Clinical relevance of H-RAS, K-RAS and N-RAS in a large cohort of primary breast cancer patients
26. November 2018 (online)
Since the first description of the RAS (Rat sarcoma) proteins over three decades ago, the RAS family has become one of the most extensively studied oncogenes. Although nearly ubiquitously expressed, the expression ratios among different RAS isoforms vary depending on the cell type and tissue. The aim of the present study was to evaluate the clinical significance of the H-RAS/K-RAS/N-RAS mRNA levels in a large cohort of primary breast cancer patients with a long-term clinical follow-up.
198 breast cancer patients were enrolled in this single-center study. Tumor tissue was collected at primary surgery. H-RAS/K-RAS/N-RAS mRNA levels were analysed using the Affymetrix (Thermo Fisher Scientific, USA) HG-U133A array and statistically correlated with clinical and tumor characteristics.
Elevated H-RAS was associated with larger tumors and positive ER-status (p = 0.021 and 0.048, respectively), while patients with lymph node metastasis and HER2-positivity were more likely to overexpress K-RAS (p = 0.001 and 0.010, respectively). Elevated N-RAS was highly associated with triple-negative subtype (p < 0.001) and higher grading (p = 0.001). No correlation was found between N-RAS and the other two genes, while elevated K-RAS was associated with elevated H-RAS (p = 0.003). After a median follow up of 183 months, 72 patients died and 76 were diagnosed with a relapse. Patients with N-RAS expression above the 75th percentile had significantly shorter overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS) than those with N-RAS < 75th percentile (OS: mean: 146.9 months vs. 211.0 months, median 169.3 months vs. not reached; p = 0.009; BCSS: mean 150.2 months vs. 225.5, median not reached; p = 0.001; DFS: mean: 150.1 vs. 227.7 months, median not reached, p = 0.004). The expression of H-RAS and K-RAS was not associated with DFS/OS. In the multivariate analysis, N-RAS levels, distant metastasis and HER2-status remained independent predictors of shorter OS, while only N-RAS levels, lymph node involvement and HER2 status independently predicted DFS.
The expression of RAS mRNA is strongly associated with the tumor subtype. Elevated N-RAS levels in primary breast cancer independently predict shorter survival while the expression of K-RAS and H-RAS is not associated with clinical outcome.