Association between clinicopathological characteristics and RAS mutation in colorectal cancer

Abstract

In colorectal cancer, KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4) mutations are associated with resistance to antiepidermal growth factor receptor monoclonal antibodies, and BRAF mutation is a molecular marker of poor prognosis. KRAS exon 2 and BRAF-mutated colorectal cancers have well-known distinct clinicopathological characteristics. Comparison of tumors with different RAS status (exons 2, 3, and 4 of KRAS and NRAS) based on their clinicopathological characteristics has never been established. All colorectal cancer patients with RAS and BRAF testing from 2011 to 2015 were included in this observational retrospective study. Patient and tumor characteristics were collected and correlation with RAS and BRAF status was evaluated. A total of 1735 patients with colorectal cancer were included. RAS-mutated colorectal cancers (n=1002), compared with RAS wild-type colorectal cancers (n=733), were significantly associated with male gender, classical adenocarcinoma subtype, well/moderately differentiated tumors, and microsatellite stable phenotype. KRAS codon 13-mutated colorectal cancers (n=171), compared with RAS wild-type colorectal cancers, more frequently presented classical adenocarcinoma subtype and microsatellite stable phenotype. In comparison with other RAS mutations, KRAS exon 3-mutated colorectal cancers (n=23) were associated with mucinous/rare histological subtypes and, most likely to located in the rectum. KRAS exon 4-mutated colorectal cancers (n=33) were more frequently associated with mucinous/rare histological subtypes. There was no significant association between NRAS mutation (n=37) and clinicopathological features. Colorectal cancers are associated with different clinicopathological features according to the type of RAS mutation. Consequently, these particular characteristics must be considered when assessing the prognostic value of RAS status in colorectal cancer.

Colorectal carcinomas with mucinous differentiation are associated with high frequent mutation of KRAS or BRAF mutations, irrespective of quantity of mucinous component.

“…Similar to Fuchs's study 15 , we found that both ≥ 50% and <50% mucinous tumors showed similar molecular features with more frequent BRAF or KRAS mutations in comparison to tumors without mucinous component; this distinct molecular profile has no correlation with amount of mucinous component in the tumors as long as the mucin is more than 5%. Like in other studies, these two gene (KRAS and BRAF) mutations were mutually exclusive 6,8 . Consistent with the previous studies 16,17 , our result had the same increased proportion of cases of MMR-deficient mucinous adenocarcinoma.…”

“…According to a meta-analysis, MACs result in 2-8% increased hazard of death, which persists after correction for stage 5 , and this tumor also showed a poorer response to both adjuvant chemotherapy and chemoradiotherapy 3,4 . The difference of the biological and clinical behaviors between the conventional CRCs and MACs has a molecular basis, for example, increased microsatellite instability (MSI) 13 , CpG island methylation phenotype 14 and, PIK3CA 10 , TGFR 10 and BRAF mutation in MACs 6,8,10 . However, the conventional CRCs comprise of tumors with variable amount of mucin (0-49%), and they may have variable genetics.…”

“…The mutation of these two genes is frequently seen in MACs [8][9][10] , resulting in a poor response to anti-EGFR therapy 7,11,12 . However, approximately 35% of conventional CRCs are also positive for KRAS and BRAF mutations.…”

Clinicopathological characteristics, molecular alterations and prognosis of mucinous histology in colorectal adenocarcinoma patients

“…BRAF mutation rates are signi cantly different in previous studies of Chinese population [16]. Like in other studies, these two gene (KRAS and BRAF) mutations were mutually exclusive [17,18]. Similar to Xiaodong Li's study [16], we found that both BRAF or KRAS mutations has no correlation with amount of mucinous component in the tumours.…”

Ultra-performance liquid chromatography/mass spectrometry technology and high-throughput metabolomics for deciphering the preventive mechanism of mirabilite on colorectal cancer via the modulation of complex metabolic networks

“…Colorectal cancer (CRC) is always detected in the middle and late stages due to which the mortality rate is very high; 1 the 5 year relative survival rate is more than 90% when CRC is diagnosed in Phase I, and it decreases to 3/4 in Phase IV. [2][3][4][5] Therefore, early diagnosis of colorectal cancer is particularly important, which can signicantly improve the efficacy of the treatment and the chances of survival. 6 Currently, there are no effective therapeutic drugs for CRC treatment.…”