IndraLab
Statements
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)."
"The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases."
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 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
"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
"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
"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
"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
"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
"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
"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 ]."
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
"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
"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
"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
"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
"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
"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."
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
"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
"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
"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)."
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."
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
"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
"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
"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."
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
"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
"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
"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
"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
"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
"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
"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
"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 ]."