ABSTRACT
NRAS mutations occur in 3-5% of colorectal cancer. Differently from KRAS and BRAF mutations, the role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer (mCRC) has been investigated to a lesser extent. A retrospective series suggested the role of NRAS mutations as predictors of resistance to anti-EGFR monoclonal antibodies (MoAbs) in chemo-refractory patients with mCRC. In our study, KRAS codons 12, 13, 61 and BRAF codon 600 mutational status were evaluated in mCRCs referred to our Institution from 2009 to 2012. NRAS codons 12, 13 and 61 mutational status was analyzed in KRAS/BRAF wt patients. We collected pathological and clinical features in the overall population and outcome data in a subset of NRAS mutated chemo-refractory patients treated with anti-EGFR MoAbs in advanced lines. NRAS was mutated in 47/786 (6%) mCRCs. NRAS and KRAS mutated tumors did not show significant differences in terms of clinical and pathological characteristics, except for a lower prevalence of mucinous histology (p = 0.012) and lung metastases (p = 0.012) among NRAS mutated tumors. In the uni- and multivariate model, NRAS mutations were associated with shorter overall survival (OS) compared to all wt patients (median OS 25.6 vs 42.7 months; univ: HR = 1.91, 95% CI 1.39-3.86, p = 0.0013; multiv: HR = 1.75, 95% CI 1.1.3-2.72, p = 0.013). None of the chemo-refractory NRAS mutated patients evaluable for response to anti-EGFRs achieved response. In conclusion, NRAS mutations have a relevant incidence in patients with mCRC and showed an association with specific clinical and pathological features. NRAS mutations affect mCRC patients' prognosis and predict lack of response to anti-EGFRs.
Subject(s)
Biomarkers, Tumor/genetics , Colorectal Neoplasms/genetics , GTP Phosphohydrolases/genetics , Liver Neoplasms/genetics , Membrane Proteins/genetics , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Cetuximab , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , DNA Mutational Analysis , Disease-Free Survival , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , Female , Genetic Association Studies , Humans , Kaplan-Meier Estimate , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Male , Middle Aged , Mutation, Missense , Prognosis , Proportional Hazards Models , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras) , Retrospective Studies , ras Proteins/geneticsABSTRACT
A chemical genetics approach has been applied in the screening of yeast deletants strains with a pool of morpholine-derived compounds in order to identify candidate small molecules able to produce phenotypic effects on yeast cells. The analysis of the effects of structurally diverse molecules towards cell growth rate in both exponential and stationary phases provides a tool to select candidate compounds for subsequent assays to identify new chemical entities as chemical probes for drug discovery.
