{"id":11858,"date":"2020-05-05T23:15:57","date_gmt":"2020-05-05T20:15:57","guid":{"rendered":"https:\/\/www.synevo.ro\/shop\/mutatia-braf-v600e-in-tumori\/"},"modified":"2025-01-30T15:35:57","modified_gmt":"2025-01-30T13:35:57","slug":"mutatia-braf-v600e-in-tumori","status":"publish","type":"product","link":"https:\/\/old.synevo.md\/ru\/shop\/mutatia-braf-v600e-in-tumori\/","title":{"rendered":"\u0412\u044b\u044f\u0432\u043b\u0435\u043d\u0438\u0435 \u043c\u0443\u0442\u0430\u0446\u0438\u0439 \u0433\u0435\u043d\u0430 BRAF V600E  \u0432 \u0442\u043a\u0430\u043d\u044f\u0445 \u043e\u043f\u0443\u0445\u043e\u043b\u0435\u0439"},"content":{"rendered":"<p style=\"text-align: justify;\"><strong><em>Informa\u021bii generale<\/em><\/strong><\/p>\n<p style=\"text-align: justify;\">Proto-oncogena BRAF (v-raf murine sarcoma viral oncogene homolog B1) cu locusul 7q34 este alc\u0103tuit\u0103 din 18 exoni \u0219i codific\u0103 o serin\/treonin protein-kinaz\u0103 de 84.4 kDa, din familia kinazelor Raf implicat\u0103 \u00een calea de semnalizare intracelular\u0103 Ras\/Raf\/MEK\/ERK (MAPK\/ERK), ce transmite semnale de la receptori celulari (de exemplu, EGFR &#8211; epidermal growth factor receptor = receptorul pentru factorul de cre\u0219tere epidermic\u0103) la nucleu, cu rol \u00een diferen\u021bierea, proliferarea, senescen\u021ba \u0219i supravie\u021buirea celular\u0103. Aceast\u0103 cale de transduc\u021bie a semnalului este activat\u0103 constitutiv \u00een numeroase tipuri de tumori maligne umane de obicei ca urmare a unor muta\u021bii ale oncogenelor KRAS \u0219i \u00a0BRAF<sup>1;2;3<\/sup>.<\/p>\n<p style=\"text-align: justify;\">Muta\u021biile genei BRAF pot fi de dou\u0103 tipuri:<\/p>\n<ul style=\"text-align: justify;\">\n<li>mo\u0219tenite (ale liniei germinale) &#8211; asociate cu <em>sindromul cardiofaciocutanat<\/em> \u2013 condi\u021bie genetic\u0103 rar\u0103 caracterizat\u0103 prin defecte cardiace, retard mental \u0219i un aspect facial distinctiv;<\/li>\n<li>dob\u00e2ndite (somatice) &#8211; asociate cu forme diferite de cancer (limfom non-Hodgkin, cancer colorectal, melanom malign, cancer tiroidian papilar, cancer pulmonar altul dec\u00e2t cel cu celule mici \u2013NSCLC, cancer ovarian)<sup>4;5<\/sup>. Aproximativ 7% dintre tumorile maligne umane con\u021bin muta\u021bii BRAF<sup>6<\/sup>.<\/li>\n<\/ul>\n<p style=\"text-align: justify;\">P\u00e2n\u0103 \u00een prezent au fost identificate peste 50 muta\u021bii distincte ale genei BRAF multe dintre acestea fiind responsabile de cre\u0219terea activit\u0103\u021bii BRAF de 1.5 p\u00e2n\u0103 la 700 ori, \u00een func\u021bie de tipul muta\u021biei. Dintre muta\u021biile BRAF activatoare asociate cu tumori cea mai frecvent\u0103 (responsabil\u0103 de peste 80% din cazuri) este V600E care are la baz\u0103 o tranzi\u021bie T-A la nivelul nucleotidei 1799 din exonul 15, ce induce o substitu\u021bie a valinei cu acidul glutamic \u00een codonul 600 din segmentul activator. Consecin\u021ba acestei muta\u021bii punctiforme missens este c\u0103 situsul de activare al protein-kinazei devine expus (\u00een mod normal fiind ascuns \u00eentr-o pung\u0103 hidrofob\u0103), ceea ce conduce\u00a0 la o activare constitutiv\u0103 BRAF. \u00a0Astfel, celulele maligne care prezint\u0103 muta\u021bia V600E prolifereaz\u0103 \u00eentr-un mod independent de factorul de cre\u0219tere<sup>2<\/sup>. Muta\u021bia predispune de asemenea la inhibarea apoptozei, cre\u0219terea invazivit\u0103\u021bii tumorii \u0219i reprezint\u0103 un eveniment timpuriu \u00een cursul carcinogenezei<sup>6<\/sup>.<\/p>\n<p style=\"text-align: justify;\">Aceast\u0103 muta\u021bie a fost identificat\u0103 \u00een urm\u0103toarele tipuri de tumori:<\/p>\n<ul style=\"text-align: justify;\">\n<li><b><strong><u>Cancerul tiroidian papilar<\/u><\/strong><\/b><\/li>\n<\/ul>\n<p style=\"text-align: justify;\">Muta\u021bia V600E constituie cea mai frecvent\u0103 modificare genetic\u0103 \u00een cancerul tiroidian papilar (~40-50% din cazuri). \u00cen\u00a0 urma unui studiu care a urm\u0103rit pe o perioad\u0103 de 15 ani evolu\u021bia unui grup de pacien\u021bi cu aceast\u0103 form\u0103 de cancer s-a constatat c\u0103 muta\u021bia V600E reprezint\u0103 un factor de prognostic nefavorabil independent de celelalte caracteristici clinico-patologice<sup>7<\/sup>.<\/p>\n<ul style=\"text-align: justify;\">\n<li><b><strong><u>Melanomul malign<\/u><\/strong><\/b><\/li>\n<\/ul>\n<p style=\"text-align: justify;\">Muta\u021bia este prezent\u0103 \u00een aproximativ 50% din cazurile de melanom malign. Studii recente au ar\u0103tat c\u0103 V600E este asociat\u0103 formei de boal\u0103 cu risc \u00eenalt (debut precoce, afectarea primar\u0103 a trunchiului, lipsa unei afect\u0103ri cutanate cronice, supravie\u021buire redus\u0103) \u0219i de aici importan\u021ba inhib\u0103rii teraputice a proteinei Braf mutante. \u00cen 2011 FDA a aprobat medicamentul <em>vemurafenib<\/em> \u2013 inhibitor oral selectiv al activit\u0103\u021bii kinazice a Braf ce con\u021bine muta\u021bia V600E &#8211; ca tratment \u00een melanomul malign metastatic. Vemurafenib nu este aprobat \u00een cazul pacien\u021bilor cu gen\u0103 BRAF de tip s\u0103lbatic<sup>8<\/sup>.<\/p>\n<ul style=\"text-align: justify;\">\n<li><b><strong><u>Cancerul pulmonar altul dec\u00e2t cel cu celule mici (NSCLC)<\/u><\/strong><\/b><\/li>\n<\/ul>\n<p style=\"text-align: justify;\">\u00cen NSCLC se raporteaz\u0103 o frecven\u021b\u0103 a muta\u021biei de 1-4%. \u00cen aceast\u0103 form\u0103 de cancer muta\u021bia BRAF V600E este prezent\u0103 mai frecvent la femei, fiind asociat\u0103 cu o form\u0103 histologic\u0103 agresiv\u0103 \u0219i cu un prognostic rezervat<sup>9<\/sup>.<\/p>\n<ul style=\"text-align: justify;\">\n<li><b><strong><u>Cancerul ovarian<\/u><\/strong><\/b><\/li>\n<\/ul>\n<p style=\"text-align: justify;\">\u00centr-un studiu recent publicat s-a constatat c\u0103 muta\u021bia V600E este asociat\u0103 cu tumori ovariene \u00een stadiu ini\u021bial, histologie de tip borderline seros (cu poten\u021bial malign redus) \u0219i cu prognostic favorabil. Observa\u021biile pot influen\u021ba abordarea terapeutic\u0103 a pacientelor cu aceast\u0103 form\u0103 de tumori ovariene<sup>10<\/sup>.<\/p>\n<ul style=\"text-align: justify;\">\n<li><b><strong><u>Leucemia cu celule p\u0103roase (Hairy-cell Leukemia, HCL)<\/u><\/strong><\/b><\/li>\n<\/ul>\n<p style=\"text-align: justify;\">Muta\u021bia somatic\u0103 V600E a fost recent descris\u0103 ca un marker molecular pentru HCL. Deoarece prezen\u021ba sa a fost constatat\u0103 la majoritatea pacien\u021bilor se consider\u0103 c\u0103 muta\u021bia de\u021bine un rol esen\u021bial \u00een patogenia bolii. De asemenea formele refractare ar putea beneficia de tratamentul cu inhibitori BRAF<sup>11<\/sup>.<\/p>\n<ul style=\"text-align: justify;\">\n<li><b><strong><u>Cancerul colo-rectal (CRC)<\/u><\/strong><\/b><\/li>\n<\/ul>\n<p style=\"text-align: justify;\">Calea de semnalizare intracelular\u0103 MAPK\/ERK este perturbat\u0103 frecvent \u00een cancerul colo-rectal, supraexpresia EGFR fiind raportat\u0103 \u00een aproximativ 50% din cazuri, iar muta\u021bii activatoare ale genelor KRAS \u0219i BRAF \u00een 30-50% \u0219i, respectiv, 10% din cazuri<sup>3 <\/sup>(<em>vezi fig.1<\/em>)<\/p>\n<p style=\"text-align: justify;\">Celulele epiteliale normale din colon, \u00een evolu\u021bia lor spre malignitate, pot urma mai multe c\u0103i:<\/p>\n<ul style=\"text-align: justify;\">\n<li>secven\u021ba tradi\u021bional\u0103 adenom-carcinom asociat\u0103 cu instabilitate cromozomial\u0103 \u0219i caracterizat\u0103 prin acumularea treptat\u0103 de muta\u021bii ale unor gene specifice &#8211; APC, KRAS \u0219i TP53 &#8211; ce induc modific\u0103ri displazice progresive ale epiteliului colonic;<\/li>\n<li>o cale asociat\u0103 cu instabilitatea microsateli\u021bilor (MSI), muta\u021bii BRAF \u0219i metilarea extensiv\u0103 a ADN-ului;<\/li>\n<li>o cale de \u201cfuziune\u201d asociat\u0103 cu metilarea enzimei O-6 metilguanin-ADN-metiltransferaza (MGMT), muta\u021bia KRAS \u0219i inactivarea genei care codific\u0103 proteina tumoral\u0103 p53 (TP53).<\/li>\n<\/ul>\n<p style=\"text-align: justify;\">De\u0219i muta\u021biile BRAF au fost observate \u00een principal \u00een CRC sporadic cu MSI, acestea au fost detectate \u00eentr-un procent mic \u0219i \u00een formele de cancer cu stabilitate a microsateliti\u021bilor (MSS). \u00cen particular, muta\u021biile BRAF au fost g\u0103site mai frecvent \u00een polipii colonici premaligni \u0219i \u00een CRC timpuriu. Deoarece prezen\u021ba concomitent\u0103 a muta\u021biilor KRAS \u0219i BRAF este rar \u00eent\u00e2lnit\u0103 \u00een polipii colonici premaligni \u0219i \u00een stadiile timpurii de CRC, acestea sunt considerate muta\u021bii alternative sau muta\u021bii ce se exclud reciproc<sup>12<\/sup>.<\/p>\n<p style=\"text-align: justify;\">At\u00e2t muta\u021biile KRAS c\u00e2t \u0219i cele BRAF nu sunt dec\u00e2t \u00een mod excep\u021bional prezente \u00een CCR asociat cu sindromul Lynch (sindromul cancerului colorectal nonpolipozic ereditar &#8211; HNPCC). Aceast\u0103 afec\u021biune este cauzat\u0103 de muta\u021bii ale liniei germinale ce afecteaz\u0103 genele care intervin \u00een repararea erorilor ap\u0103rute la nivelul materialului genetic \u00een timpul procesului de replicare \u2013 MMR (MMR \u2013 \u201cmismatch repair genes\u201d) reprezentate de MLH1, MSH2, MSH6, PMS2. Alterarea func\u021biei acestor gene este str\u00e2ns asociat\u0103 cu fenomenul MSI, respectiv inser\u021bia sau dele\u021bia unor scurte unit\u0103\u021bi repetitive (tip CA) din constitu\u021bia microsateli\u021bilor (segmente de ADN alc\u0103tuite din secven\u021be care cuprind 1-5 perechi de nucleotide, repetate \u00een tandem \u0219i localizate \u00een regiunile codificatoare sau necodificatoare ale unor gene). Din acest motiv, testarea \u021besuturilor tumorale pentru prezen\u021ba MSI \u00eempreun\u0103 cu demonstrarea pierderii expresiei proteinelor MMR prin imunohistochimie este util\u0103 pentru stabilirea diagnosticului de sindrom Lynch. Totu\u0219i trebuie avut \u00een vedere faptul c\u0103 fenotipul tumoral asociat cu MSI nu este limitat la cancerele ereditare, fiind \u00eent\u00e2lnit \u0219i \u00een aproximativ 20% din cazurile de CRC sporadic. Astfel, testarea MSI nu poate distinge \u00eentre o muta\u021bie somatic\u0103 (sporadic\u0103) \u0219i o muta\u021biei a liniei germinale (mo\u0219tenit\u0103) \u0219i nici nu poate identifica gena afectat\u0103. De asemnea nici testarea imunohistochimic\u0103 nu poate face aceast\u0103 distinc\u021bie, de\u0219i identific\u0103 gena responsabil\u0103.<\/p>\n<p style=\"text-align: justify;\">Cel mai adesea prezen\u021ba unor defecte MMR \u00een CRC sporadic se datoreaz\u0103 unor anomalii la nivelul genei MLH1, iar cea mai frecvent\u0103 cauz\u0103 de inactivare a genei este hipermetilarea promotorului (fenomen epigenetic). Mai mult, \u00een aproximativ 70% din tumorile care prezint\u0103 hipermetilarea promotorului MLH1 a fost identificat\u0103 muta\u021bia BRAF V600E. Este important faptul c\u0103 muta\u021bia V600E nu a fost identificat\u0103 p\u00e2n\u0103 \u00een prezent \u00een tumori asociate cu muta\u021bii MLH1 ale liniei germinale. Astfel, testarea muta\u021biei BRAF V600E poate diferen\u021bia o muta\u021bie a liniei germinale de o inactivare somatic\u0103\/epigenetic\u0103 MLH1<sup>13<\/sup>.<\/p>\n<p style=\"text-align: justify;\">Testarea muta\u021biei V600E \u00een CRC prezint\u0103 \u0219i implica\u021bii terapeutice. Deoarece Braf kinaza este situat\u0103 \u00een aval de EGFR \u0219i KRAS \u00een cascada MAPK, tumorile ce con\u021bin muta\u021bia V600E cu activare persistent\u0103 a acestei c\u0103i de transduc\u021bie a semnalului sunt rezistente la orice tip de terapie anti-EGFR. <strong>Prin urmare, \u00eenainte de administrarea tratamentului cu inhibitori de tirozinkinaz\u0103 EGFR este necesar\u0103 testarea<\/strong> prezen\u021bei muta\u021biei V600E a genei BRAF pentru identificarea corect\u0103 a pacien\u021bilor care pot beneficia de terapie<sup>3<\/sup>.<\/p>\n<p style=\"text-align: justify;\"><strong><em>Recomand\u0103ri pentru testarea muta\u021biei BRAF V600E<\/em><\/strong><\/p>\n<ul style=\"text-align: justify;\">\n<li>\u00een CRC metastatic pentru selectarea pacien\u021bilor la care este oportun\u0103 administrarea unui inhibitor EGFR (marker molecular cu valoare predictiv\u0103 privind r\u0103spunsul la tratamentul anti-EGFR);<\/li>\n<li>screening-ul sindromului Linch \u00een cazul tumorilor cu MSI ce demonstreaz\u0103 imunohistochimic pierderea expresiei proteinei MLH1;<\/li>\n<li>\u00een melanomul malign pentru a anticipa r\u0103spunsul clinic la inhibitori BRAF (de exemplu vemurafenib) sau MEK;<\/li>\n<li>\u00een carcinomul tiroidian papilar pentru evaluarea prognosticului<sup>6;14<\/sup>.<\/li>\n<\/ul>\n<p style=\"text-align: justify;\"><strong><em>Specimen recoltat<\/em><\/strong> \u2013 sec\u021biuni nefixate, necolorate din \u021besut conservat \u00een parafin\u0103 (4-5 lame); cu ajutorul unui marker carioc\u0103 vor fi eviden\u021biate zonele \u00een care este prezent \u021besutul tumoral<sup>15<\/sup>.<\/p>\n<p style=\"text-align: justify;\"><strong><em>Metod\u0103 <\/em><\/strong>&#8211; <u>secven\u021bierea exonului 15 al genei BRAF<\/u><sup>15<\/sup>.<\/p>\n<p style=\"text-align: justify;\"><em><strong>Raportarea \u0219i interpretarea rezultatelor<\/strong><\/em><\/p>\n<p style=\"text-align: justify;\">Va fi comunicata prezen\u021ba sau absen\u021ba muta\u021biei BRAF V600E \u00een ADN-ul extras din \u021besutul tumoral<sup>15<\/sup>.<\/p>\n<p style=\"text-align: justify;\">Interpretarea rezultatului ob\u021binut este \u00een func\u021bie de tipul \u021besutului tumoral:<\/p>\n<ul style=\"text-align: justify;\">\n<li>\u00cen cancerul papilar tiroidian muta\u021bia BRAF V600E reprezint\u0103 un nou indicator de progresie \u0219i agresivitate a bolii.<\/li>\n<li>Pacien\u021bii cu melanom malign care prezint\u0103 muta\u021bia V600E pot beneficia de tratmentul cu vemurafenib.<\/li>\n<li>Tumorile colonice care prezint\u0103 al\u0103turi de hipermetilarea promotorului MLH1 \u0219i muta\u021bia BRAF V600E sunt cu mare probabilitate sporadice.<\/li>\n<li>Prezen\u021ba muta\u021biei V600E \u00een gena BRAF se asociaz\u0103 cu un prognostic nefavorabil \u0219i cu absen\u021ba r\u0103punsului la tratamentul cu anti-EGFR a pacien\u021bilor cu tumori metastatice de colon<sup>6;13;14<\/sup>.<\/li>\n<\/ul>\n<p style=\"text-align: justify;\"><strong><em>Limite \u0219i interferen\u021be<\/em><\/strong><\/p>\n<div style=\"text-align: justify;\">Muta\u021bia BRAF V600E poate fi detectat\u0103 numai dac\u0103 \u00een prob\u0103 se g\u0103se\u0219te un procent de celule tumorale de minimum 25%<sup>14;15<\/sup>.<\/div>\n<div style=\"text-align: justify;\">Testarea muta\u021biei \u00een tumora primar\u0103 vs. leziunile metastatice poate da uneori rezultate discordante.<\/div>\n<div style=\"text-align: justify;\">Nu to\u021bi pacien\u021bii cu melanom malign av\u00e2nd muta\u021bia V600E vor r\u0103spunde la tratamentul anti-BRAF.<\/div>\n<div style=\"text-align: justify;\">Nu to\u021bi pacien\u021bii cu CCR metastic \u0219i gen\u0103 BRAF de tip s\u0103lbatic vor benficia de terapia anti-EGFR<sup>13<\/sup>.<\/div>\n<p style=\"text-align: justify;\"><span style=\"font-size: 10pt;\"><strong>\u0411\u0438\u0431\u043b\u0438\u043e\u0433\u0440\u0430\u0444\u0438\u044f<\/strong><\/span><\/p>\n<div>1.\u00a0<span style=\"font-size: 10pt;\">BRAF (v-raf murine sarcoma viral oncogene homolog B1). In Atlas of Genetics and Cytogenetics in Oncology and Haematology. <a href=\"http:\/\/atlasgeneticsoncology.org\/Genes\/BRAFID828.html\" rel=\"nofollow noopener\" target=\"_blank\">http:\/\/atlasgeneticsoncology.org<\/a>. Reference Type: Internet Communication.<\/span><\/div>\n<div><span style=\"font-size: 10pt;\">2.\u00a0Safaee Ardekani G, Jafarnejad SN, Tan L, Saeedi A, Li G. The Prognostic Value of <em>BRAF<\/em> Mutation in Colorectal Cancer and Melanoma: A Systematic Review and Meta-Analysis. In <em>PloS<\/em> 2012;7(10):e47054.<\/span><\/div>\n<div><span style=\"font-size: 10pt;\">3. \u00a0Tie J, \u00a0Desai J.\u00a0 BRAFV600E as a Therapeutic Target in Colorectal Cancer. In <em>European Oncology<\/em>,\u00a02010:6(1):60-4.\u00a0\u00a0\u00a0<\/span><\/div>\n<div><span style=\"font-size: 10pt;\">4.\u00a0BRAF (v-raf murine sarcoma viral oncogene homolog B1). <a href=\"http:\/\/www.ncbi.nlm.nih.gov\/\" rel=\"nofollow noopener\" target=\"_blank\">www.ncbi.nlm.nih.gov<\/a>. Reference Type:Internet Communication.<\/span><\/div>\n<div><span style=\"font-size: 10pt;\">5.\u00a0Sarcozy A, Carta C et al. Germline BRAF mutations in Noonan, LEOPARD and cardiofaciocutaneous Syndrome: moleculatr diversity and associted phenotypic spectrum. In <em>Hum. Mutat<\/em>. 2009 Apr;30(4):695-702.<\/span><\/div>\n<div><span style=\"font-size: 10pt;\">6. BRAF V600E Mutation Detection. Henry Ford Health System. Pathology and Laboratory \u00a0Medicine. www.henryford.com. Reference Type:\u00a0 Internet Communication.\u00a0<\/span><\/div>\n<div><span style=\"font-size: 10pt;\">7. Elisei R, Ugolini C et al. BRAF<sup>V600E<\/sup> Mutation and Outcome of Patients with Papillary Thyroid Carcinoma: A 15-Year Median Follow-Up Study. In <em>J. Clin. Endocrinol. Metab<\/em>. 2008 Oct;93(10):3943-9.<\/span><\/div>\n<div><span style=\"font-size: 10pt;\">8. Vora N, Buehler B et al. Melanoma and BRAF. Medscape Reference. <a href=\"http:\/\/emedicine.medscape.com\/\" rel=\"nofollow noopener\" target=\"_blank\">http:\/\/emedicine.medscape.com<\/a>. 2011.<\/span><\/div>\n<div><span style=\"font-size: 10pt;\">9. Marchetti A, Felicioni L, et al. Clinical features and Outcome of patients with Non-Small-Cell Lung Cancer Harboring BRAF Mutations. In JCO Sept. 2011, vol.29, no.26, 3574-3579.<\/span><\/div>\n<div style=\"text-align: justify;\"><span style=\"font-size: 10pt;\">10. Grisham RN, Iyer G, et al. BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer. In <em>Cancer<\/em> 2013 Feb 1;119(3):548-54.<\/span><\/div>\n<div style=\"text-align: justify;\"><span style=\"font-size: 10pt;\">11. Dietrich S, Glimm H. BRAF Inhibition in Refractory\u00a0 Hairy-Cell Leukemia. In <em>N Engl J Med<\/em> 2012; 366:2038-2040.<\/span><\/div>\n<div style=\"text-align: justify;\"><span style=\"font-size: 10pt;\">12. <a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/?term=Monticone%20M%5Bauth%5D\" rel=\"nofollow noopener\" target=\"_blank\">Monticone<\/a> M,<a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/?term=Biollo%20E%5Bauth%5D\" rel=\"nofollow noopener\" target=\"_blank\"> Biollo<\/a> E et al. Gene expression deregulation by <em>KRAS <\/em>G12D and G12V in a <em>BRAF <\/em>V600E context. In <em>Mol Cancer<\/em>, 2008;7: 92.<\/span><\/div>\n<div style=\"text-align: justify;\"><span style=\"font-size: 10pt;\">13.\u00a0Mayo Clinic. Mayo Medical Laboratories. BRAF Mutation (V600E) Analysis. <a href=\"http:\/\/www.mayomedicallaboratories.com\/\" rel=\"nofollow noopener\" target=\"_blank\">www.mayomedicallaboratories.com<\/a>. Reference Type: Internet Communication, 2016.<\/span><\/div>\n<div style=\"text-align: justify;\"><span style=\"font-size: 10pt;\">14.\u00a0Cleveland Clinic Laboratories. BRAF V600E Mutation Analysis. Reference Type\u00a0: Internet Communication, 2016.<\/span><\/div>\n<div style=\"text-align: justify;\"><span style=\"font-size: 10pt;\">15. Laborator Synevo. Referin\u021bele specifice tehnologiei de lucru utilizate 2016. Ref Type: Catalog.<\/span><\/div>\n<p style=\"text-align: justify;\">","protected":false},"excerpt":{"rendered":"<p>\u041d\u0430\u043b\u0438\u0447\u0438\u0435 \u043c\u0443\u0442\u0430\u0446\u0438\u0438 V600E \u0432 \u0433\u0435\u043d\u0435 BRAF \u2013 \u043f\u0440\u0435\u0434\u0438\u043a\u0442\u043e\u0440 \u043e\u0442\u0432\u0435\u0442\u0430 \u043d\u0430 \u043a\u043e\u043c\u0431\u0438\u043d\u0438\u0440\u043e\u0432\u0430\u043d\u043d\u0443\u044e \u0442\u0430\u0440\u0433\u0435\u0442\u043d\u0443\u044e \u0442\u0435\u0440\u0430\u043f\u0438\u044e \u0442\u0438\u0440\u043e\u0437\u0438\u043d\u043a\u0438\u043d\u0430\u0437\u043d\u044b\u043c\u0438 \u0438\u043d\u0433\u0438\u0431\u0438\u0442\u043e\u0440\u0430\u043c\u0438 BRAF\/MEK \u0443 \u043f\u0430\u0446\u0438\u0435\u043d\u0442\u043e\u0432 \u0441 \u043c\u0435\u043b\u0430\u043d\u043e\u043c\u043e\u0439 \u043a\u043e\u0436\u0438 \u0440\u0435\u0437\u0435\u043a\u0442\u0430\u0431\u0435\u043b\u044c\u043d\u043e\u0439 \u0438 \u043d\u0435\u0440\u0435\u0437\u0435\u043a\u0442\u0430\u0431\u0435\u043b\u044c\u043d\u043e\u0439 III \u0441\u0442\u0430\u0434\u0438\u0438 \u0438 IV \u0441\u0442\u0430\u0434\u0438\u0439, \u0443 \u043f\u0430\u0446\u0438\u0435\u043d\u0442\u043e\u0432 \u0441 \u043c\u0435\u0442\u0430\u0441\u0442\u0430\u0442\u0438\u0447\u0435\u0441\u043a\u0438\u043c \u043d\u0435\u043c\u0435\u043b\u043a\u043e\u043a\u043b\u0435\u0442\u043e\u0447\u043d\u044b\u043c \u0440\u0430\u043a\u043e\u043c \u043b\u0435\u0433\u043a\u043e\u0433\u043e, \u0443 \u043f\u0430\u0446\u0438\u0435\u043d\u0442\u043e\u0432 \u0441 \u043c\u0435\u0442\u0430\u0441\u0442\u0430\u0442\u0438\u0447\u0435\u0441\u043a\u0438\u043c \u041a\u0420\u0420, \u0443 \u043f\u0430\u0446\u0438\u0435\u043d\u0442\u043e\u0432 \u0441 \u043c\u0435\u0442\u0430\u0441\u0442\u0430\u0442\u0438\u0447\u0435\u0441\u043a\u0438\u043c \u0440\u0430\u043a\u043e\u043c \u0449\u0438\u0442\u043e\u0432\u0438\u0434\u043d\u043e\u0439 \u0436\u0435\u043b\u0435\u0437\u044b. \u0422\u0430\u043a\u0436\u0435 \u0438\u0441\u0441\u043b\u0435\u0434\u043e\u0432\u0430\u043d\u0438\u0435 \u043d\u0430 \u043d\u0430\u043b\u0438\u0447\u0438\u0435 \u043c\u0443\u0442\u0430\u0446\u0438\u0438 V600E \u0432 \u0433\u0435\u043d\u0435 BRAF \u0440\u0435\u043a\u043e\u043c\u0435\u043d\u0434\u043e\u0432\u0430\u043d\u043e \u0434\u043b\u044f \u0434\u0438\u0430\u0433\u043d\u043e\u0441\u0442\u0438\u043a\u0438 \u0440\u0430\u043a\u0430 \u0449\u0438\u0442\u043e\u0432\u0438\u0434\u043d\u043e\u0439 \u0436\u0435\u043b\u0435\u0437\u044b \u0438 \u0434\u043b\u044f \u043f\u043e\u0441\u043b\u0435\u043e\u043f\u0435\u0440\u0430\u0446\u0438\u043e\u043d\u043d\u043e\u0439 \u0441\u0442\u0440\u0430\u0442\u0438\u0444\u0438\u043a\u0430\u0446\u0438\u0438 \u0440\u0438\u0441\u043a\u0430 \u0440\u0435\u0446\u0438\u0434\u0438\u0432\u0430 \u0440\u0430\u043a\u0430 \u0449\u0438\u0442\u043e\u0432\u0438\u0434\u043d\u043e\u0439 \u0436\u0435\u043b\u0435\u0437\u044b \u0432 \u0446\u0435\u043b\u044f\u0445 \u043e\u043f\u0440\u0435\u0434\u0435\u043b\u0435\u043d\u0438\u044f \u043f\u043e\u0441\u043b\u0435\u043e\u043f\u0435\u0440\u0430\u0446\u0438\u043e\u043d\u043d\u043e\u0439 \u0442\u0430\u043a\u0442\u0438\u043a\u0438 \u0432\u0435\u0434\u0435\u043d\u0438\u044f \u043f\u0430\u0446\u0438\u0435\u043d\u0442\u043e\u0432.<\/p>\n<p><strong>\u041e\u0431\u0449\u0430\u044f \u0438\u043d\u0444\u043e\u0440\u043c\u0430\u0446\u0438\u044f \u043e\u0431 \u0438\u0441\u0441\u043b\u0435\u0434\u043e\u0432\u0430\u043d\u0438\u0438<\/strong><\/p>\n<p>BRAF \u043f\u0440\u0435\u0434\u0441\u0442\u0430\u0432\u043b\u044f\u0435\u0442 \u0441\u043e\u0431\u043e\u0439 \u0441\u0435\u0440\u0438\u043d \/ \u0442\u0440\u0435\u043e\u043d\u0438\u043d\u043e\u0432\u0443\u044e \u043f\u0440\u043e\u0442\u0435\u0438\u043d\u043a\u0438\u043d\u0430\u0437\u0443, \u043a\u043e\u0442\u043e\u0440\u0430\u044f \u0438\u0433\u0440\u0430\u0435\u0442 \u0432\u0430\u0436\u043d\u0443\u044e \u0440\u043e\u043b\u044c \u0432 \u0441\u0438\u0433\u043d\u0430\u043b\u044c\u043d\u043e\u043c \u043f\u0443\u0442\u0438 RAS-RAF-MEK-ERK (MAPK). \u0410\u043a\u0442\u0438\u0432\u0430\u0446\u0438\u044f \u044d\u0442\u043e\u0433\u043e \u043f\u0443\u0442\u0438 \u043f\u0435\u0440\u0435\u0434\u0430\u0435\u0442 \u0432\u043d\u0435\u043a\u043b\u0435\u0442\u043e\u0447\u043d\u044b\u0435 \u0441\u0438\u0433\u043d\u0430\u043b\u044b \u0432 \u043a\u043b\u0435\u0442\u043a\u0443 \u0447\u0435\u0440\u0435\u0437 \u043a\u0430\u0441\u043a\u0430\u0434 \u0441\u043e\u0431\u044b\u0442\u0438\u0439 \u0444\u043e\u0441\u0444\u043e\u0440\u0438\u043b\u0438\u0440\u043e\u0432\u0430\u043d\u0438\u044f, \u0447\u0442\u043e \u043f\u0440\u0438\u0432\u043e\u0434\u0438\u0442 \u043a \u0438\u0437\u043c\u0435\u043d\u0435\u043d\u0438\u044e \u044d\u043a\u0441\u043f\u0440\u0435\u0441\u0441\u0438\u0438 \u0433\u0435\u043d\u043e\u0432, \u0440\u043e\u0441\u0442\u0443, \u0432\u044b\u0436\u0438\u0432\u0430\u043d\u0438\u044e \u0438 \u0434\u0438\u0444\u0444\u0435\u0440\u0435\u043d\u0446\u0438\u0440\u043e\u0432\u043a\u0435 \u043a\u043b\u0435\u0442\u043e\u043a \u0432 \u043d\u043e\u0440\u043c\u0430\u043b\u044c\u043d\u044b\u0445 \u0438 \u0442\u0440\u0430\u043d\u0441\u0444\u043e\u0440\u043c\u0438\u0440\u043e\u0432\u0430\u043d\u043d\u044b\u0445 \u043a\u043b\u0435\u0442\u043a\u0430\u0445. \u0411\u043e\u043b\u044c\u0448\u0438\u043d\u0441\u0442\u0432\u043e \u043c\u0443\u0442\u0430\u0446\u0438\u0439 BRAF \u043f\u0440\u043e\u0438\u0441\u0445\u043e\u0434\u0438\u0442 \u0432 \u043a\u0438\u043d\u0430\u0437\u043d\u043e\u043c \u0434\u043e\u043c\u0435\u043d\u0435, \u0447\u0442\u043e \u043f\u0440\u0438\u0432\u043e\u0434\u0438\u0442 \u043a \u043a\u043e\u043d\u0441\u0442\u0438\u0442\u0443\u0442\u0438\u0432\u043d\u043e\u0439 \u0430\u043a\u0442\u0438\u0432\u0430\u0446\u0438\u0438 BRAF \u0438 \u0444\u043e\u0441\u0444\u043e\u0440\u0438\u043b\u0438\u0440\u043e\u0432\u0430\u043d\u0438\u044e MEK, \u043d\u0435\u0437\u0430\u0432\u0438\u0441\u0438\u043c\u043e \u043e\u0442 \u043f\u0440\u0435\u0434\u0448\u0435\u0441\u0442\u0432\u0443\u044e\u0449\u0435\u0439 \u0430\u043a\u0442\u0438\u0432\u0430\u0446\u0438\u0438 \u0442\u0438\u0440\u043e\u0437\u0438\u043d\u043a\u0438\u043d\u0430\u0437\u043d\u044b\u043c\u0438 \u0440\u0435\u0446\u0435\u043f\u0442\u043e\u0440\u0430\u043c\u0438 \u0438\u043b\u0438 RAS. \u042d\u0442\u043e \u043e\u0431\u0443\u0441\u043b\u0430\u0432\u043b\u0438\u0432\u0430\u0435\u0442 \u043a\u043e\u043d\u0441\u0442\u0438\u0442\u0443\u0442\u0438\u0432\u043d\u0443\u044e \u0430\u043a\u0442\u0438\u0432\u0430\u0446\u0438\u044e ERK, \u043a\u043e\u0442\u043e\u0440\u0430\u044f \u043f\u0440\u0438\u0432\u043e\u0434\u0438\u0442 \u043a \u0441\u0442\u0438\u043c\u0443\u043b\u0438\u0440\u043e\u0432\u0430\u043d\u0438\u044e \u043a\u043b\u0435\u0442\u043e\u0447\u043d\u043e\u0433\u043e \u0440\u043e\u0441\u0442\u0430 \u0438 \u0443\u043a\u043b\u043e\u043d\u0435\u043d\u0438\u044e \u043e\u0442 \u0430\u043f\u043e\u043f\u0442\u043e\u0437\u0430 \u0438 \u043a \u043d\u0435\u043e\u043f\u043b\u0430\u0441\u0442\u0438\u0447\u0435\u0441\u043a\u043e\u0439 \u0442\u0440\u0430\u043d\u0441\u0444\u043e\u0440\u043c\u0430\u0446\u0438\u0438. \u041d\u0430\u0438\u0431\u043e\u043b\u0435\u0435 \u0447\u0430\u0441\u0442\u0430\u044f \u043c\u0443\u0442\u0430\u0446\u0438\u044f BRAF, \u043e\u0431\u043d\u0430\u0440\u0443\u0436\u0438\u0432\u0430\u0435\u043c\u0430\u044f \u0431\u043e\u043b\u0435\u0435 \u0447\u0435\u043c \u0432 90 % \u043e\u043f\u0443\u0445\u043e\u043b\u0435\u0439 \u0441 \u043c\u0443\u0442\u0430\u0446\u0438\u0435\u0439 BRAF, \u043f\u0440\u0435\u0434\u0441\u0442\u0430\u0432\u043b\u044f\u0435\u0442 \u0441\u043e\u0431\u043e\u0439 \u0437\u0430\u043c\u0435\u043d\u0443 \u0432\u0430\u043b\u0438\u043d\u0430 \u043d\u0430 \u0433\u043b\u0443\u0442\u0430\u043c\u0438\u043d\u043e\u0432\u0443\u044e \u043a\u0438\u0441\u043b\u043e\u0442\u0443 \u043f\u043e \u0430\u043c\u0438\u043d\u043e\u043a\u0438\u0441\u043b\u043e\u0442\u0435 600 (V600E) \u0432 \u043a\u0438\u043d\u0430\u0437\u043d\u043e\u043c \u0434\u043e\u043c\u0435\u043d\u0435. \u042d\u0442\u0430 \u0437\u0430\u043c\u0435\u043d\u0430 \u0438\u043c\u0438\u0442\u0438\u0440\u0443\u0435\u0442 \u0444\u043e\u0441\u0444\u043e\u0440\u0438\u043b\u0438\u0440\u043e\u0432\u0430\u043d\u0438\u0435 \u043f\u0435\u0442\u043b\u0438 \u0430\u043a\u0442\u0438\u0432\u0430\u0446\u0438\u0438, \u0442\u0435\u043c \u0441\u0430\u043c\u044b\u043c \u0438\u043d\u0434\u0443\u0446\u0438\u0440\u0443\u044f \u043a\u043e\u043d\u0441\u0442\u0438\u0442\u0443\u0442\u0438\u0432\u043d\u0443\u044e \u0430\u043a\u0442\u0438\u0432\u043d\u043e\u0441\u0442\u044c \u043f\u0440\u043e\u0442\u0435\u0438\u043d\u043a\u0438\u043d\u0430\u0437\u044b BRAF. BRAF-\u043c\u0443\u0442\u0430\u0446\u0438\u0438 \u0431\u044b\u043b\u0438 \u043e\u043f\u0438\u0441\u0430\u043d\u044b \u043f\u0440\u0438 \u043c\u0435\u043b\u0430\u043d\u043e\u043c\u0435 (50-60 %), \u043a\u043e\u043b\u043e\u0440\u0435\u043a\u0442\u0430\u043b\u044c\u043d\u043e\u043c \u0440\u0430\u043a\u0435 (10 %), \u043a\u0430\u0440\u0446\u0438\u043d\u043e\u043c\u0430\u0445 \u0449\u0438\u0442\u043e\u0432\u0438\u0434\u043d\u043e\u0439 \u0436\u0435\u043b\u0435\u0445\u044b (30-50 %) \u0438 \u043d\u0435\u043c\u0435\u043b\u043a\u043e\u043a\u043b\u0435\u0442\u043e\u0447\u043d\u043e\u043c \u0440\u0430\u043a\u0435 \u043b\u0435\u0433\u043a\u043e\u0433\u043e (3 %).<\/p>\n<p>\u0418\u0434\u0435\u043d\u0442\u0438\u0444\u0438\u043a\u0430\u0446\u0438\u044f \u043c\u0443\u0442\u0430\u0446\u0438\u0438 V600E\u0432 \u0433\u0435\u043d\u0435 BRAF \u0432 \u0440\u0430\u0437\u043b\u0438\u0447\u043d\u044b\u0445 \u0442\u0438\u043f\u0430\u0445 \u043c\u0435\u0442\u0430\u0441\u0442\u0430\u0442\u0438\u0447\u0435\u0441\u043a\u0438\u0445 \u0437\u043b\u043e\u043a\u0430\u0447\u0435\u0441\u0442\u0432\u0435\u043d\u043d\u044b\u0445 \u043e\u043f\u0443\u0445\u043e\u043b\u0435\u0439 (\u043c\u0435\u043b\u0430\u043d\u043e\u043c\u0430 \u043a\u043e\u0436\u0438, \u043a\u043e\u043b\u043e\u0440\u0435\u043a\u0442\u0430\u043b\u044c\u043d\u044b\u0439 \u0440\u0430\u043a, \u043d\u0435\u043c\u0435\u043b\u043a\u043e\u043a\u043b\u0435\u0442\u043e\u0447\u043d\u044b\u0439 \u0440\u0430\u043a \u043b\u0435\u0433\u043a\u043e\u0433\u043e) \u0441\u043b\u0443\u0436\u0438\u0442 \u043f\u043e\u043a\u0430\u0437\u0430\u043d\u0438\u0435\u043c \u043a \u043d\u0430\u0437\u043d\u0430\u0447\u0435\u043d\u0438\u044e \u0410\u0422\u0424-\u043a\u043e\u043d\u043a\u0443\u0440\u0435\u043d\u0442\u043d\u044b\u0445 \u0438\u043d\u0433\u0438\u0431\u0438\u0442\u043e\u0440\u043e\u0432 BRAF \u0432 \u043c\u043e\u043d\u043e\u0442\u0435\u0440\u0430\u043f\u0438\u0438 \u043b\u0438\u0431\u043e \u0432 \u043a\u043e\u043c\u0431\u0438\u043d\u0430\u0446\u0438\u0438 \u0441 \u0438\u043d\u0433\u0438\u0431\u0438\u0442\u043e\u0440\u0430\u043c\u0438 MEK.<\/p>\n<p>\u041c\u0443\u0442\u0430\u0446\u0438\u044f BRAF V600E \u043f\u0440\u0435\u0434\u0441\u0442\u0430\u0432\u043b\u044f\u0435\u0442 \u0441\u043e\u0431\u043e\u0439 \u043d\u0430\u0438\u0431\u043e\u043b\u0435\u0435 \u0447\u0430\u0441\u0442\u0443\u044e \u0430\u0431\u0435\u0440\u0440\u0430\u0446\u0438\u044e, \u043e\u0431\u043d\u0430\u0440\u0443\u0436\u0438\u0432\u0430\u0435\u043c\u0443\u044e \u043f\u0440\u0438 \u043f\u0430\u043f\u0438\u043b\u043b\u044f\u0440\u043d\u043e\u043c \u0440\u0430\u043a\u0435 \u0449\u0438\u0442\u043e\u0432\u0438\u0434\u043d\u043e\u0439 \u0436\u0435\u043b\u0435\u0437\u044b (40-50 % \u0441\u043b\u0443\u0447\u0430\u0435\u0432). \u0422\u0430\u043a\u0436\u0435 \u0434\u0430\u043d\u043d\u0430\u044f \u043c\u0443\u0442\u0430\u0446\u0438\u044f \u0432\u0441\u0442\u0440\u0435\u0447\u0430\u0435\u0442\u0441\u044f \u0432 20-40 % \u0441\u043b\u0443\u0447\u0430\u0435\u0432 \u043d\u0438\u0437\u043a\u043e\u0434\u0438\u0444\u0444\u0435\u0440\u0435\u043d\u0446\u0438\u0440\u043e\u0432\u0430\u043d\u043d\u044b\u0445 \u043a\u0430\u0440\u0446\u0438\u043d\u043e\u043c \u0438 30-40 % \u0441\u043b\u0443\u0447\u0430\u0435\u0432 \u0430\u043d\u0430\u043f\u043b\u0430\u0441\u0442\u0438\u0447\u0435\u0441\u043a\u0438\u0445 \u043a\u0430\u0440\u0446\u0438\u043d\u043e\u043c. \u041d\u0430\u043b\u0438\u0447\u0438\u0435 \u043c\u0443\u0442\u0430\u0446\u0438\u0438 BRAF V600E \u043e\u0431\u0443\u0441\u043b\u0430\u0432\u043b\u0438\u0432\u0430\u0435\u0442 \u0440\u0438\u0441\u043a \u043e\u0431\u043d\u0430\u0440\u0443\u0436\u0435\u043d\u0438\u044f \u0437\u043b\u043e\u043a\u0430\u0447\u0435\u0441\u0442\u0432\u0435\u043d\u043d\u043e\u0439 \u043e\u043f\u0443\u0445\u043e\u043b\u0438 \u0432 \u0446\u0438\u0442\u043e\u043b\u043e\u0433\u0438\u0447\u0435\u0441\u043a\u043e\u043c \u043c\u0430\u0442\u0435\u0440\u0438\u0430\u043b\u0435 \u043a\u0430\u0442\u0435\u0433\u043e\u0440\u0438\u0438 Bethesda III-V \u0432 &gt; 95 % \u0441\u043b\u0443\u0447\u0430\u0435\u0432. \u041e\u043f\u0440\u0435\u0434\u0435\u043b\u0435\u043d\u0438\u0435 \u043c\u0443\u0442\u0430\u0446\u0438\u0438 BRAF V600E \u0440\u0435\u043a\u043e\u043c\u0435\u043d\u0434\u043e\u0432\u0430\u043d\u043e \u0432\u0441\u0435\u043c \u043f\u0430\u0446\u0438\u0435\u043d\u0442\u0430\u043c \u0441 \u0432\u044b\u0441\u043e\u043a\u043e\u0434\u0438\u0444\u0444\u0435\u0440\u0435\u043d\u0446\u0438\u0440\u043e\u0432\u0430\u043d\u043d\u044b\u043c \u0440\u0430\u043a\u043e\u043c \u0449\u0438\u0442\u043e\u0432\u0438\u0434\u043d\u043e\u0439 \u0436\u0435\u043b\u0435\u0437\u044b \u0434\u043b\u044f \u043f\u043e\u0441\u043b\u0435\u043e\u043f\u0435\u0440\u0430\u0446\u0438\u043e\u043d\u043d\u043e\u0439 \u0441\u0442\u0440\u0430\u0442\u0438\u0444\u0438\u043a\u0430\u0446\u0438\u0438 \u0440\u0438\u0441\u043a\u0430 \u0440\u0435\u0446\u0438\u0434\u0438\u0432\u0430 \u0432 \u0446\u0435\u043b\u044f\u0445 \u043e\u043f\u0440\u0435\u0434\u0435\u043b\u0435\u043d\u0438\u044f \u0442\u0430\u043a\u0442\u0438\u043a\u0438 \u0432\u0435\u0434\u0435\u043d\u0438\u044f \u043f\u0430\u0446\u0438\u0435\u043d\u0442\u043e\u0432.<\/p>\n<p><strong>\u0414\u043b\u044f \u0447\u0435\u0433\u043e \u0438\u0441\u043f\u043e\u043b\u044c\u0437\u0443\u0435\u0442\u0441\u044f \u0438\u0441\u0441\u043b\u0435\u0434\u043e\u0432\u0430\u043d\u0438\u0435?<\/strong><\/p>\n<p>\u0414\u043b\u044f \u043e\u043f\u0440\u0435\u0434\u0435\u043b\u0435\u043d\u0438\u044f \u043f\u043e\u043a\u0430\u0437\u0430\u043d\u0438\u0439 \u043a \u043f\u0440\u0438\u043c\u0435\u043d\u0435\u043d\u0438\u044e \u043a\u043e\u043c\u0431\u0438\u043d\u0438\u0440\u043e\u0432\u0430\u043d\u043d\u043e\u0439 \u0442\u0430\u0440\u0433\u0435\u0442\u043d\u043e\u0439 \u0442\u0435\u0440\u0430\u043f\u0438\u0438 \u0442\u0438\u0440\u043e\u0437\u0438\u043d\u043a\u0438\u043d\u0430\u0437\u043d\u044b\u043c\u0438 \u0438\u043d\u0433\u0438\u0431\u0438\u0442\u043e\u0440\u0430\u043c\u0438 BRAF\/MEK \u043f\u0440\u0438 \u043c\u0435\u043b\u0430\u043d\u043e\u043c\u0435 \u043a\u043e\u0436\u0438, \u043d\u0435\u043c\u0435\u043b\u043a\u043e\u043a\u043b\u0435\u0442\u043e\u0447\u043d\u043e\u043c \u0440\u0430\u043a\u0435 \u043b\u0435\u0433\u043a\u043e\u0433\u043e, \u043a\u043e\u043b\u043e\u0440\u0435\u043a\u0442\u0430\u043b\u044c\u043d\u043e\u043c \u0440\u0430\u043a\u0435 \u0438 \u0440\u0430\u043a\u0435 \u0449\u0438\u0442\u043e\u0432\u0438\u0434\u043d\u043e\u0439 \u0436\u0435\u043b\u0435\u0437\u044b. \u0418\u0441\u0441\u043b\u0435\u0434\u043e\u0432\u0430\u043d\u0438\u0435 \u043c\u0443\u0442\u0430\u0446\u0438\u0438 \u0442\u0430\u043a\u0436\u0435 \u0438\u0441\u043f\u043e\u043b\u044c\u0437\u0443\u0435\u0442\u0441\u044f \u0434\u043b\u044f \u0434\u0438\u0430\u0433\u043d\u043e\u0441\u0442\u0438\u043a\u0438 \u0440\u0430\u043a\u0430 \u0449\u0438\u0442\u043e\u0432\u0438\u0434\u043d\u043e\u0439 \u0436\u0435\u043b\u0435\u0437\u044b \u0438 \u043f\u043e\u0441\u043b\u0435\u043e\u043f\u0435\u0440\u0430\u0446\u0438\u043e\u043d\u043d\u043e\u0439 \u0441\u0442\u0440\u0430\u0442\u0438\u0444\u0438\u043a\u0430\u0446\u0438\u0438 \u0440\u0438\u0441\u043a\u0430 \u0440\u0435\u0446\u0438\u0434\u0438\u0432\u0430 \u0440\u0430\u043a\u0430 \u0449\u0438\u0442\u043e\u0432\u0438\u0434\u043d\u043e\u0439 \u0436\u0435\u043b\u0435\u0437\u044b.<\/p>\n<p><strong>\u041a\u043e\u0433\u0434\u0430 \u043d\u0430\u0437\u043d\u0430\u0447\u0430\u0435\u0442\u0441\u044f \u0438\u0441\u0441\u043b\u0435\u0434\u043e\u0432\u0430\u043d\u0438\u0435?<\/strong><\/p>\n<p>\u0420\u0435\u043a\u043e\u043c\u0435\u043d\u0434\u043e\u0432\u0430\u043d\u043e \u0432\u0441\u0435\u043c \u043f\u0430\u0446\u0438\u0435\u043d\u0442\u0430\u043c \u0441 \u043c\u0435\u043b\u0430\u043d\u043e\u043c\u043e\u0439 \u043a\u043e\u0436\u0438 \u0440\u0435\u0437\u0435\u043a\u0442\u0430\u0431\u0435\u043b\u044c\u043d\u043e\u0439 \u0438 \u043d\u0435\u0440\u0435\u0437\u0435\u043a\u0442\u0430\u0431\u0435\u043b\u044c\u043d\u043e\u0439 III \u0438 IV \u0441\u0442\u0430\u0434\u0438\u0439, \u043c\u0435\u0441\u0442\u043d\u043e-\u0440\u0430\u0441\u043f\u0440\u043e\u0441\u0442\u0440\u0430\u043d\u0435\u043d\u043d\u044b\u043c \u0438 \u043c\u0435\u0442\u0430\u0441\u0442\u0430\u0442\u0438\u0447\u0435\u0441\u043a\u0438\u043c \u043d\u0435\u043c\u0435\u043b\u043a\u043e\u043a\u043b\u0435\u0442\u043e\u0447\u043d\u044b\u043c \u0440\u0430\u043a\u043e\u043c \u043b\u0435\u0433\u043a\u043e\u0433\u043e, \u043c\u0435\u0442\u0430\u0441\u0442\u0430\u0442\u0438\u0447\u0435\u0441\u043a\u0438\u043c \u043a\u043e\u043b\u043e\u0440\u0435\u043a\u0442\u0430\u043b\u044c\u043d\u044b\u043c \u0440\u0430\u043a\u043e\u043c, \u043c\u0435\u0442\u0430\u0441\u0442\u0430\u0442\u0438\u0447\u0435\u0441\u043a\u0438\u043c \u0440\u0430\u043a\u043e\u043c \u0449\u0438\u0442\u043e\u0432\u0438\u0434\u043d\u043e\u0439 \u0436\u0435\u043b\u0435\u0437\u044b \u0434\u043b\u044f \u043e\u043f\u0440\u0435\u0434\u0435\u043b\u0435\u043d\u0438\u044f \u0432\u043e\u0437\u043c\u043e\u0436\u043d\u043e\u0441\u0442\u0438 \u043f\u0440\u0438\u043c\u0435\u043d\u0435\u043d\u0438\u044f \u043a\u043e\u043c\u0431\u0438\u043d\u0438\u0440\u043e\u0432\u0430\u043d\u043d\u043e\u0439 \u0442\u0430\u0440\u0433\u0435\u0442\u043d\u043e\u0439 \u0442\u0435\u0440\u0430\u043f\u0438\u0438 \u0442\u0438\u0440\u043e\u0437\u0438\u043d\u043a\u0438\u043d\u0430\u0437\u043d\u044b\u043c\u0438 \u0438\u043d\u0433\u0438\u0431\u0438\u0442\u043e\u0440\u0430\u043c\u0438 BRAF\/MEK.<br \/>\n\u0420\u0435\u043a\u043e\u043c\u0435\u043d\u0434\u043e\u0432\u0430\u043d\u043e \u0432\u0441\u0435\u043c \u043f\u0430\u0446\u0438\u0435\u043d\u0442\u0430\u043c \u0441 \u043f\u043e\u0434\u043e\u0437\u0440\u0435\u043d\u0438\u0435\u043c \u043d\u0430 \u0440\u0430\u043a \u0449\u0438\u0442\u043e\u0432\u0438\u0434\u043d\u043e\u0439 \u0436\u0435\u043b\u0435\u0437\u044b (\u043a\u0430\u0442\u0435\u0433\u043e\u0440\u0438\u044f Bethesda III-V) \u0434\u043b\u044f \u0434\u0438\u0430\u0433\u043d\u043e\u0441\u0442\u0438\u043a\u0438 \u0437\u043b\u043e\u043a\u0430\u0447\u0435\u0441\u0442\u0432\u0435\u043d\u043d\u043e\u0433\u043e \u043f\u0440\u043e\u0446\u0435\u0441\u0441\u0430, \u0430 \u0442\u0430\u043a\u0436\u0435 \u0434\u043b\u044f \u043f\u043e\u0441\u043b\u0435\u043e\u043f\u0435\u0440\u0430\u0446\u0438\u043e\u043d\u043d\u043e\u0439 \u0441\u0442\u0440\u0430\u0442\u0438\u0444\u0438\u043a\u0430\u0446\u0438\u0438 \u0440\u0438\u0441\u043a\u0430 \u0440\u0435\u0446\u0438\u0434\u0438\u0432\u0430 \u043a\u0430\u0440\u0446\u0438\u043d\u043e\u043c\u044b \u0449\u0438\u0442\u043e\u0432\u0438\u0434\u043d\u043e\u0439 \u0436\u0435\u043b\u0435\u0437\u044b \u0432 \u0446\u0435\u043b\u044f\u0445 \u043f\u0435\u0440\u0441\u043e\u043d\u0430\u043b\u0438\u0437\u0430\u0446\u0438\u0438 \u0432\u0435\u0434\u0435\u043d\u0438\u044f \u043f\u0430\u0446\u0438\u0435\u043d\u0442\u043e\u0432.<\/p>\n<p><strong>\u041a\u0430\u043a\u043e\u0439 \u0431\u0438\u043e\u043c\u0430\u0442\u0435\u0440\u0438\u0430\u043b \u043c\u043e\u0436\u043d\u043e \u0438\u0441\u043f\u043e\u043b\u044c\u0437\u043e\u0432\u0430\u0442\u044c \u0434\u043b\u044f \u0438\u0441\u0441\u043b\u0435\u0434\u043e\u0432\u0430\u043d\u0438\u044f?<\/strong><\/p>\n<p>\u041e\u0431\u0440\u0430\u0437\u0435\u0446 \u0442\u043a\u0430\u043d\u0438, \u043e\u0431\u0440\u0430\u0437\u0435\u0446 \u0442\u043a\u0430\u043d\u0438 \u0432 \u043f\u0430\u0440\u0430\u0444\u0438\u043d\u043e\u0432\u043e\u043c \u0431\u043b\u043e\u043a\u0435.<\/p>\n<p><strong>\u0427\u0442\u043e \u043e\u0437\u043d\u0430\u0447\u0430\u044e\u0442 \u0440\u0435\u0437\u0443\u043b\u044c\u0442\u0430\u0442\u044b?<\/strong><\/p>\n<p>\u0420\u0435\u0444\u0435\u0440\u0435\u043d\u0441\u043d\u044b\u0435 \u0437\u043d\u0430\u0447\u0435\u043d\u0438\u044f: \u041c\u0443\u0442\u0430\u0446\u0438\u0438 V600E \u0432 \u0433\u0435\u043d\u0435 BRAF \u043d\u0435 \u043e\u0431\u043d\u0430\u0440\u0443\u0436\u0435\u043d\u043e.<\/p>\n<p>\u041f\u043e\u043b\u043e\u0436\u0438\u0442\u0435\u043b\u044c\u043d\u044b\u0439 \u0440\u0435\u0437\u0443\u043b\u044c\u0442\u0430\u0442: \u041e\u0431\u043d\u0430\u0440\u0443\u0436\u0435\u043d\u0430 \u043c\u0443\u0442\u0430\u0446\u0438\u044f V600E \u0432 \u0433\u0435\u043d\u0435 BRAF, \u0430\u0441\u0441\u043e\u0446\u0438\u0438\u0440\u043e\u0432\u0430\u043d\u043d\u0430\u044f \u0441 \u044d\u0444\u0444\u0435\u043a\u0442\u0438\u0432\u043d\u043e\u0441\u0442\u044c\u044e \u043f\u0440\u0438\u043c\u0435\u043d\u0435\u043d\u0438\u044f \u043a\u043e\u043c\u0431\u0438\u043d\u0430\u0446\u0438\u0438 \u0438\u043d\u0433\u0438\u0431\u0438\u0442\u043e\u0440\u043e\u0432 BRAF\/MEK.<\/p>\n<p><strong>\u0412\u0430\u0436\u043d\u044b\u0435 \u0437\u0430\u043c\u0435\u0447\u0430\u043d\u0438\u044f<\/strong><\/p>\n<p>\u0414\u043b\u044f \u043f\u043e\u043b\u0443\u0447\u0435\u043d\u0438\u044f \u0437\u0430\u043a\u043b\u044e\u0447\u0435\u043d\u0438\u044f \u043f\u043e \u0440\u0435\u0437\u0443\u043b\u044c\u0442\u0430\u0442\u0443 \u043e\u0431\u0441\u043b\u0435\u0434\u043e\u0432\u0430\u043d\u0438\u044f \u043d\u0435\u043e\u0431\u0445\u043e\u0434\u0438\u043c\u043e \u043f\u0440\u043e\u043a\u043e\u043d\u0441\u0443\u043b\u044c\u0442\u0438\u0440\u043e\u0432\u0430\u0442\u044c\u0441\u044f \u0443 \u0432\u0440\u0430\u0447\u0430-\u043e\u043d\u043a\u043e\u043b\u043e\u0433\u0430.<\/p>\n<p><strong>\u041a\u0442\u043e \u043d\u0430\u0437\u043d\u0430\u0447\u0430\u0435\u0442 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