The opposite association of HRAS and KRAS mutations with clinical variables of bladder cancer

Abstract

The HRAS, KRAS, and NRAS gene products belong to the superfamily of small GTPases. These proteins regulate the cellular response to extracellular stimuli through the activation of different signaling pathways. Although the role of the RAS gene mutations in the pathogenesis of various human cancers has been established, the clinical significance of these molecular alterations in bladder cancer remains unclear. The aim of this study was to determine the frequency and spectrum of the HRAS, KRAS, and NRAS mutations, to analyze their association with the clinicopathological variables, and to determine the prognostic value of these alterations in terms of recurrence, progression and mortality, in a prospective cohort of 249 bladder cancer patients. The frequency of the RAS mutations, detected by the SNaPshot method, was 11.2%, of which the HRAS mutations accounted for 64.3%, KRAS, for 28.6%, and NRAS, for 7.1%. We failed to find any correlation between all the RAS gene mutations and pathomorphological characteristics. However, when analyzed separately, the opposite association of the HRAS and KRAS mutations with the clinical parameters of bladder cancer was for the first time shown: the HRAS mutations were significantly associated with low stage low grade papillary tumors of a small size (p < 0.05), whereas the KRAS mutations were associated with non-papillary urothelial carcinomas and the presence of metastases (p < 0.05). Analysis of the prognostic value of the molecular alterations revealed the association of the KRAS mutations with decreased cancer-specific survival in both the total group of patients and the subgroup with nonmuscle invasive disease. The data obtained suggest that the HRAS and KRAS gene mutations may characterize alternative pathways of bladder cancer pathogenesis: the HRAS mutations indicating benign and KRAS mutations, aggressive disease course.