Abstract
This study aimed to estimate the incidence of KRAS, NRAS, and BRAF mutations in the Moroccan population, and investigate the associations of KRAS and NRAS gene mutations with clinicopathological characteristics and their prognosis value. To achieve these objectives, we reviewed medical and pathology reports for 210 patients. RAS testing was investigated by Sanger sequencing and Pyrosequencing technology. BRAF (exon 15) status was analyzed by the Sanger method. The expression of MMR proteins was evaluated by Immunohistochemistry. KRAS and NRAS mutations were found in 36.7% and 2.9% of 210 patients, respectively. KRAS exon 2 mutations were identified in 76.5% of the cases. RAS-mutated colon cancers were significantly associated with female gender, presence of vascular invasion, classical adenocarcinoma, moderately differentiated tumors, advanced TNM stage III-IV, left colon site, higher incidence of distant metastases at the time of diagnostic, microsatellite stable phenotype, lower number of total lymph nodes, and higher means of positive lymph nodes and lymph node ratio. KRAS exon 2-mutated colon cancers, compared with KRAS wild-type colon cancers were associated with the same clinicopathological features of RAS-mutated colon cancers. NRAS-mutated patients were associated with lower total lymph node rate and the presence of positive lymph node. Rare RAS-mutated tumors, compared with wild-type tumors were more frequently moderately differentiated and associated with lower lymph node rate. We found that KRAS codon 13-mutated, tumors compared to codon 12-mutated tumors were significantly correlated with a higher death cases number, a lower rate of positive lymph, lower follow-up time, and poor overall survival. Our findings show that KRAS and NRAS mutations have distinct clinicopathological features. KRAS codon 13-mutated status was the worst predictor of prognosis at all stages in our population.
Highlights
Ras-family G-proteins transduce growth factor signals, such as EGF receptor (EGFR) signaling pathway [1]
When comparing the different KRAS exon 2 mutation groups to each other, we found that KRAS codon 13-mutated tumors were significantly correlated with a higher death cases number (P = 0.03) and lower follow-up time (p = 0.03), lower rate of positive lymph node and lower rate of Lymph node Ratio (LNR)
The frequency of KRAS mutations in this cohort is in accordance with that in previous reports, which reported that approximately 34~45% of the patients had KRAS mutations [16,17].While, the rate of RAS, BRAF and KRAS exon 2 mutations was slightly lower than that in two recently published studies [12,15]
Summary
Ras-family G-proteins transduce growth factor signals, such as EGF receptor (EGFR) signaling pathway [1]. In the field of metastatic colorectal treatment, previous studies have demonstrated that KRAS exon 2 mutations have a negative effect on response to anti epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab and panitumumab) [7]. Mutations in KRAS outside exon 2 (KRAS exons 3,4) and in other downstream effectors of the EGFR signalling pathway, such as NRAS have been reported to be associated with resistance to anti-EGFR monoclonal antibodies [8]. For this reason, since 2013 full RAS WT state was recommended to be confirmed in all mCRC patients before initiating treatment with Anti- EGFR monoclonal antibodies, panitumumab and cetuximab. Others found noassociation [13]
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