Dataset Information

BRAF V600E mutation and KRAS codon 13 mutations predict poor survival in Chinese colorectal cancer patients.

ABSTRACT:

Background

Mutations in KRAS, BRAF and PIK3CA are the most common somatic alterations found in the colorectal cancer (CRC) patients from Western countries; but their prevalence and prognostic value have not been adequately assessed in Asian patients. The aim of this study was to determine the mutation frequencies of these genes in Chinese CRC patients and to investigate their impact on prognosis.

Methods

The sequences of exon 2 of KRAS, exon 15 of BRAF and exons 9 and 20 of PIK3CA were evaluated by PCR and direct sequencing using DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues from primary CRC tumors of 214 patients (colon/rectum: 126/88).

Results

KRAS, BRAF and PIK3CA mutations were identified in 44.9% (96/214), 4.2% (9/214) and 12.3% (26/212) CRCs, respectively. The most frequent mutations in KRAS, BRAF and PIK3CA were G12D, V600E and H1047R, respectively. All BRAF and 80.8% PIK3CA mutations were from colon cancer patients. BRAF V600E was associated with advanced TNM (P?ConclusionOur findings indicate that PI3K/RAS-RAF signaling pathway genes are frequently mutated in Chinese CRC patients, but have different characteristics than found in Western patients. BRAF V600E is an independent prognostic factor for Chinese patients. Our finding that KRAS codon 13 mutations (in particular G13D) are associated with inferior survival in BRAF wild-type CRCs in Chinese patients was not reported thus far. Our data emphasizes the importance of prospective evaluation of molecular features in CRC patients, because a single mutation type may represent a distinct biologic effect and clinical implication.

SUBMITTER: Chen J

PROVIDER: S-EPMC4233032 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Publications

BRAF V600E mutation and KRAS codon 13 mutations predict poor survival in Chinese colorectal cancer patients.

Chen Jing J Guo Fang F Shi Xin X Zhang Lihua L Zhang Aifeng A Jin Hui H He Youji Y

BMC cancer 20141103

<h4>Background</h4>Mutations in KRAS, BRAF and PIK3CA are the most common somatic alterations found in the colorectal cancer (CRC) patients from Western countries; but their prevalence and prognostic value have not been adequately assessed in Asian patients. The aim of this study was to determine the mutation frequencies of these genes in Chinese CRC patients and to investigate their impact on prognosis.<h4>Methods</h4>The sequences of exon 2 of KRAS, exon 15 of BRAF and exons 9 and 20 of PIK3CA ...[more]

PMID: 25367198

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Project description:BackgroundApproximately 40% of colorectal cancer (CRC) cases are linked to Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. KRAS mutations are associated with poor CRC prognosis, especially KRAS codon 12 mutation, which is associated with metastasis and poorer survival. However, the clinicopathological characteristics and prognosis of KRAS codon 13 mutation in CRC remain unclear.AimTo evaluate the clinicopathological characteristics and prognostic value of codon-specific KRAS mutations, especially in codon 13.MethodsThis retrospective, single-center, observational cohort study included patients who underwent surgery for stage I-III CRC between January 2009 and December 2019. Patients with KRAS mutation status confirmed by molecular pathology reports were included. The relationships between clinicopathological characteristics and individual codon-specific KRAS mutations were analyzed. Survival data were analyzed to identify codon-specific KRAS mutations as recurrence-related factors using the Cox proportional hazards regression model.ResultsAmong the 2203 patients, the incidence of KRAS codons 12, 13, and 61 mutations was 27.7%, 9.1%, and 1.3%, respectively. Both KARS codons 12 and 13 mutations showed a tendency to be associated with clinical characteristics, but only codon 12 was associated with pathological features, such as stage of primary tumor (T stage), lymph node involvement (N stage), vascular invasion, perineural invasion, tumor size, and microsatellite instability. KRAS codon 13 mutation showed no associations (77.2% vs 85.3%, P = 0.159), whereas codon 12 was associated with a lower 5-year recurrence-free survival rate (78.9% vs 75.5%, P = 0.025). In multivariable analysis, along with T and N stages and vascular and perineural invasion, only codon 12 (hazard ratio: 1.399; 95% confidence interval: 1.034-1.894; P = 0.030) among KRAS mutations was an independent risk factor for recurrence.ConclusionThis study provides evidence that KRAS codon 13 mutation is less likely to serve as a prognostic biomarker than codon 12 mutation for CRC in a large-scale cohort.

Project description:Right-sided colorectal cancer (RCRC) demonstrates worse survival outcome compared with left-sided CRC (LCRC). Recently, the importance of RNF43 mutation and BRAF V600E mutation has been reported in the serrated neoplasia pathway, which is one of the precancerous lesions in RCRC. It was hypothesized that the clinical significance of RNF43 mutation differs according to primary tumor sidedness. To test this hypothesis, the clinicopathological characteristics and survival outcome of patients with RNF43 mutation in RCRC and LCRC were investigated. Stage I-IV CRC patients (n=201) were analyzed. Genetic alterations including RNF43 using a 415-gene panel were investigated. Clinicopathological characteristics between RNF43 wild-type and RNF43 mutant-type were analyzed. Moreover, RNF43 mutant-type was classified according to primary tumor sidedness, i.e., right-sided RNF43 mutant-type or left-sided RNF43 mutant-type, and the clinicopathological characteristics between the two groups were compared. RNF43 mutational prevalence, spectrum and frequency between our cohort and TCGA samples were compared. RNF43 mutation was observed in 27 out of 201 patients (13%). Multivariate analysis revealed that age (≥65), absence of venous invasion, and BRAF V600E mutation were independently associated with RNF43 mutation. Among the 27 patients with RNF43 mutation, 12 patients were right-sided RNF43 mutant-type and 15 left-sided RNF43 mutant-type. Right-sided RNF43 mutant-type was significantly associated with histopathological grade 3, presence of lymphatic invasion, APC wild, BRAF V600E mutation, microsatellite instability-high (MSI-H), and RNF43 nonsense/frameshift mutation compared with left-sided RNF43 mutant-type. Similarly, RNF43 nonsense/frameshift mutations were more frequently observed in RCRC compared with LCRC in the TCGA cohort (P=0.042). Right-sided RNF43 mutant-type exhibited significantly worse overall survival than RNF43 wild-type and left-sided RNF43 mutant-type (P=0.001 and P=0.023, respectively) in stage IV disease. RNF43 mutation may be a distinct molecular subtype which is associated with aggressive tumor biology along with BRAF V600E mutation in RCRC.

Dataset Information

BRAF V600E mutation and KRAS codon 13 mutations predict poor survival in Chinese colorectal cancer patients.

Background

Methods

Results

Publications

BRAF V600E mutation and KRAS codon 13 mutations predict poor survival in Chinese colorectal cancer patients.

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