriel Capellà, MD, PhD, Institut Català d’Oncologia. Av. Gran Via s/n Km 2,7 08907 L’Hospitalet de Llobregat, Barcelona, Spain; email gcapella{at}ico.scs.es

PURPOSE: Mutations in the K-ras gene are frequent in human cancer. ras activation in primary cells results in a cellular senescence phenotype that is precluded by inactivation of p16. At the clinical level, this may imply a differential behavior for tumors with alternative or cooperative activation of K-ras function and impairment of p16 pathways.

PATIENTS AND METHODS: We have determined the presence of mutations in the K-ras gene and the methylation status of p16 promoter in a series of 119 prospectively collected colorectal carcinomas. p53 mutations and p14 alternative reading frame methylation status were also assessed. Associations with survival were investigated.

RESULTS: K-ras mutations were present in 44 (38%) of 115 cases, and p16 methylation was present in 42 (37%) of 113 cases. p53 mutations were detected in 50% (56 of 115) and p14 methylation in 29% (32 of 112) of cases. K-ras and p16 alterations were independent genetic events. Presence of K-ras or p16 genetic alterations (analyzed independently) was associated with shorter survival, although differences were not statistically significant. Cox analysis of the two variables combined showed a diminished survival as the results of an interaction between p16 and K-ras. Alternative alteration of K-ras and p16 genes was an independent prognostic factor in human colorectal cancer in univariate and multivariate analysis. Differences were maintained when cases undergoing radical surgery and without distant metastases were considered.

CONCLUSION: These results suggest that the combined K-ras and p16 analyses may be of prognostic use in human colorectal cancer.

The first two authors contributed equally to this work.

J.G.H. is a Valvano Foundation Scholar. J.G.H. receives research funding and is entitled to sales royalties from ONCOR, Intengen, Purchase, NY, which is developing products related to research described in this paper. The terms of this arrangement have been reviewed and approved by The Johns Hopkins University in accordance with its conflict of interest policies.

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