Abstract
BackgroundColorectal cancer (CRC) is a heterogeneous disease with multiple underlying causative genetic mutations. The B-type Raf proto-oncogene (BRAF) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade during CRC. The presence of BRAFV600E mutation can determine the response of a tumor to chemotherapy. However, the association between the BRAFV600E mutation and the clinicopathological features of CRC remains controversial. We performed a systematic review and meta-analysis to estimate the effect of BRAFV600E mutation on the clinicopathological characteristics of CRC.MethodsWe identified studies that examined the effect of BRAFV600E mutation on CRC within the PubMed, ISI Science Citation Index, and Embase databases. The effect of BRAFV600E on outcome parameters was estimated by odds ratios (ORs) with 95% confidence intervals (CIs) for each study using a fixed effects or random effects model.Results25 studies with a total of 11,955 CRC patients met inclusion criteria. The rate of BRAFV600 was 10.8% (1288/11955). The BRAFV600E mutation in CRC was associated with advanced TNM stage, poor differentiation, mucinous histology, microsatellite instability (MSI), CpG island methylator phenotype (CIMP). This mutation was also associated with female gender, older age, proximal colon, and mutL homolog 1 (MLH1) methylation.ConclusionsThis meta-analysis demonstrated that BRAFV600E mutation was significantly correlated with adverse pathological features of CRC and distinct clinical characteristics. These data suggest that BRAFV600E mutation could be used to supplement standard clinical and pathological staging for the better management of individual CRC patients, and could be considered as a poor prognostic marker for CRC.
Highlights
Colorectal cancer (CRC) is the third most common cancer and the most frequent cause of cancer-related deaths worldwide, and so poses a serious threat to human health. [1,2] It is widely accepted that CRC develops via a series of genetic and epigenetic changes that lead to the transformation of normal mucosa into a premalignant polyp, and to a malignancy. [3,4] There are at least three different molecular pathways that lead to CRC. [5,6] The chromosomal instability pathway is characterized by some of mutations such as P53 and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)
The B-type raf proto-oncogene (BRAF) encodes a serine/ threonine kinase that plays a role in intracellular signaling and cell growth, and is a downstream effector of KRAS in the mitogenactivated protein kinase (MAPK) signaling pathway. [11,12] The BRAFV600E mutation, which accounts for approximately 90% B-type Raf proto-oncogene (BRAF) mutations, is frequently observed in CRC with microsatellite instability (MSI)
It arises from the serrated pathway, and occurs in 5–22% of patients. [11,13] It was demonstrated that KRAS or BRAFV600E mutations in CRC are associated with clinical resistance to treatment with epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies. [14,15,16] the association between the BRAFV600E mutation and the clinicopathological characteristics of CRC remains controversial
Summary
Colorectal cancer (CRC) is the third most common cancer and the most frequent cause of cancer-related deaths worldwide, and so poses a serious threat to human health. [1,2] It is widely accepted that CRC develops via a series of genetic and epigenetic changes that lead to the transformation of normal mucosa into a premalignant polyp, and to a malignancy. [3,4] There are at least three different molecular pathways that lead to CRC. [5,6] The chromosomal instability pathway is characterized by some of mutations such as P53 and v-Ki-ras Kirsten rat sarcoma viral oncogene homolog (KRAS). [7] The second is the mutator pathway, which involves the loss of function of DNA mismatch repair proteins secondary to germline mutations in mismatch repair genes. [8,9] there is the serrated pathway. [10].The B-type raf proto-oncogene (BRAF) encodes a serine/ threonine kinase that plays a role in intracellular signaling and cell growth, and is a downstream effector of KRAS in the mitogenactivated protein kinase (MAPK) signaling pathway. [11,12] The BRAFV600E mutation, which accounts for approximately 90% BRAF mutations, is frequently observed in CRC with microsatellite instability (MSI). [11,12] The BRAFV600E mutation, which accounts for approximately 90% BRAF mutations, is frequently observed in CRC with microsatellite instability (MSI). It arises from the serrated pathway, and occurs in 5–22% of patients. [14,15,16] the association between the BRAFV600E mutation and the clinicopathological characteristics of CRC remains controversial. We performed a systematic review and meta-analysis to quantify the association of the BRAFV600E mutation with sociodemographic factors and clinicopathological characteristics of the CRC. We performed a systematic review and meta-analysis to estimate the effect of BRAFV600E mutation on the clinicopathological characteristics of CRC
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