BioMCP

{ "allCuratedGenes": [ { "grch37Isoform": "ENST00000288602", "grch37RefSeq": "NM_004333.4", "grch38Isoform": "ENST00000646891", "grch38RefSeq": "NM_004333.4", "entrezGeneId": 673, "hugoSymbol": "BRAF", "geneType": "ONCOGENE", "highestSensitiveLevel": "1", "highestResistanceLevel": "", "summary": "BRAF, an intracellular kinase, is frequently mutated in melanoma, thyroid and lung cancers among others.", "background": "BRAF is a serine/threonine kinase that plays a key role in the regulation of the mitogen-activated protein kinase (MAPK) cascade (PMID: 15520807), which under physiologic conditions regulates the expression of genes involved in cellular functions, including proliferation (PMID: 24202393). Genetic alterations in BRAF are found in a large percentage of melanomas, thyroid cancers and histiocytic neoplasms as well as a small fraction of lung and colorectal cancers. The most common BRAF point mutation is V600E, which deregulates the protein's kinase activity leading to constitutive BRAF activation, as BRAF V600E can signal as a monomer independently of RAS or upstream activation (PMID: 20179705). Other BRAF mutations have been found that affect the protein's propensity to dimerize (PMID: 16858395, 26343582, 12068308). The product of these alterations is a BRAF kinase that can activate MAPK signaling in an unregulated manner and, in some instances, is directly responsible for cancer growth (PMID: 15520807). Inhibitors of mutant BRAF, including vemurafenib and dabrafenib, are FDA-approved for the treatment of late-stage or unresectable melanoma.", "highestResistancLevel": "" }, { "grch37Isoform": "ENST00000368508", "grch37RefSeq": "NM_002944.2", "grch38Isoform": "ENST00000368508", "grch38RefSeq": "NM_002944.2", "entrezGeneId": 6098, "hugoSymbol": "ROS1", "geneType": "ONCOGENE", "highestSensitiveLevel": "1", "highestResistanceLevel": "R2", "summary": "ROS1, a receptor tyrosine kinase, is altered by mutation or chromosomal rearrangement in a diverse range of cancers, including lung cancer.", "background": "The ROS1 gene encodes a transmembrane protein with intracellular tyrosine kinase activity (PMID: 18778756). ROS1 is a member of the sevenless subfamily of tyrosine kinase insulin receptor genes (PMID: 27256160). The normal physiological role and ligand of this protein in humans is currently unknown (PMID: 23814043). ROS1 rearrangements where the kinase domain is retained (PMID: 22327623) are implicated in a range of human epithelial cancers including cholangiocarcinoma (PMID: 21253578), ovarian carcinoma (PMID: 22163003), gastric carcinoma (PMID: 23400546), angiosarcoma (PMID: 23637631) and most commonly non-small cell lung cancer (PMID: 22215748). Although ROS1 rearrangements were first discovered in a human glioblastoma cell line (PMID: 2827175), there is a paucity of ROS1 rearrangements in human gliomas (PMID: 24999209). The mechanism by which ROS1 rearrangements leads to dysregulated kinase activity is not clear, as its ligand has not yet been deciphered; however, it is hypothesized to occur through constitutive kinase activation (PMID: 18083107).", "highestResistancLevel": "R2" }, { "grch37Isoform": "ENST00000269305", "grch37RefSeq": "NM_000546.5", "grch38Isoform": "ENST00000269305", "grch38RefSeq": "NM_000546.5", "entrezGeneId": 7157, "hugoSymbol": "TP53", "geneType": "TSG", "highestSensitiveLevel": "3A", "highestResistanceLevel": "", "summary": "TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.", "background": "TP53 encodes the p53 tumor suppressor protein, a transcription factor that responds to cellular stresses, including DNA damage and oncogenic activation, by inducing downstream anti-tumor responses such as DNA repair and apoptosis (PMID: 11099028). p53 levels are kept low in healthy cells due to negative regulation by MDM2/4, Cop1 and Trim24 and constant degradation by the ubiquitin-proteasome system (PMID: 36859359, 36207426). When DNA is damaged, a network of pathways is activated to detect and repair lesions in a cell- and context-specific manner (PMID: 36207426). p53 is rapidly phosphorylated by upstream regulators such as ATM, ATR, and CHL1/2, which results in the accumulation of stable p53 (PMID: 36207426). p53 then binds to specific DNA sequences to direct the expression of a wide variety of genes, including those involved in apoptosis, cell cycle arrest, DNA repair, senescence, stem cell differentiation, autophagy, cellular metabolism, and others (PMID: 27141080, 36859359, 36207426). Oncogenic mutations of TP53 often result in the dysregulation of p53 function, usually due to structural changes in the DNA binding domain (PMID: 36859359). Loss of p53 function can have various outcomes including tumorigenesis, invasion and metastasis, drug resistance, metabolic reprogramming, immune evasion and overall genomic instability (PMID: 36859359). TP53 is the most commonly mutated gene in human cancers, and germline mutations occur in the cancer predisposition syndrome Li-Fraumeni (PMID: 22713868, 21765642). Clinical and preclinical research into drugs that target TP53 is ongoing, notably with MDM2 inhibitors that aim to restore p53 function and are being tested in combination with other cancer therapies (PMID: 36859359, 37818252).", "highestResistancLevel": "" } ], "genesByHugoSymbol": [ { "entrezGeneId": 673, "hugoSymbol": "BRAF", "geneType": "ONCOGENE", "grch37Isoform": "ENST00000288602", "grch37RefSeq": "NM_004333.4", "grch38Isoform": "ENST00000646891", "grch38RefSeq": "NM_004333.4", "geneAliases": ["BRAF1"], "genesets": [] }, { "entrezGeneId": 6098, "hugoSymbol": "ROS1", "geneType": "ONCOGENE", "grch37Isoform": "ENST00000368508", "grch37RefSeq": "NM_002944.2", "grch38Isoform": "ENST00000368508", "grch38RefSeq": "NM_002944.2", "geneAliases": ["MCF3", "ROS", "c-ros-1"], "genesets": [] }, { "entrezGeneId": 7157, "hugoSymbol": "TP53", "geneType": "TSG", "grch37Isoform": "ENST00000269305", "grch37RefSeq": "NM_000546.5", "grch38Isoform": "ENST00000269305", "grch38RefSeq": "NM_000546.5", "geneAliases": ["LFS1", "p53"], "genesets": [] } ], "variantAnnotation": { "BRAF_V600E_melanoma": { "query": { "id": null, "referenceGenome": "GRCh37", "hugoSymbol": "BRAF", "entrezGeneId": 673, "alteration": "V600E", "alterationType": null, "svType": null, "tumorType": "melanoma", "consequence": null, "proteinStart": null, "proteinEnd": null, "hgvs": null, "hgvsInfo": null, "canonicalTranscript": null }, "geneExist": true, "variantExist": true, "alleleExist": true, "oncogenic": "Oncogenic", "mutationEffect": { "knownEffect": "Gain-of-function", "description": "The class I activating exon 15 BRAF V600E mutation is located in the kinase domain of the BRAF protein and is highly recurrent in melanoma, lung and thyroid cancer, among others (PMID: 28783719, 26091043, 25079552, 23833300, 25417114, 28783719, 12068308). This mutation has been comprehensively biologically characterized and has been shown to activate the downstream MAPK pathway independent of RAS (PMID: 15035987, 12068308, 19251651, 26343582), to render BRAF constitutively activated in monomeric form (PMID: 20179705), and to retain sensitivity to RAF monomer inhibitors such as vemurafenib and dabrafenib (PMID:26343582, 28783719, 20179705, 30351999).", "citations": { "pmids": [ "25417114", "20179705", "23833300", "26091043", "26343582", "12068308", "30351999", "25079552", "28783719", "19251651", "15035987" ], "abstracts": [] } }, "highestSensitiveLevel": "LEVEL_1", "highestResistanceLevel": null, "highestDiagnosticImplicationLevel": null, "highestPrognosticImplicationLevel": null, "highestFdaLevel": "LEVEL_Fda2", "otherSignificantSensitiveLevels": [], "otherSignificantResistanceLevels": [], "hotspot": true, "exon": null, "geneSummary": "BRAF, an intracellular kinase, is frequently mutated in melanoma, thyroid and lung cancers among others.", "variantSummary": "The BRAF V600E mutation is known to be oncogenic.", "tumorTypeSummary": "The RAF-targeted inhibitors encorafenib, dabrafenib and vemurafenib alone or in combination with the MEK-targeted inhibitors binimetinib, trametinib and cobimetinib, respectively, are FDA-approved for the treatment of patients with BRAF V600E/K mutant melanoma.", "prognosticSummary": "", "diagnosticSummary": "", "diagnosticImplications": [], "prognosticImplications": [], "treatments": [ { "alterations": ["V600E"], "drugs": [ { "ncitCode": "C82386", "drugName": "Dabrafenib" } ], "approvedIndications": [ "Dabrafenib is FDA-approved for BRAF V600E mutant unresectable or metastatic melanoma." ], "level": "LEVEL_1", "fdaLevel": "LEVEL_Fda2", "levelAssociatedCancerType": { "id": 172, "code": "MEL", "color": "Black", "name": "Melanoma", "mainType": { "id": null, "name": "Melanoma", "tumorForm": "SOLID" }, "tissue": "Skin", "children": {}, "parent": "SKIN", "level": 2, "tumorForm": "SOLID" }, "levelExcludedCancerTypes": [], "pmids": ["22608338", "23051966", "22735384"], "abstracts": [], "description": "Dabrafenib is an orally bioavailable RAF inhibitor that is FDA-approved for use in patients with BRAF V600E- and V600K-mutant metastatic melanoma. FDA approval is based on the randomized Phase III trial in which dabrafenib (150 mg orally twice daily) was compared with dacarbazine (1000 mg/m2 intravenously every three weeks) in 250 patients with BRAF V600E-mutated metastatic melanoma. Dabrafenib was associated with improved progression-free survival (median 5.1 months vs. 2.7 months with dacarbazine; hazard ratio = 0.30, p<0.0001) (PMID: 22735384). Dabrafenib may also be effective against brain metastases, as demonstrated by a Phase II trial in which approximately 40% of previously untreated and 30% of previously treated patients experienced an overall intracranial response and a separate trial in which nine out of ten patients had a reduction in the size of their brain metastases (PMID: 23051966, 22608338)." }, { "alterations": ["V600E", "V600K"], "drugs": [ { "ncitCode": "C82386", "drugName": "Dabrafenib" }, { "ncitCode": "C77908", "drugName": "Trametinib" } ], "approvedIndications": [ "Dabrafenib + Trametinib is FDA-approved for BRAF V600E or V600K mutant unresectable or metastatic melanoma" ], "level": "LEVEL_1", "fdaLevel": "LEVEL_Fda2", "levelAssociatedCancerType": { "id": 172, "code": "MEL", "color": "Black", "name": "Melanoma", "mainType": { "id": null, "name": "Melanoma", "tumorForm": "SOLID" }, "tissue": "Skin", "children": {}, "parent": "SKIN", "level": 2, "tumorForm": "SOLID" }, "levelExcludedCancerTypes": [], "pmids": [ "31171876", "28891408", "31171878", "31171879", "25265492", "25287827", "29361468", "28991513", "23020132", "25399551" ], "abstracts": [], "description": "Dabrafenib, an orally bioavailable RAF inhibitor, and trametinib, an orally bioavailable MEK1/2 inhibitor, are FDA-approved alone or in combination for the treatment of patients with metastatic melanoma harboring a V600E or V600K BRAF mutation. FDA approval of dabrafenib in combination with trametinib was based on results from an open-label Phase III study of combination therapy versus dabrafenib monotherapy in 247 patients with metastatic melanoma who were naive to treatment with BRAF inhibitors. Combined dabrafenib and trametinib, administered in full monotherapy doses, improved the response rate in patients with BRAF V600-mutant metastatic melanoma versus dabrafenib monotherapy (67% vs.51%; p<0.002). However, median progression-free survival improved by only 2 weeks (9.3 months vs 8.8 months; HR = 0.75) compared with dabrafenib monotherapy (PMID: 23020132). Combination therapy is associated with less cutaneous toxicity than monotherapy, but systemic toxicity may be increased (PMID: 25287827, 25399551). Follow-up trials have demonstrated that all clinical measures inclusive of overall and median progression-free survival as well as objective response rates, median duration of response and number of patients with complete response favored patients treated with combination dabrafenib and trametinib, administered in full monotherapy doses, compared to either dabrafenib or vemurafenib monotherapy, including patients who previously progressed on BRAF inhibitor monotherapy (PMID: 25287827, 25399551, 25265492). Additionally, patients with melanoma treated with dabrafenib and trametinib in both the neoadjuvant and adjuvant settings have improved survival over patients given standard of care (PMID: 29361468, 28991513, 28891408). Promising clinical data has also suggested that addition of an immunotherapy agent to combination RAF and MEK inhibitor treatment may improve rate of overall response and duration of response in melanoma patients (PMID: 31171876, 31171879, 31171878)." }, { "alterations": ["V600E"], "drugs": [ { "ncitCode": "C64768", "drugName": "Vemurafenib" } ], "approvedIndications": [ "Vemurafenib is FDA-approved for BRAF V600E mutant unresectable or metastatic melanoma" ], "level": "LEVEL_1", "fdaLevel": "LEVEL_Fda2", "levelAssociatedCancerType": { "id": 172, "code": "MEL", "color": "Black", "name": "Melanoma", "mainType": { "id": null, "name": "Melanoma", "tumorForm": "SOLID" }, "tissue": "Skin", "children": {}, "parent": "SKIN", "level": 2, "tumorForm": "SOLID" }, "levelExcludedCancerTypes": [], "pmids": ["28961848", "24508103", "25399551"], "abstracts": [], "description": "Vemurafenib is an orally available kinse inhibitor of V600-mutant BRAF that is FDA-approved for treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation. Vemurafenib has been shown to have nearly equivalent activity against melanomas with BRAF V600E and V600K mutations (PMID: 24508103). In a randomized Phase III trial comparing vemurafenib (960 mg orally twice daily) with dacarbazine (1000 mg/m2 i.v. every 3 weeks) for treatment-naive, metastatic, BRAF V600E-mutant melanoma, vemurafenib was associated with better overall survival (median survival 13.6 months vs. 9.7 months; hazard ratio 0.70, p=.0008) and longer median progression-free survival (6.9 months vs. 1.6 months) (PMID: 24508103). Final overall survival data from the BRIM-3 study showed that the survival advantage of vemurafenib over dacarbazine persisted through the 4-year landmark, with survival rates for vemurafenib and dacarbazine at the 4-year landmark being 17.0% and 15.6%, respectively (PMID: 28961848). However, a trial evaluating clinical outcomes in patients with melanoma treated with either combination therapy of dabrafenib and trametinib compared to those treated with vemurafenib monotherapy demonstrated improved survival outcomes in the combination-therapy group compared to the vemurafenib group (PMID: 25399551)." } ], "dataVersion": "v5.3", "lastUpdate": "02/06/2025", "vus": false } } }