IndraLab
Statements
sparser
"Response to neoadjuvant chemotherapy has been related to improved survival, xref whereas KRAS and BRAF mutations have been associated with more aggressive disease and a poor prognosis. xref , xref , xref , xref While liver resection for metastatic CRC (mCRC) has become routine practice, xref the fact that the majority of patients undergoing surgery subsequently relapse xref underlines the need for better predictive markers guiding treatment decisions."
sparser
"In a Japanese study by Kadowaki et al, KRAS and BRAF mutations were associated with a shorter survival, xref whereas another Japanese study revealed that the prognostic impact of KRAS mutations on recurrence-free survival was limited in patients with stage II CRC, and KRAS mutations were not associated with OS. xref Conversely, our analysis showed that the KRAS status affects OS and DFS in patients with CRC: KRAS mutations were associated with a shorter OS and DFS compared with wild-type KRAS ."
sparser
"However, except for a weak interaction between KRAS and BRAF wild‐type status and benefit from preoperative chemotherapy ( p = 0.02), no statistically significant interaction between mutation status for any of the genes analyzed and benefit from chemotherapy administered in the preoperative or postoperative setting was recorded (Supporting Information Figs."
reach
"Although these two proteins have high structural and sequence identities with KRAS, subtle conformational changes in the side chains still make their binding to BRAF weaker compared to the binding between KRAS and BRAF, according to the alignment and scoring result (Additional file 1: Fig. S1, Table S2)."
sparser
"Binding kinetic analysis showed that FL-BRAF purified from mammalian cells interacts with KRAS with the same affinity as NT1, providing strong evidence that the truncated BRAF constructs used in our study can represent FL-BRAF and the physiological conditions with post-translational modifications, native intramolecular interactions, and potential conformational changes that occur upon binding."
sparser
"According to the molecular features of common pancreatic ductal neoplasms, IPMNs are frequently associated with mutations in KRAS and BRAF [ xref ]; however, mutations in the genes involved in the PI3K pathway, including PIK3CA, PTEN, and AKT1, are very rare in common pancreatic ductal neoplasms [ xref , xref ]."
sparser
"Several research groups have provided evidence that two proto-oncogenes, KRAS and BRAF , are associated with resistance to chemotherapy and poor prognosis [ xref , xref , xref , xref , xref , xref , xref , xref , xref , xref ], as confirmed by the survival analysis of the BRAF mutated CRCLM included in the TCGA cohort ( xref B)."
sparser
"To optimise the selection of patients who are more likely to benefit from anti-EGFR we investigated in a cohort of patients treated with the combination of cetuximab and irinotecan and bearing KRAS codons 12 and 13 wild-type tumours, the association of KRAS codons 61 and 146 mutations and BRAF V600E mutation with clinical outcomes."
sparser
"A recent systematic review demonstrated that KRAS and BRAF are negatively associated with disease relapse and survival after resection of CRLM. xref RAS mutation has also been found to confer worse survival in patients who underwent surgical resection for CRLM. xref In addition, prognostic roles for alterations in genes other than RAS and BRAF have also been reported, such as CDX2 , xref TP53 , xref and SMAD4 . xref However, few studies have investigated the prognostic role of biologic markers in patients who underwent TSH for CRLM."
sparser
"Indeed, the use of isogenic colorectal cancer cell lines that express either the mutant or the wild-type form of K-RAS or B-RAF shows that the enzymes of the non-oxidative branch of the PPP (ribose-5-phosphate isomerase and TKT) are upregulated in the K-RAS-mutant cell lines ( xref )."
sparser
"Structural modeling based on this observation and on structures of RBD-CRD complexes with RAS led to the suggestion that upon recruitment of BRAF to the membrane by KRAS, binding of KRAS to the autoinhibited BRAF complex could directly promote RAF activation by sterically perturbing the inhibitory interactions of both the RBD and CRD domains and freeing the CRD domain to interact with KRAS and the membrane xref ."
sparser
"A single-particle cryo-EM reconstruction at ~4.3 Å resolution revealed that the complex indeed retains an autoinhibited configuration, with KRAS bound to the BRAF RBD domain and extending “up” from the 14-3-3 dimer, positioning KRAS alongside the C-lobe of the MEK1 kinase domain (Fig. xref and Supplementary Table xref )."
sparser
"In this review, we will first describe the function of GSTP1 and then extend the details onto its role in the mitogen-activated protein kinase signal pathway, referring to the results of our recent study that proposed a novel autocrine signal loop formed by the CRAF/GSTP1 complex in mutated KRAS and BRAF cancers."
sparser
"Whereas mice with inactivating mutations in APC rapidly develop tubular adenomas, BRAF or KRAS mutations that are associated with serrated polyps are alone insufficient to provoke intestinal tumorigenesis. xref , xref After a brief period of hyperproliferation, crypt cells undergo growth arrest due to metabolic and replicative stress, a process termed oncogene-induced senescence (OIS)."
sparser
"Since mutations in the KRAS and BRAF genes are associated with resistance to therapy with anticancer drugs targeting the EGF receptor pathway, the analysis of KRAS and BRAF mutational status has become an important tool in the clinical management of patients with advanced colorectal cancer."
sparser
"Ogino et al . reported that the KRAS mutational status is not associated with DFS or OS in a study of 508 patients with Stage III CRC. xref Similarly, Roth et al . reported that KRAS mutations do not have major prognostic value based on a study of 1,404 patients with Stage II–III CRC. xref However, Hutchins et al . found that the risk of recurrence is significantly higher for KRAS mutants than wild‐type KRAS in the QUASAR study, which included 1,708 Stage II cases and 163 Stage III cases. xref Taieb et al . evaluated 4,411 patients with Stage III colorectal and found that BRAF or KRAS mutations were independently associated with a shorter time to recurrence, survival after recurrence and OS in patients with MSS, but not in MSI tumors. xref In the univariate analysis, prognosis was worse in KRAS mutants than all‐wild‐type cases and this could be explained by the increase in the rate of KRAS mutations as the tumor stage increased in our study (Table xref )."
sparser
"On the basis of previous reports, xref , xref , xref , xref , xref , xref we investigated the prognostic associations of KRAS and BRAF mutations in relation to MSI status by pooling data from an extended set of the QUASAR 2 and Australian cohorts, including an additional 676 colorectal cancers from QUASAR 2 and 362 stage II or III colorectal cancers from the Australian cohort (n=1732)."
sparser
"As an example, sessile serrated polyps can potentially develop more aggressively into colorectal cancer as compared to other colorectal polyps, because of the serrated pathway in tumorigenesis.[ xref ] The serrated pathway is associated with mutations in the BRAF or KRAS oncogenes, and CpG island methylation, which can lead to the silencing of mismatch repair genes (e.g., MLH1 ) and a more rapid progression to malignancy.[ xref ] Therefore, differentiating sessile serrated polyps from other types of polyps is critical for an appropriate surveillance.[ xref ] Histopathological characterization is the only reliable existing method for diagnosing sessile serrated polyps because other screening methods designed to detect premalignant lesions (such as fecal blood, fecal DNA, or virtual colonoscopy) are not well suited for differentiating sessile serrated polyps from other polyps.[ xref ] However, differentiation between sessile serrated polyps and innocuous hyperplastic polyps is a challenging task for pathologists.[ xref xref xref xref ] This is because sessile serrated polyps, such as hyperplastic polyps, often lack the dysplastic nuclear changes that characterize conventional adenomatous polyps, and their histopathological diagnosis is entirely based on morphological features, such as serration, dilatation, and branching."
sparser
"The preferential binding of B-Raf to activated K-Ras was also observed in live-cell imaging experiments as well as in co-immunoprecipitation assays examining the ability of endogenous B-Raf to bind Ras members in cells overexpressing Venus-tagged Ras proteins, in Ras-deficient MEFs reconstituted to express untagged mutant H-Ras or K-Ras proteins at endogenous levels, and in human cancer cell lines harboring H-Ras or K-Ras mutant alleles."
sparser
"Our findings show that virtually all of the PI3K/PTEN pathway altered tumor cell lines that lack a co-occurring KRAS-BRAF mutation are highly addicted to AKT maintenance of Aurora kinase B and that a large percentage of human cancers have a genotype that could benefit from AKT degradation therapy."
sparser
"To confirm whether this assembly involved a nucleotide‐dependent BRAF:KRAS4B interaction, we repeated the incubation and SEC using GDP‐loaded KRAS4B. The chromatogram revealed a broad peak (10.5–12 mL) (Figure xref ) consistent with the superposition of the peaks produced when BRAF:14‐3‐3 and RAS‐ND were run separately, demonstrating that formation of the reconstituted complex requires GTP, and supporting the biological relevance of this assembly."
sparser
"Recently, molecular alterations in CLM have been a focus for identifying patients who may benefit from liver resection. xref – xref Previous studies have shown that mutations in BRAF and KRAS are associated with a poor outcome after CLM resection. xref , xref – xref Passot et al. demonstrated the importance of RAS as a biologic marker to select patients with bilateral CLM for liver resection. xref In this series, the 5-year OS rate was 67 % in patients with RAS wild-type, compared to only 12% in patients with RAS mutation."
sparser
"Currently, drugs that inhibit the Hh signaling pathway inhibition (HPI) are now available in advanced BCC patients, such as vismodegib and sonidegib, which act as SMO inhibitors to block Gli1 under partial activation of the canonical pathway, thereby inhibiting tumor evolution. xref In contrast, while SMO inhibitors are not highly effective in clinical observations, recent studies in colorectal cancer have shown that suppression of Gli1, which is activated by a non-canonical pathway (KRAS-BRAF), is more sensitive to decrease cellular proliferation and induce apoptosis. xref Gli1 is currently considered the primary effector of Hh signaling."
sparser
"However, these values are likely to be altered when full‐length, 14‐3‐3‐bound BRAF interacts with KRAS4B on a bilayer due to the entropic and enthalpic effects of conformational changes and additional interaction interfaces being formed and disrupted, as well as steric constraint induced by anchoring RAS on the membrane."
sparser
"The KRAS–BRAF -ME mutations were prominent in the IEN phase and enhanced the oxidative phosphorylation; the chr20q gain, ME with chr17q loss, was a key event in the transmit process from the IEN phase to the IFT phase, leading to colorectal cancer cell proliferation; TP53 mutation was frequent in the advanced stage colorectal cancer phase, which impacted TME activity."
sparser
"The results from the CRYSTAL and OPUS studies indicate that the benefit from the addition of cetuximab to first-line chemotherapy is restricted to patients with the wild-type KRAS gene, with the best outcomes observed among those with unmutated forms of both the KRAS and BRAF genes."
sparser
"Conversely, two recent studies conclude KRAS and BRAF mutations are associated with inferior survival in Japanese patients with stage I–III disease xref and significantly poorer disease-free survival (DFS) (3-year DFS 79% and 92% in mutant and wild-type respectively; p = 0.006) xref ."
sparser
"The study suggested that CIMP-H/non-MSI-H subtype was significantly correlated with worst DFS in patients treated without irinotecan. xref , xref Han et al (2013) studied the effect of FOLFOX (5-Flourouracil, leucovorin, oxaliplatin) therapy over stage III and high-risk stage II patients and found no significant difference in overall survival rate between the 4 subtypes. xref Sinicrope et al, reported the significance of KRAS mutation in non MSI-H colon cancer and reported that mutated KRAS and BRAF were associated with poorer DFS in comparison to wild-type KRAS/BARF and non-MSI-H. xref "
sparser
"Alterations in any of these RAS family genes is associated with poor patient prognosis in pan-cancer analyses ( xref , xref ) ( xref ), and RAS pathway gene alterations frequently co-occur with the exception of KRAS-BRAF and KRAS-NRAS gene pairs, which are mutually exclusive ( xref , xref ) ( xref )."
sparser
"In our study, BRAF and KRAS mutations associated with a tendency towards higher proliferation rate ( P =0.091) and with a tendency towards lower tumour necrosis percentage ( P =0.172), while SACs had similar proliferation rate ( P =0.354) but significantly lower tumour necrosis percentage relative to CCs ( P =0.014)."
sparser
"Of the 19 drugs that had at least one known target, only AZD6244 had its associated proteins and PFRs enriched with its targets, as mutations in two of the five genes known to code for proteins interacting directly with the drug, BRAF and KRAS, are also associated with differential activity for this drug (p<0.005)."
sparser
"Results from other clinical trials have also indicated that the benefit from the addition of cetuximab to first-line chemotherapy seems to be restricted to patients with the wild-type KRAS gene; with the best outcomes being observed in those with unmutated forms of both the KRAS and BRAF genes [ xref - xref ]."
reach
"The finding of no interaction (except for a weak association between KRAS and BRAF wild-type status and benefit from preoperative therapy) between gene mutation status and mutation heterogeneity on the one hand and benefit from chemotherapy on the other hand further supports a prognostic role of these mutations, suggesting mechanisms related to tumor cell growth, invasion, metastatic propensity and others and not resistance to chemotherapy to explain our observations."
reach
"However, except for a weak interaction between KRAS and BRAF wild-type status and benefit from preoperative chemotherapy (p = 0.02), no statistically significant interaction between mutation status for any of the genes analyzed and benefit from chemotherapy administered in the preoperative or postoperative setting was recorded (Supporting Information Figs."
sparser
"EGFR mutations are strongly associated with acinar, lepidic and papillary subtypes and are rarely found in mucinous. xref – xref In contrast, the association of KRAS and BRAF mutations with histologic subtypes is controversial. xref Multiple reports have shown KRAS mutations to be prominent in invasive mucinous ADCA, whereas others have reported them to be associated with the solid subtypes. xref , xref – xref We found significant correlation of EGFR mutation with acinar, lepidic and papillary patterns; however, KRAS mutations were not associated with mucinous histology ( P = 0.036)."
sparser
"To this end we employed HEK293 cells and transiently transfected ERK5 and its upstream activator MEK5 (wt), together with either the active forms of KRAS (KRAS G12V ) or BRAF (BRAF V600E ) or the kinase dead form of BRAF (BRAF D594A ) and KRAS G12V (as they are known to co-operate with CRAF in ERK1/2 signaling xref )."
sparser
"As an alternative and more sensitive measure of ERK5 activity in cells, we used a GAL4 UAS:luciferase reporter system which is driven by the transactivation domain of MEF2D (an ERK5 substrate that is transcriptionally active when phosphorylated) fused to the GAL4 DNA binding domain. xref The ERK5 MEF2D:GAL4 UAS:luciferase reporter system was transfected into HEK293 cells with either wild type MEK5 and the oncogenic forms of KRAS or BRAF or MEK5D for 24h."
sparser
"Previously believed to be mutually exclusive to other known oncodrivers such as KRAS , EGFR , and ALK , xref , xref more contemporary studies, including this review of Alberta patients with BRAF mutation, suggest that co-mutation of BRAF and EGFR , KRAS , or PIK3CA occurs with some frequency, recorded at 25% in this study and identified in 14% to 16% of other reviews, depending on type of co-mutation investigated. xref , xref , xref We excluded from the analysis two co-occurring EGFR -mutated patients owing to different treatment options available in the context of a canonical EGFR mutation, but we made a decision to retain dual BRAF-KRAS and BRAF-PIK3CA mutation-positive patients within our cohort."
sparser
"The presence of other oncodrivers in conjunction with BRAF is clinically significant, as it creates both possibilities and challenges: the possibility of using co-inhibition of BRAF and other oncogenic pathways either in tandem or sequentially and the possibility of co-mutations (i.e., KRAS and PIK3CA ) encouraging up-regulation of PD-L1 and subsequent benefit of ICI-based regimens xref , xref ; the challenge of co-occurring mutations (specifically KRAS ) being a mechanism of primary resistance to dual BRAF/MEK inhibition. xref Indeed, in this study, we observed both primary resistance to dabrafenib/trametinib in the context of a dual BRAF-KRAS mutation, including a rate of primary resistance double that found within the phase 2 clinical trial of dabrafenib/trametinib (33% versus 14%), which did not include dual BRAF-KRAS mutations. xref Conversely, although the rate of intrinsic BRAF mutations is relatively low, BRAF mutations may also be acquired, thereby representing one mechanism of resistance to EGFR-inhibiting–targeted therapies."
sparser
"In addition, of note, this study was able to find a high level of concurrent mutation; the impact of double BRAF-KRAS or BRAF-PIK3CA mutations on TMB and PD-L1 expression has known implications for ICI response and should be a focus of future investigation to lend clarity to use of ICI for BRAF mutations, including the role of ICI-based regimens after targeted BRAF/MEK inhibition."
reach
"Potential interactions between KRAS, NRAS, and BRAF with the other covariates were evaluated prior to final model selection, and no significant interaction was observed.Multivariable Cox proportional hazard regressions were conducted to estimate the hazard ratio (HR) of all-cause mortality."
sparser
"KRAS mutation, present in 30%-40% of tumors, does not appear to be an independent negative prognostic factor, in that patients in the control arms of studies of EGFR inhibitors in colorectal cancer demonstrate similar outcomes regardless of KRAS mutational status. xref - xref Interestingly, the V600E mutation in BRAF, another gene in the KRAS signal transduction pathway, is also associated with nonresponse to EGFR-targeted therapy based upon early data. xref - xref Subset analyses from the CAIRO-2, CRYSTAL, and PETACC-3 trials suggest that the BRAF V600E mutation, unlike KRAS mutation, is associated with poor prognosis which may confound interpretation of its predictive value. xref - xref BRAF mutations are present in approximately 5% to 10% of colorectal tumors and appear to be mutually exclusive with KRAS mutations. xref , xref , xref , xref BRAF mutation may be more common in patients with the CpG island methylator phenotype (CIMP), which itself has been associated with a positive prognosis, highlighting the complexity of these molecular pathways. xref "
sparser
"Non-mutated forms of BRAF ( v-raf murine sarcoma viral oncogene homolog B1) and KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ) genes are required for response to tyrosine kinase inhibitors (TKI).( xref )Immunohistochemistry studies with EGFR showed that patients with high expression are more likely to respond to these drugs than those with reduced expression.( xref )"
sparser
"In Chinese CRC patients, Shen et al found that gender was the only factor that showed an obvious relationship with KRAS mutations (female 44.7% vs male 28.2%, P = 0.037) xref ; Liou et al reported more frequent KRAS mutations in females and in non-smokers, and KRAS and BRAF mutations were significantly associated with the proximal location of cancer xref ."
sparser
"The validity of the findings are however strengthened by the expected associations of KRAS and BRAF mutations with clinicopathological factors, e.g. KRAS and BRAF mutations being mutually exclusive [ xref ], the significant associations between BRAF mutation, MSI [ xref , xref , xref ] and mucinous phenotype [ xref , xref ]."
reach
"Consistent with this hypothesis, stimulation of wild-type KRAS H1703 cells with serum or EGF increased KRAS–RanGAP1 complex formation (Fig. 3j–m), while transfection of DN KRAS-S17N mutant in NCI-H23 cells reduced KRAS–RanGAP1 and KRAS–BRAF complex formation to a similar degree (Fig. 3n–p)."
sparser
"Accumulation of specific genetic and epigenetic events results in disease progression along three distinct clinico-pathologic pathways involving DNA methylation, microsatellite instability, and epigenetic-genetic interactions affecting mutations of KRAS or BRAF oncogenes and the p53 tumor suppressor genes xref , xref ."
sparser
"This mutation has a minimal impact on MAPK signaling in vitro and has been associated with good response to EGFR-directed therapy and a favorable prognosis in metastatic CRC patients. xref , xref Several individuals with multiple polyps had both serrated and adenomatous polyps associated with BRAF and KRAS mutation, respectively."
sparser
"To determine whether this complex formation–enhancing effect is a general property of vemurafenib, we set out to test the drug effect on the BRAF interactions with KRAS G12V , NRAS G12V , and HRAS G12V . This time, we analyzed the dose-dependent effect using 100 nM and 1 μM vemurafenib."