***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: PURPOSE Mutations affecting the KRAS gene are established predictive markers of outcome with anti-epithelial growth factor receptor ( EGFR ) antibodies in advanced colorectal cancer ( CRC ) . The relevance of these markers for anti-vascular endothelial growth factor ( VEGF ) therapy is controversial . This analysis was performed to assess the predictive and prognostic impact of KRAS and BRAF gene mutation status in patients receiving capecitabine with bevacizumab ( CG ) or capecitabine without bevacizumab in the phase III AGITG MAX ( Australasian Gastrointestinal Trials Group MAX ) study . PATIENTS AND METHODS Mutation status was determined for 315 ( 66.9 % ) of the original 471 patients . Mutation status was correlated with efficacy outcomes ( response rate , progression-free survival [ PFS ] , and overall survival [ OS ] ) , and a predictive analyses was undertaken . RESULTS Mutations in KRAS and BRAF genes were observed in 28.8 % and 10.6 % of patients , respectively . KRAS gene mutation status ( wild type [ WT ] v mutated [ MT ] ) had no prognostic impact for PFS ( hazard ratio [ HR ] , 0.89 ; CI , 0.69 to 1.14 ) or OS ( HR , 0.97 ; CI , 0.73 to 1.28 ) . BRAF mutation status ( WT v MT ) was not prognostic for PFS ( HR , 0.80 ; CI , 0.54 to 1.18 ) but was prognostic for OS ( HR , 0.49 ; CI , 0.33 to 0.73 ; P = .001 ) . By using the comparison of capecitabine versus capecitabine and bevacizumab ( CB ) and CB plus mitomycin ( CBM ) , KRAS gene mutation status was not predictive of the effectiveness of  bevacizumab for PFS or OS ( test for interaction P = .95 and 0.43 , respectively ) . Similarly , BRAF gene mutation status was not predictive of the effectiveness of bevacizumab for PFS or OS ( test for interaction P = .46 and 0.32 , respectively ) . CONCLUSION KRAS gene mutation status was neither prognostic for OS nor predictive of bevacizumab outcome in patients with advanced CRC . BRAF gene mutation status was prognostic for OS but was not predictive of outcome with bevacizumab PURPOSE Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer . We took advantage of PETACC-3 , an adjuvant trial with 3,278 patients with stage II to III colon cancer , to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting . PATIENTS AND METHODS  Formalin-fixed paraffin-embedded tissue blocks ( n = 1,564 ) were prospect ively collected and DNA was extracted from tissue sections from 1,404 cases . Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction .  Survival analyses were based on univariate and multivariate proportional hazard regression models . RESULTS KRAS and BRAF tumor mutation rates were 37.0 % and 7.9 % , respectively , and were not significantly different according to tumor stage . In a multivariate analysis containing stage , tumor site , nodal status , sex , age , grade , and microsatellite instability ( MSI ) status , KRAS mutation was associated with grade ( P = .0016 ) , while BRAF mutation was significantly associated with female sex ( P = .017 ) , and highly significantly associated with right-sided tumors , older age , high grade , and MSI-high tumors ( all P < 10(-4 ) ) . In univariate and multivariate analysis , KRAS mutations did not have a major prognostic value regarding relapse-free survival ( RFS ) or overall survival ( OS ) . BRAF mutation was not prognostic for RFS , but was for OS , particularly in patients with MSI-low ( MSI-L ) and stable ( MSI-S ) tumors ( hazard ratio , 2.2 ; 95 % CI , 1.4 to 3.4 ; P = .0003 ) . CONCLUSION In stage II-III colon cancer , the KRAS mutation status does not have major prognostic value . BRAF is prognostic for OS in MS-L/S tumors Purpose : Colon tumors with defective DNA mismatch repair ( dMMR ) have a well-characterized phenotype and accounts for ∼15 % to 20 % of sporadic colon cancer as well as those colon cancer patients with Lynch syndrome . Although the presence of dMMR seems to be a favorable prognostic marker , data suggest that these patients do not respond as well to adjuvant chemotherapy . Experimental Design : In this study , we examined the prognostic significance of tumor MMR deficiency and the presence of a specific mutation in BRAF ( V600E ) in a group of patients ( n = 533 ) who participated in a r and omized prospect i ve clinical trial through the North Central Cancer Treatment Group . Results : Tumors with dMMR were found to be associated with higher tumor grade ( P = 0.001 ) , proximal location ( P < 0.0001 ) , and improved overall and disease-free survival ( P = 0.05 and 0.04 , respectively ) . Among all cases examined , evaluation of the BRAF V600E mutation status revealed no statistically significant differences in either disease-free or overall survival . Patients were then grouped into four categories for further analysis : dMMR/BRAF(− ) , dMMR/BRAF(+ ) , pMMR/BRAF(− ) , and pMMR/BRAF(+ ) . The dMMR/BRAF(− ) group had a significantly improved overall survival ( 5-year overall survival of 100 % versus 73 % , P = 0.002 ) compared with all others . The remaining three groups had very similar survival outcomes . An additional cohort of tumors previously classified as having dMMR were also tested for the BRAF V600E alteration . Results remained significant ( P = 0.006 ) when the two groups were combined for analysis . Conclusions : Overall , these data suggest that the underlying molecular etiology of those tumors having dMMR may influence the disease outcome in these patients Purpose : Alterations in the RAS-RAF-MAP2 K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis . In colorectal cancer , BRAF mutation is associated with microsatellite instability ( MSI ) , and typically predicts inferior prognosis . We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer . Methods : We assessed status of BRAF c.1799T > A ( p . V600E ) mutation and MSI in 506 stage III colon cancer patients enrolled in a r and omized adjuvant chemotherapy trial [ 5-fluorouracil and leucovorin ( FU/LV ) vs. irinotecan ( CPT11 ) , FU and LV ( IFL ) ;  CALGB 89803 ] . Cox proportional hazards model was used to assess the prognostic role of BRAF mutation , adjusting for clinical features , adjuvant chemotherapy arm , and MSI status . Results : Compared with 431 BRAF wild-type patients , 75 BRAF-mutated patients experienced significantly worse overall survival [ OS ; log-rank P = 0.015 ; multivariate HR = 1.66 ; 95 % CI : 1.05–2.63 ] . By assessing combined status of BRAF and MSI , it seemed that BRAF-mutated MSS ( microsatellite stable ) tumor was an unfavorable subtype , whereas BRAF wild-type MSI-high tumor was a favorable subtype , and BRAF-mutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes . Among patients with BRAF-mutated tumors , a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm ( multivariate HR = 0.52 ; 95 % CI : 0.25–1.10 ) . Among patients with BRAF wild-type cancer , IFL conferred no suggestion of benefit beyond FU/LV alone ( multivariate HR = 1.02 ; 95 % CI : 0.72–1.46 ) . Conclusions : BRAF mutation is associated with inferior survival in stage III colon cancer . Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy . Clin Cancer Res ; 18(3 ) ; 890–900 . © 2011 AACR Background BRAF and K-ras proto-oncogenes encode components of the ERK signalling pathway and are frequently mutated in colorectal cancer . This study investigates the associations between BRAF and K-ras mutations and clinicopathological , lifestyle and dietary factors in colorectal cancers . Methods 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for BRAF and K-ras mutations .  Diet and lifestyle data were collected prospect ively using seven day food diaries . Results BRAF V600E mutation was found in 15.6 % of colorectal cancers but at higher frequencies in cancers with proximal location , poor differentiation and microsatellite instability ( MSI ) ( all p < 0.001 ) . K-ras mutation ( mostly in codons 12 and 13 ) was found in 22.0 % of colorectal cancers but at higher frequencies in cancers of more advanced Dukes ' stage ( p = 0.001 ) , microsatellite stable ( MSS ) status ( p = 0.002 ) and in individuals with lower blood high-density lipoprotein concentrations ( p = 0.04 ) . Analysis of dietary factors demonstrated no link between BRAF mutation and any specific dietary constituent , however , K-ras mutation was found at higher frequencies in individuals with higher white meat consumption ( p < 0.001 ) . Further analysis of specific mutation type demonstrated that G to A transitions in K-ras were observed at higher frequencies in individuals consuming lower amounts of fruit ( p = 0.02 ) . Conclusion These data support the model of BRAF and K-ras mutations arising in distinct colorectal cancer subsets associated with different clinicopathological and dietary factors , acting as mutually exclusive mechanisms of activation of the same signalling pathway The aim of this study was to identify KRAS and BRAF gene mutations in colorectal cancer patients and to assess whether they are linked with clinicopathological features . The results of KRAS and BRAF mutation analysis could be used in the selection of patients for anti-EGFR therapy .  All specimens were obtained during routine surgery of patients with colorectal carcinoma . The diagnoses were established by st and ard procedures and confirmed histopathologically . After DNA extraction , KRAS mutations were analyzed using quantitative real-time PCR and BRAF mutations were analyzed using real-time PCR by fluorescence melting curve analysis . Our results show that KRAS gene mutations were detected in 35.6 % sample s and the most frequent mutation was Gly12Val . BRAF gene mutation Val600Glu was detected in 8.5 % sample s. Statistical analysis revealed a significant association between the KRAS mutation and Dukes ' stage ( p=0.034 ) , with the lowest frequency in Dukes'A , and between the KRAS mutation and histological grade ( p=0.044 ) , with no KRAS mutation found in poor differentiated tumors . The first data about KRAS and BRAF mutational status in the sample of Croatian population with colorectal cancer shows that the incidence of KRAS and BRAF mutations is within generally valid limits . Prospect i ve studies are to be continued in order to determine whether these mutations contribute to progression of colorectal cancer 
    Output:
    
This 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 st and ard clinical and pathological staging for the better management of individual CRC patients , and could be considered as a poor prognostic marker for CRC