共查询到20条相似文献,搜索用时 46 毫秒
1.
Background:
Melanoma, the most lethal form of skin cancer, is responsible for over 80% of all skin cancer deaths and is highly metastatic, readily spreading to the lymph nodes or metastasising to other organs. The frequent genetic mutation found in metastatic melanoma, BRAFV600E, results in constitutive activation of the mitogen-activated protein kinase pathway.Methods:
In this study, we utilised genetically engineered melanoma cell lines and xenograft mouse models to investigate how BRAFV600E affected cytokine (IL-1β, IL-6, and IL-8) and matrix metalloproteinase-1 (MMP-1) expression in tumour cells and in human dermal fibroblasts.Results:
We found that BRAFV600E melanoma cells expressed higher levels of these cytokines and of MMP-1 than wild-type counterparts. Further, conditioned medium from the BRAFV600E melanoma cells promoted the activation of stromal fibroblasts, inducing expression of SDF-1 and its receptor CXCR4. This increase was mitigated when the conditioned medium was taken from melanoma cells treated with the BRAFV600E specific inhibitor, vemurafenib.Conclusions:
Our findings highlight the role of BRAFV600E in activating the stroma and suggest a mechanistic link between BRAFV600E and MMP-1 in mediating melanoma progression and in activating adjacent fibroblasts in the tumour microenvironment. 相似文献2.
M S Carlino L E Haydu H Kakavand A M Menzies A L Hamilton B Yu C C Ng W A Cooper J F Thompson R F Kefford S A O'Toole R A Scolyer G V Long 《British journal of cancer》2014,111(2):292-299
Background:
The prognostic significance of BRAF and NRAS mutations in metastatic melanoma patients remains uncertain, with several studies reporting conflicting results, often biased by the inclusion of patients treated with BRAF and MEK (MAPK) inhibitors. We therefore interrogated a historical cohort of patients free of the confounding influence of MAPK inhibitor therapy.Methods:
Patients with available archival tissue first diagnosed with metastatic melanoma between 2002 and 2006 were analysed. Mutational analysis was performed using the OncoCarta Panel. Patient characteristics, treatment outcome and survival were correlated with BRAF/NRAS mutation status.Results:
In 193 patients, 92 (48%) melanomas were BRAF-mutant, 39 (20%) were NRAS-mutant and 62 (32%) were wild-type for BRAF/NRAS mutations (wt). There was no difference in response to chemotherapy based on mutation status (35–37%). The distant disease-free interval (DDFI) was significantly shorter in patients with wt melanoma (27.9 months vs 35.1 for BRAF and 49.1 for NRAS) although this was not significant in multivariate analysis. Survival from stage IV melanoma diagnosis was not significantly different based on mutation status. The DDFI was significantly shorter in patients with BRAFV600K/R versus BRAFV600E melanoma in univariate and multivariate analyses.Conclusions:
BRAF and NRAS mutation status does not influence survival in metastatic melanoma. 相似文献3.
Imke Satzger Lena Marks Martin Kerick Sven Klages Carola Berking Rudolf Herbst Bernward V?lker Vivien Schacht Bernd Timmermann Ralf Gutzmer 《Oncotarget》2015,6(35):37895-37905
Background
The detection of BRAFV600 mutations in patients with metastatic melanoma is important because of the availability of BRAF inhibitor therapy. However, the clinical relevance of the frequency of BRAFV600 mutant alleles is unclear.Patients and Methods
Allele frequencies of BRAFV600 mutations were analyzed by ultra-deep next-generation sequencing in formalin-fixed, paraffin-embedded melanoma tissue (75 primary melanomas and 88 matched metastases). In a second study, pretreatment specimens from 76 patients who received BRAF inhibitors were retrospectively analyzed, and BRAFV600 allele frequencies were correlated with therapeutic results.Results
Thirty-five patients had concordantly BRAF-positive and 36 (48%) patients had concordantly BRAF-negative primary melanomas and matched metastases, and four patients had discordant samples with low allele frequencies (3.4–5.2%). Twenty-six of 35 patients with concordant samples had BRAFV600E mutations, three of whom had additional mutations (V600K in two patients and V600R in one) and nine patients had exclusively non-V600E mutations (V600K in eight patients and V600E -c.1799_1800TG > AA- in one patient). The frequency of mutated BRAFV600 alleles was similar in the primary melanoma and matched metastasis in 27/35 patients, but differed by >3-fold in 8/35 of samples. BRAFV600E allele frequencies in pretreatment tumor specimens were not significantly correlated with treatment outcomes in 76 patients with metastatic melanoma who were treated with BRAF inhibitors.Conclusions
BRAFV600 mutation status and allele frequency is consistent in the majority of primary melanomas and matched metastases. A small subgroup of patients has double mutations. BRAFV600 allele frequencies are not correlated with the response to BRAF inhibitors. 相似文献4.
Lin J Goto Y Murata H Sakaizawa K Uchiyama A Saida T Takata M 《British journal of cancer》2011,104(3):464-468
Background:
Oncogenic BRAF mutation had been considered to be a founder event in the formation of melanocytic tumours; however, we recently argued against this notion by showing marked polyclonality of BRAF mutations in acquired melanocytic nevi (Lin et al, J Natl Cancer Inst., 2009; 101:1423–7). Here, we tested whether similar heterogeneity of BRAF mutations exists in primary melanomas.Methods:
We isolated and sequenced single melanoma cells from five primary melanoma tissues using antibodies against human high-molecular-weight melanoma-associated antigen. We also examined 10 primary melanomas by the sensitive Mutector assay detecting the BRAFV600E mutation, as well as by cloning and sequencing of separated alleles. Furthermore, we estimated the frequency of BRAF mutant alleles in paired samples of primary tumour and recurrence or metastasis in three patients.Results:
Single-cell mutation analyses revealed that four of five primary melanomas contained both BRAF-wild-type and BRAF-mutant tumour cells. Tumour heterogeneity in terms of BRAF mutations was also shown in 8 of 10 primary melanomas. Selection of BRAF mutant alleles during progression was demonstrated in all the three patients.Conclusion:
Acquisition of a BRAF mutation is not a founder event, but may be one of the multiple clonal events in melanoma development, which is selected for during the progression. 相似文献5.
6.
Shaowei Wu Helen Kuo Wen-Qing Li Alvaro Laga Canales Jiali Han Abrar A. Qureshi 《Cancer causes & control : CCC》2014,25(10):1379-1386
Purpose
Previous studies suggest that solar UV exposure in early life is predictive of cutaneous melanoma risk in adulthood, whereas the relation of BRAF mutation with sun exposure and disease prognosis has been less certain. We investigated the associations between BRAFV600E and NRASQ61R mutations and known risk factors, clinicopathologic characteristics and clinical outcomes of melanoma in a case series of primary invasive cutaneous melanoma from the Nurses’ Health Study (NHS).Methods
Somatic BRAFV600E and NRASQ61R mutations of 127 primary invasive melanomas from the NHS cohort were determined by pyrosequencing using formalin-fixed, paraffin-embedded block tissues. Logistic regression analyses were performed to detect the associations of mutations with melanoma risk factors, and Kaplan–Meier method was used to examine associations between mutations and survival.Results
The odds ratios for harboring BRAFV600E mutations were 5.54 (95 % CI 1.19–25.8, p trend = 0.02) for women residing in states with UV index ≥ 7 versus those residing in states with UV index ≤5 at 30 years of age. Patients with BRAFV600E mutations tended to have shorter melanoma-specific survival when compared to patients with wild type at both loci (median survival time 110 vs. 159 months) (p = 0.03). No association was found between NRASQ61R mutation and melanoma risk factors or melanoma-specific survival.Conclusions
BRAFV600E mutations in primary cutaneous melanomas were associated with residence in locations with medium and high UV indices in mid-life. BRAFV600E mutation may be associated with an unfavorable prognosis among melanoma patients. 相似文献7.
Levent Dizdar Thomas A. Werner Jasmin C. Drusenheimer Birte Möhlendick Katharina Raba Inga Boeck Martin Anlauf Matthias Schott Wolfgang Göring Irene Esposito Nikolas H. Stoecklein Wolfram T. Knoefel Andreas Krieg 《International journal of cancer. Journal international du cancer》2019,144(6):1379-1390
To determine the role of BRAFV600E mutation and MAPK signaling as well as the effects of BRAF and MEK directed therapy in gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN), with a focus on highly aggressive gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Using Sanger sequencing of BRAF exon 15 we determined the frequency of BRAFV600E mutations in 71 primary GEP-NENs. MEK phosphorylation was examined by immunohistochemistry in corresponding tissue samples. To evaluate the biological relevance of BRAFV600E mutation and MAPK signaling in GEP-NECs, effects of a pharmacological BRAF and MEK inhibition were analyzed in NEC cell lines both in vitro and in vivo. BRAFV600E mutation was detected in 9.9% of all GEP-NENs. Interestingly, only NECs of the colon harbored BRAFV600E mutations, leading to a mutation frequency of 46.7% in this subgroup of patients. In addition, a BRAFV600E mutation was significantly associated with high levels of MEK phosphorylation (pMEK) and advanced tumor stages. Pharmacological inhibition of BRAF and MEK abrogated NEC cell growth, inducing G1 cell cycle arrest and apoptosis only in BRAFV600E mutated cells. BRAF inhibitor dabrafenib and MEK inhibitor trametinib prevented growth of BRAFV600E positive NEC xenografts. High frequencies of BRAFV600E mutation and elevated expression levels of pMEK were detected in biologically aggressive and highly proliferative colorectal NECs. We provide evidence that targeting BRAF oncogene may represent a therapeutic strategy for patients with BRAF mutant colorectal NECs. 相似文献
8.
Siraj M. Ali Je He Wade Carson Phil J. Stephens Joseph Fiorillo Doron Lipson Gary A. Palmer Jeffrey S. Ross Vincent A. Miller Jeffrey Sharman 《Case reports in oncology》2014,7(2):343-348
Context
For patients with metastatic papillary thyroid carcinoma (PTC) refractory to radioactive iodine (RAI) treatment, systemic chemotherapy has limited efficacy. Such tumors frequently harbor BRAF V600E, and this alteration may predict responsiveness to vemurafenib treatment.Objective
We report a metastatic PTC patient refractory to RAI treatment that underwent genomic profiling by next-generation sequencing. The sole genomic alteration identified was BRAF V600E on a near diploid genome with trisomy 1q. With vemurafenib treatment, the patient experienced a dramatic radiographic and clinical improvement, with the duration of an ongoing antitumor response exceeding 23 months.Design
Hybridization capture of 3,769 exons of 236 cancer-related genes and the introns of 19 genes frequently rearranged in cancer was applied to >50 ng of DNA extracted from a formalin-fixed, paraffin-embedded biopsy of a lymph node containing metastatic PTC and was sequenced to a high, uniform coverage of ×616.Results
A BRAF V600E alteration was identified with no other somatic genomic alterations present within a near diploid tumor genome. The patient initially received vemurafenib at 960 mg twice daily that was reduced to 480 mg twice daily due to rash and diarrhea and has experienced an ongoing antitumor response exceeding 23 months by both PET-CT and dedicated CT imaging.Conclusions
Genomic profiling in metastatic, RAI-refractory PTC can reveal a targetable BRAF V600E alteration without compounding somatic alterations, and such patients may derive a more prolonged benefit from vemurafenib treatment. Prospective clinical trials are ongoing to confirm our preliminary observation.Key words: Papillary thyroid carcinoma, BRAF V600E, Vemurafenib 相似文献9.
M Beloueche-Babari Y Jamin V Arunan S Walker-Samuel M Revill P D Smith J Halliday J C Waterton H Barjat P Workman M O Leach S P Robinson 《British journal of cancer》2013,109(6):1562-1569
Background:
Non-invasive imaging biomarkers underpin the development of molecularly targeted anti-cancer drugs. This study evaluates tumour apparent diffusion coefficient (ADC), measured by diffusion-weighted magnetic resonance imaging (DW-MRI), as a biomarker of response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in human tumour xenografts.Methods:
Nude mice bearing human BRAFV600D WM266.4 melanoma or BRAFV600E Colo205 colon carcinoma xenografts were treated for 4 days with vehicle or selumetinib. DW-MRI was performed before and 2 h after the last dose and excised tumours analysed for levels of phospho-ERK1/2, cleaved caspase 3 (CC3) and necrosis.Results:
Selumetinib treatment induced tumour stasis and reduced ERK1/2 phosphorylation in both WM266.4 and Colo205 tumour xenografts. Relative to day 0, mean tumour ADC was unchanged in the control groups but was significantly increased by up to 1.6-fold in selumetinib-treated WM266.4 and Colo205 tumours. Histological analysis revealed a significant increase in necrosis in selumetinib-treated WM266.4 and Colo205 xenografts and CC3 staining in selumetinib-treated Colo205 tumours relative to controls.Conclusion:
Changes in ADC following treatment with the MEK1/2 inhibitor selumetinib in responsive human tumour xenografts were concomitant with induction of tumour cell death. ADC may provide a useful non-invasive pharmacodynamic biomarker for early clinical assessment of response to selumetinib and other MEK-ERK1/2 signalling-targeted therapies. 相似文献10.
Jiayin Zhang Biao Lu Dong Liu Ru Shen Yinfa Yan Liuqing Yang 《Cancer biology & therapy》2016,17(2):199-207
The oncogenic mutation of BRAFV600E has been found in approximately 8% of all human cancers, including more than 60% of melanoma and 10% of colorectal cancers. The clinical proof of concept in treating BRAFV600E-driving melanoma patients with the BRAF inhibitors has been well established. We have sought to identify and develop novel BRAFV600E inhibitors with more favorable profiles. Our chemistry effort has led to the discovery of EBI-907 as a novel BRAFV600E inhibitor with potent anti-tumor activity in vitro and in vivo. In a LanthaScreen BRAFV600E kinase assay, EBI-907 showed an IC50 of 4.8 nM, which is >10 -fold more potent than Vemurafenib (IC50 = 58.5 nM). In addition, EBI-907 showed a broader kinase selectivity profile, with potent activity against a number of important oncogenic kinases including FGFR1-3, RET, c-Kit, and PDGFRb. Concomitant with such properties, EBI-907 exhibits potent and selective cytotoxicity against a broader range of BRAFV600E-dependent cell lines including certain colorectal cancer cell lines with innate resistance to Vemurafenib. In BRAFV600E-dependent human Colo-205 and A375 tumor xenograft mouse models, EBI-907 caused a marked tumor regression in a dose-dependent manner, with superior efficacy to Vemurafenib. Our results also showed that combination with EGFR or MEK inhibitor enhanced the potency of EBI-907 in cell lines with innate or acquired resistance to BRAF inhibition alone. Our findings present EBI-907 as a potent and promising BRAF inhibitor, which might be useful in broader indications. 相似文献
11.
Rawson JB Mrkonjic M Daftary D Dicks E Buchanan DD Younghusband HB Parfrey PS Young JP Pollett A Green RC Gallinger S McLaughlin JR Knight JA Bapat B 《British journal of cancer》2011,104(12):1906-1912
Background:
In colorectal cancer (CRC), tumour microsatellite instability (MSI) status and CpG island methylator phenotype (CIMP) status are indicators of patient outcome, but the molecular events that give rise to these outcomes remain largely unknown. Wnt5a is a critical regulator of non-canonical Wnt activity and promoter hypermethylation of this gene has emerging prognostic roles in CRC; however the frequency and prognostic significance of this epigenetic event have not been explored in the context of colorectal tumour subtype. Consequently, we investigated the frequency and prognostic significance of Wnt5a methylation in a large cohort of MSI-stratified CRCs.Methods:
Methylation was quantified in a large cohort of 1232 colorectal carcinomas from two clinically distinct populations from Canada. Associations were examined between methylation status and clinicopathlogical features, including tumour MSI status, BRAF V600E mutation, and patient survival.Results:
In Ontario, Wnt5a methylation was strongly associated with MSI tumours after adjustment for age, sex, and tumour location (odds ratio (OR)=4.2, 95% confidence interval (CI)=2.4–7.4, P<10−6) and with BRAF V600E mutation, a marker of CIMP (OR=12.3, 95% CI=6.9–21.7, P<10−17), but was not associated with patient survival. Concordant results were obtained in Newfoundland.Conclusion:
Methylation of Wnt5a is associated with distinct tumour subtypes, strengthening the evidence of an epigenetic-mediated Wnt bias in CRC. 相似文献12.
L Heinzerling S Kühnapfel D Meckbach M Baiter E Kaempgen P Keikavoussi G Schuler A Agaimy J Bauer A Hartmann F Kiesewetter R Schneider-Stock 《British journal of cancer》2013,108(10):2164-2171
Background:
The detection of V600E BRAF mutation in melanoma is fundamental since here BRAF inhibitors represent an effective treatment. Non-V600E BRAF mutations that may also respond are not detected by certain screening methods. Thus, knowledge about detection of these mutations is needed.Methods:
A total of 276 tumour samples from 174 melanoma patients were investigated for BRAF mutations by pyrosequencing. Rare mutations were confirmed by capillary sequencing and compared with findings from COBAS test and immunohistochemistry using a novel BRAF antibody. Melanoma type, localisation, and survival were summarised.Results:
BRAF mutations were found in 43% of patients (124 tumours in 75 patients). Among those, 14 patients (18.7%) exhibited rare mutations. The V600EK601del and V600DK601del mutations have never been described before in melanoma. Furthermore, V600K, V600E2, and V600D, V600G, V600R, and L597S mutations were detected. Mutations were not detected by COBAS test in 7 out of these 14 patients and immunohistochemistry only reliably detected patients with the V600E2 and V600EK601del mutation.Conclusion:
Accurate diagnosis of rare BRAF mutations is crucial. We show that pyrosequencing is accurate, highly sensitive, reliable, and time saving to detect rare BRAF mutations. Missing these rare variant mutations would exclude a subset of patients from available effective BRAF-targeting therapy. 相似文献13.
14.
L Heinzerling M Baiter S Kühnapfel G Schuler P Keikavoussi A Agaimy F Kiesewetter A Hartmann R Schneider-Stock 《British journal of cancer》2013,109(11):2833-2841
Background:
The detection of V600E BRAF mutations has fundamental clinical consequences as the treatment option with BRAF inhibitors such as vemurafenib or dabrafenib yields response rates of ∼48%. Heterogeneity with respect to BRAF mutation in different metastases has been described in single cases. As this has important implications for the determination of BRAF status and treatment of patients, it is essential to acquire more data.Methods:
A total of 300 tumour samples from 187 melanoma patients were analysed for BRAF mutations by pyrosequencing. Equivocal results were confirmed by capillary sequencing. Clinical data with respect to melanoma type, tumour site and survival were summarised for 53 patients with multiple analysed tumour samples (2–13 per patient).Results:
BRAF mutations were found in 84 patients (44.9%) and 144 tumour samples (48%) with BRAF mutations in 45.5% of primary tumours and 51.3% of metastases, respectively. In 10 out of 53 patients (18.9%) where multiple samples were analysed results were discordant with respect to mutation findings with wild-type and mutated tumours in the same patient. Mutations did not appear more frequently over the course of disease nor was its occurrence associated with a specific localisation of metastases.Conclusion:
As heterogeneity with respect to BRAF mutation status is detected in melanoma patients, subsequent testing of initially wild-type patients can yield different results and thus make BRAF inhibitor therapy accessible. The role of heterogeneity in testing and for clinical response to therapy with a BRAF inhibitor needs to be further investigated. 相似文献15.
Rossella Loria Giulia Bon Valentina Perotti Enzo Gallo Ilaria Bersani Paola Baldassari Manuela Porru Carlo Leonetti Selene Di Carlo Paolo Visca Maria Felice Brizzi Andrea Anichini Roberta Mortarini Rita Falcioni 《Oncotarget》2015,6(5):2779-2793
We used whole genome microarray analysis to identify potential candidate genes with differential expression in BRAFV600E
vs NRASQ61R melanoma cells. We selected, for comparison, a peculiar model based on melanoma clones, isolated from a single tumor characterized by mutually exclusive expression of BRAFV600E and NRASQ61R in different cells. This effort led us to identify two genes, SEMA6A and MICAL1, highly expressed in BRAF-mutant vs NRAS-mutant clones. Real-time PCR, Western blot and immunohistochemistry confirmed preferential expression of Sema6A and Mical1 in BRAFV600E melanoma. Sema6A is a member of the semaphorin family, and it complexes with the plexins to regulate actin cytoskeleton, motility and cell proliferation. Silencing of Sema6A in BRAF-mutant cells caused cytoskeletal remodeling, and loss of stress fibers, that in turn induced cell death. Furthermore, Sema6A depletion caused loss of anchorage-independent growth, inhibition of chemotaxis and invasion. Forced Sema6A overexpression, in NRASQ61R clones, induced anchorage-independent growth, and a significant increase of invasiveness. Mical1, that links Sema/PlexinA signaling, is also a negative regulator of apoptosis. Indeed, Mical-1 depletion in BRAF mutant cells restored MST-1-dependent NDR phosphorylation and promoted a rapid and massive NDR-dependent apoptosis. Overall, our data suggest that Sema6A and Mical1 may represent new potential therapeutic targets in BRAFV600E melanoma. 相似文献
16.
Tsun-Wen Yao Jie Zhang Michael Prados William A. Weiss C. David James Theodore Nicolaides 《Oncotarget》2015,6(26):21993-22005
Mutational activation of BRAF (BRAFV600E) occurs in pediatric glioma and drives aberrant MAPK signaling independently of upstream cues. Targeted monotherapy against BRAFV600E displays efficacy in pre-clinical models of glioma, however xenograft tumors adapt rapidly and escape from the growth-inhibitory effects of BRAF-targeted therapy. Here, we show that intrinsic resistance to a BRAFV600E specific inhibitor stems, in part, from feedback activation of EGFR and downstream signaling pathways. BRAFV600E inhibition suppresses MAPK signaling, which in turn downregulates the EGFR phosphatase PTPN9, resulting in sustained EGFR phosphorylation and enhanced EGFR activity. We demonstrated that overexpression of PTPN9 reduces EGFR phosphorylation and cooperates with BRAFV600E inhibitor PLX4720 to reduce MAPK and Akt signaling, resulting in decreased glioma cell viability. Moreover, pharmacologic inhibition of EGFR combined with inhibition of BRAFV600E to reduce growth of glioma cell lines and orthotopic glioma xenograft by decreasing tumor cell proliferation while increasing apoptosis, with resultant significant extension of animal subject survival. Our data support clinical evaluation of BRAFV600E and EGFR targeted therapy in treating BRAFV600E glioma. 相似文献
17.
K H T Paraiso I V Fedorenko L P Cantini A C Munko M Hall V K Sondak J L Messina K T Flaherty K S M Smalley 《British journal of cancer》2010,102(12):1724-1730
Background:
Resistance to BRAF inhibitors is an emerging problem in the melanoma field. Strategies to prevent and overcome resistance are urgently required.Methods:
The dynamics of cell signalling, BrdU incorporation and cell-cycle entry after BRAF inhibition was measured using flow cytometry and western blot. The ability of combined BRAF/MEK inhibition to prevent the emergence of resistance was demonstrated by apoptosis and colony formation assays and in 3D organotypic cell culture.Results:
BRAF inhibition led to a rapid recovery of phospho-ERK (pERK) signalling. Although most of the cells remained growth arrested in the presence of drug, a minor population of cells retained their proliferative potential and escaped from BRAF inhibitor therapy. A function for the rebound pERK signalling in therapy escape was demonstrated by the ability of combined BRAF/MEK inhibition to enhance the levels of apoptosis and abrogate the onset of resistance.Conclusion:
Combined BRAF/MEK inhibition may be one strategy to prevent the emergence of drug resistance in BRAF-V600E-mutated melanomas. 相似文献18.
Z Saridaki D Papadatos-Pastos M Tzardi D Mavroudis E Bairaktari H Arvanity E Stathopoulos V Georgoulias J Souglakos 《British journal of cancer》2010,102(12):1762-1768
Background:
The significance of BRAF mutations, microsatelite instability (MSI) status and cyclin D1 expression in patients with metastatic colorectal cancer (mCRC) was evaluated.Methods:
Primary tumours from 144 patients treated for mCRC were assessed for BRAF (V600E) mutation, MSI status and cyclin D1. The data were correlated with progression-free survival (PFS) and overall survival (OS).Results:
BRAF mutations were detected in 10 (out of 22, 45%) patients with MSI-H tumours compared with 2 (out of 122, 1.6%) in those with microsatellite stable tumours (P<0.001). The presence of BRAF mutations was correlated with cyclin D1 overexpression (7 out of 26 patients, 58% vs 5 out of 118 patients, 14% P=0.001). Patients with BRAF-mutated primary tumours had a significantly decreased PFS (2.7 vs 9.8 months; P<0.001) and median OS (14 vs 30 months; P<0.001) than patients with wild-type (wt) tumours. Patients with MSI-H and BRAF-mutated tumours experienced significantly lower PFS (3.1 vs 11.4 months; P=0.008) and OS (14.5 vs 35.5 months; P=0.004) than patients with MSI-H and BRAF wt tumours. Similarly, BRAF mutations and cyclin D1 overexpression were correlated with decreased PFS (3.1 vs 8.6 months; P=0.03) and OS (17.8 vs 39.2 months; P=0.01).Conclusion:
BRAF V600E mutations are associated with MSI-H status and cyclin D1 overexpression and characterize a subgroup of patients with poor prognosis. 相似文献19.
20.
Christian Schafroth José A. Galván Irene Centeno Viktor H. Koelzer Heather E. Dawson Lena Sokol Gregor Rieger Martin D. Berger Marion H?drich Robert Rosenberg Ulrich Nitsche Beat Schnüriger Rupert Langer Daniel Inderbitzin Alessandro Lugli Inti Zlobec 《Oncotarget》2015,6(39):41453-41463