BRAF p.Val600Glu (V600E) Somatic Mutation Is Mainly Associated with MSS Phenotype in Metastatic Colorectal Cancer
Institut Paoli-Calmettes, Marseille, France.
Cancer genomics & proteomics
Oncogenic activation of EGF-signalling pathway is central to the progression of colorectal cancer. The use of mutations of the KRAS codons 12 and 13 as a selection biomarker for anti-endothelial growth factor receptor (EGFR) monoclonal antibody treatment is at present the first major step towards individualised treatment for patients with metastatic colorectal cancer. The impact of BRAF V600E mutation is not well documented.
A total of 803 metastatic cancer samples from colorectal cancer patients were explored for KRAS exon 2 and BRAF exon 15 mutations. BRAF mutated samples were characterized for mismatch repair function.
Overall, 344 tumours were mutated, with 34 of them involving BRAF mutations (8 of microsatellite instability type). No specificity was found according to gender, age at diagnosis and tumour localisation.
A complete analysis of KRAS, BRAF and PIK3CA status may identify approximately 10-15% additional patients who are unlikely to respond an EGFR-targeted monoclonal antibody and who may benefit from prospective and specific new biomarker-driven studies.
Available from: Seong Jae Cha
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ABSTRACT: BRAF mutation and expression of extracellular signal regulated kinase (ERK) are linked with colorectal carcinogenesis through the serrated pathway. BRAF and ERK1/2 play important roles in the activation of mitogen-activated protein (MAP) kinase signaling pathways. The present study investigated the clinicopathologic outcomes of BRAF mutation and ERK1/2 expression in patients with colorectal cancer (CRC) and the possibility of using them as prognostic indicators.
Dual-priming oligonucleotide-based multiplex polymerase chain reaction for BRAF (V600E) mutation and immunohistochemical analysis of ERK1/2 were performed using 65 formalin-fixed, paraffin-embedded samples from patients with CRC. We analyzed the dependences of the clinicopathologic features on BRAF mutation and ERK1/2 expression.
Out of 65 samples from CRC patients, BRAF mutation was detected in 3 (4.6%). The 3 patients with BRAF mutation presented with T3 CRC with lymph node metastasis (stage III) showing moderately or poorly differentiated histology. ERK1 and ERK2 were positively detected in 73.8% and 15.4% of the patients with CRC, respectively. ERK1 expression was significantly correlated with lymph node metastasis (P = 0.049). ERK2 expression was significantly correlated with tumor emboli (P < 0.05), tumor invasion (P = 0.035), lymph node metastasis (P = 0.017), and stage (P = 0.02).
BRAF mutation and ERK1/2 expression may be associated with advanced or more aggressive CRC. These molecular markers might play prognostic roles in CRC developed through the serrated pathway.
Available from: PubMed Central
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ABSTRACT: KRAS mutation occurs in 35%-40% of colorectal cancer (CRC). The aim of our study was to evaluate the pathological and molecular features of specific KRAS mutated colorectal carcinomas. KRAS and BRAF (V600E) mutation tests were performed in 762 primary tumors from a consecutive cohort study of Chinese CRC patients.
DNA mismatch repair (MMR) status was determined by immunohistochemistry (IHC) staining. Assessment of KRAS and BRAF V600E mutational status was performed using a multiplex allele-specific PCR-based assay.
Mutations of KRAS (34.8%) and BRAF (V600E) (3.1%) were nearly mutually exclusive. Both KRAS- and BRAF- mutated tumors were more likely to be located at proximal colon than wild-type (WT) carcinomas. KRAS-mutated carcinomas were more frequently observed in female patients (47.5% vs 37.1%, p = 0.005) and mucinous differentiation (34.7% vs 24.8%, p = 0.004), but have no difference between lymph node (LN) metastases and among pTNM stages. Whereas, BRAF-mutated carcinomas more frequently demonstrated histologic features such as proximal location (60.9% vs 20.9%, p = 0.001), low-grade histology (43.5% vs 18.0%, p = 0.005), mucinous differentiation (69.6% vs 25.9%, p = 0.001) and deficient MMR (dMMR) (21.7% vs 7.6%, p = 0.03). In particular, KRAS codon 12 mutated carcinomas had increased lymph node metastasis (odds ratio [OR] = 1.31; 95% confidence interval [CI] = 1.04 to 1.65; P = 0.02) and were more likely in higher disease stage (III-IV) than that of WT carcinomas (OR = 1.30; 95% CI = 1.03 to 1.64; P = 0.03). However, there were no significant differences in lymph node metastasis and disease stage between KRAS codon 13 mutated carcinoma and WT carcinoma patients.
In summary, KRAS codon 12 mutation, but not codon 13 mutation, is associated with lymph node metastasis and higher tumor stages.
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