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作者 Stella S, Vitale SR, Martorana F, Massimino M, Pavone G, Lanzafame K, Bianca S, Barone C, Gorgone C, Fichera M, Manzella L
Stefania Stella, 1,2 Silvia Rita Vitale, 1,2 Federica Martorana, 1,2 Michele Massimino, 1,2 Giuliana Pavone, 3 Katia Lanzafame, 3 Sebastiano Bianca, 4 Chiara Barone, 5 Cristina Gorgone, 6 Marco Fichera, 2 Department of Liviazella Clinic Daawooyinka, Jaamacadda Catania, Catania, 95123, Italy; 2 Xarunta Tijaabada Oncology iyo Hematology, AOU Policlinico "G.Rodolico - San Marco", Catania, 95123, Italy; 3 Caafimaadka Oncology, AOU Policlinico "G. Rodolico - San Marco", Catania, 95123, Italy; 4 Genetics Medical, ARNAS Garibaldi, Catania, 95123, Italy; 5 Daawooyinka Genetics, ASP, Syracuse, 96100, Italy; 6 Waaxda Sayniska Biomedical iyo Biotechnology, Jaamacadda Catania, Genetics Medical, Catania, Italy, 95123; 7Oasi Research Institute-IRCCS, Troina, 94018, Italy Isgaarsiinta: Stefania Stella, tel +39 095 378 1946, email [email protected]; [email protected] Ujeedada: Isbeddellada Germline ee BRCA1 iyo BRCA2 iyo kansarka naasaha la aasaasay (BC), ugxan-sidaha (OC) iyo kuwa kale ee la xidhiidha khatarta nolosha ee kansarka. Tijaabinta hidda-wadaha BRCA ayaa fure u ah qiimeynta khatarta shakhsi ahaaneed, iyo sidoo kale helitaanka hababka ka hortagga ee sideyaasha caafimaadka leh iyo daawaynta daawaynta ee bukaannada kansarka inkastoo baahsanaanta iyo xogta gobollada CABR1 Ujeeddada daraasadayadu waxay ahayd in la baaro dhacdooyinka iyo qaybinta BRCA pathogenic germline ka ee koox ka mid ah bukaanada BC ee bariga Sicily iyo in la qiimeeyo xiriirka ay la leeyihiin sifooyin BC gaar ah iyadoo la isticmaalayo jiilka soo socda ee jiritaanka burooyinka la xidhiidha jiritaanka burooyinka. index.RESULTS: Guud ahaan, bukaanada 35 (9%) waxay lahaayeen kala duwanaansho cudur-sidaha BRCA, 17 (49%) ee BRCA1 iyo 18 (51%) ee BRCA2. BRCA1 isbeddellada ayaa ku badan bukaannada BC ee saddex-geesoodka ah, halka isbeddellada BRCA2 ay aad ugu badan yihiin bukaannada luminal BC ee aan-ka-hortagga lahayn. Heerka burada sare iyo index proliferative. Gabagabo: Natiijooyinkayagu waxay bixiyaan dulmar guud oo ku saabsan xaaladda isbeddelka BRCA ee bukaannada BC ee ka soo jeeda bariga Sicily waxayna xaqiijiyaan doorka falanqaynta NGS ee lagu aqoonsanayo bukaanada leh dhaxalka BC. Guud ahaan, xogtani waxay la socotaa caddaymihii hore ee taageeraya baaritaanka BRCA ee ka hortagga saxda ah iyo daaweynta kansarka ee sidayaasha isbeddelka.
Kansarka naasaha (BC) waa kan ugu caansan adduunka oo dhan iyo kansarka ugu dhimashada badan haweenka.1 Tilmaamaha bayoolojiga ee go'aaminaya saadaasha BC iyo habdhaqanka kiliinikada ayaa si weyn loo baaray oo qayb ahaan la caddeeyey waqti ka dib. Dhab ahaantii, dhowr calaamadood oo surrogate ah ayaa hadda loo isticmaalaa in lagu kala saaro BC noocyo kala duwan oo molecular ah. Waxay yihiin estrogen (ER) iyo / ama progesterone R) receptor der der reseptor 2. Kordhinta, index proliferation index Ki-67 iyo buro grade (G) .2 Isku-darka doorsoomayaashan ayaa aqoonsaday qaybahan BC ee soo socda: 1) Burooyinka Luminal, oo muujinaya ER iyo / ama PgR muujinta, waxay u dhigantaa 75% BCs. Burooyinkan ayaa loo sii kala qaybiyay Luminal A, marka Ki-67 uu ka hooseeyo 20% ama ka sarreeya HER20, iyo Luminal 2% waa siman yahay. joogitaanka HER2 xoojinta, iyadoon loo eegin index faafinta; 2) Burooyinka HER2+ kuwaas oo ah ER iyo PgR taban laakiin muujinaya HER2 amplification. Kooxdani waxay ka dhigan tahay 10% dhammaan burooyinka naaska; 3) Kansarka naasaha ee Triple-negative (TNBC), kaas oo aan muujin ER iyo PgR muujinta iyo kordhinta HER2, ayaa ka dhigan qiyaastii 15% kansarka naasaha.2-4
Waxaa ka mid ah noocyadan hoose ee BC, heerka burada iyo tusmada fidinta waxay ka dhigan yihiin biomarkers-qaybood oo si toos ah iyo si madaxbanaan ula xidhiidha burada gardarrada iyo saadaasha.5,6
Marka laga soo tago sifooyinka bayoolojiga ee aan soo sheegnay, doorka isbeddellada hidda-socodka ee la iska dhaxlo ee horseedaya horumarinta BC ayaa noqotay mid sii kordheysa oo muhiim ah dhowrkii sano ee la soo dhaafay.7 About 1 in 10 naasaha burooyinka naaska ayaa laga dhaxlaa sababtoo ah isbeddellada jeermiska ee hiddo-wadaha khaaska ah BRCA2, CHK2, PALB2, RAD51C, iyo RAD51D) ayaa ugu horreyn mas'uul ka ah dhaxalka BC. Waxaa ka mid ah hiddo-wadahaas, BRCA1 iyo BRCA2 (oo hadda loo yaqaan BRCA1/2) waxay muujiyeen xiriirka ugu xooggan ee horumarinta burooyinka naaska. Xannaanada, oo ay ku jiraan ugxan-sidaha, qanjirka 'prostate', pancreatic, colorectal, iyo melanoma. Laga bilaabo da'da 13 ilaa 80 sano, dhacdooyinka isugeynta ee BC waa 72% dumarka leh BRCA1 pathogenic variant (PV) iyo 69% dumarka leh BRCA2 PV.14
Waxaa xusid mudan, daabacaad dhowaan soo baxday waxay soo jeedinaysaa in khatarta BC ay ku xiran tahay nooca PV. Dhab ahaantii, marka la barbar dhigo noocyada kala duwan ee jirridda cudur-sidaha, kala duwanaansho khaldan oo muuqda, gaar ahaan hiddo-wadaha BRCA1, waxay la xiriiraan hoos u dhaca khatarta BC, gaar ahaan haweenka da'da ah.15
Joogitaanka BRCA1 ama BRCA2 PV waxay la xiriirtay sifooyin bayooloji iyo bukaan-socodyo kala duwan.16,17 BRCA1-ku xiran BCs waxay u muuqdaan inay yihiin kuwo kiliinikada ah oo dagaal badan, si liidata loo kala soocay, iyo kuwo aad u bararsan. Burooyinkan badanaa waa saddex laab taban waxayna leeyihiin da' hore oo bilaw ah. Burooyinkan waxay ku badan yihiin lumen B waxayna badanaa ku dhacaan dadka waaweyn.16-18 Waxaa xusid mudan, isbeddellada BRCA1 iyo BRCA2 waxay kordhiyaan dareenka daawaynta gaarka ah, oo ay ku jiraan cusbada platinum iyo daawooyinka la bartilmaameedsado sida poly(ADP-ribose) polymerase inhibitors (PARPi).19,20
Dhawrkii sano ee la soo dhaafay, hirgelinta taxanaha jiilka soo socda (NGS) ee ku dhaqanka kiliinikada ayaa awood u siisay tiro sii kordheysa oo bukaannada BC ah si ay u maraan baaritaanka molecular ee xanuunka u nuglaanshaha kansarka, oo ay ku jiraan BRCA1 / 2.21 Isla markaa, qeexitaanno ku salaysan shuruudaha saxda ah ee ku saabsan taariikhda qoyska, tirakoobka, iyo sifooyinka bukaan-socodka si loo aqoonsado shakhsiyaadka u qalma baaritaanka CABR23. BRCA1/2 ee baadhista dad gaar ah, taas oo muujinaysa kala duwanaanshaha gobollada juqraafiyeed.24-27 Inkasta oo ay jiraan warbixino ku saabsan kooxda BC ee galbeedka Sicily, xog yar ayaa laga heli karaa baaritaanka BRCA1/2 ee dadweynaha bariga Sicily.28,29
Waxaan halkaan ku qeexeynaa natiijooyinka baaritaanka jeermiska BRCA1/2 ee bukaannada BC ee ka yimid bariga Sicily, iyadoo la sii xiriirinayo joogitaanka BRCA1 ama BRCA2 isbeddellada oo leh astaamaha bukaan-jiifka ee ugu muhiimsan ee burooyinkan.
Daraasad dib-u-eegis ah ayaa lagu sameeyay "Xarunta Tijaabada Oncology iyo Hematology" ee Cisbitaalka Policlinico.Rodolico - San Marco ee Catania. Laga bilaabo Janaayo 2017 ilaa March 2021, wadar ahaan 455 bukaan oo qaba naaska iyo ugxan-sidaha, melanoma, pancreatic ama qanjirka 'prostate' ayaa lagu sameeyay baaritaanka unugyada CA2. iyadoo la raacayo Baaqa Helsinki, iyo dhammaan ka qaybgalayaashu waxay bixiyeen oggolaansho qoraal ah ka hor falanqaynta molecular.
Tilmaamaha taariikhiga ah iyo bayoolojiga (ER, PgR, heerka HER2, Ki-67, iyo fasalka) ee BC ayaa lagu qiimeeyay biopsy xudunta u ah ama shaybaarrada qalliinka, iyada oo la tixgelinayo oo kaliya qaybaha burooyinka gardarrada ah. Iyada oo ku saleysan sifooyinkaas, BCs ayaa loo kala saaray sida soo socota: luminal A (ER + iyo / ama PgR +, HER2-, Ki-67/20%) iyo Bluminal. HER2-, Ki-67≥20%), B-HER2+ (ER iyo/ama PgR+, HER2+), HER2+ (ER iyo PgR-, HER2+) ama saddex-laab taban (ER iyo PgR-, HER2-).
Ka hor inta aan la qiimeynin heerka isbeddelka BRCA1 iyo BRCA2, koox cilmi-nafsiyeedyo badan oo ay ku jiraan dhakhtarka kansarka, hidde-yaqaanka, iyo cilmi-nafsiga ayaa sameeyay la-talin hidde-sideed bukaan kasta si loo go'aamiyo joogitaanka BRCA1 iyo/ama BRCA1. ama shakhsiyaadka khatarta sare leh ee PV ee hidda-wadaha BRCA2. Xulashada bukaan-socodka waxaa lagu sameeyay si waafaqsan tilmaamaha Bulshada Talyaaniga ee Oncology Oncology (AIOM) iyo talooyinka Sicilian ee maxaliga ah.30,31 Shuruudahan waxaa ka mid ah: (i) taariikhda qoyska ee noocyada la yaqaan ee cudur-sidaha ee hiddaha nuglaanta (tusaale, BRCA1, BRCA2, TP53, PT); (ii) ragga leh BC; (iii) kuwa leh BC iyo OC; (iv) dumarka leh BC <36 sano, TNBC <60 sano, ama laba geesood BC <50 sano; (v) taariikhda caafimaad ee shakhsi ahaaneed ee BC <50 sano iyo ugu yaraan hal qaraabo heerka koowaad ah: (a) BC <50 sano; (b) OC-da aan-dagaalka ahayn iyo kuwa aan xuduudka lahayn; (c) labada dhinac BC; (d) lab BC; (e) Kansarka ganaca; (f) kansarka qanjirka 'prostate'; (vi) laba ama in ka badan taariikhda shakhsiyeed ee BC (vii) Taariikhda shakhsi ahaaneed ee OC iyo ugu yaraan hal qaraabo heerka koowaad ah: (a) BC <50 sano; (b) NOC; (c) labada dhinac BC; (d) lab BC; (vii) dhedig leh OC serous heerka sare ah.
Muunada dhiigga 20 mL ee wareegga dhiigga ayaa laga helay bukaan kasta waxaana lagu soo ururiyay tuubooyinka EDTA (BD Biosciences) .DNA Genomic ayaa laga soocay 0.7 mL muunadaha dhiigga oo dhan iyadoo la adeegsanayo QIAsymphony DSP DNA Midi kit Go'doominta Kit (QIAGEN, Hilden, Italy) sida ku cad tilmaamaha soo saaraha oo la dhex mariyey Qubito FIRmo 3. Waltham, MA, USA) Samee tirada Kobcinta bartilmaameedka iyo diyaarinta maktabadda waxa sameeya Oncomine™ BRCA Research Assay Chef, oo diyaar u ah in lagu shubo Ion AmpliSeq (NM_000059.3). 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) sida ku cad tilmaamaha soo saaraha Ion 510 Chip (Thermo Fisher Scientific) .Falanqaynta xogta waxaa sameeyay Amplicon Suite (SmartSeq srl) iyo Ion Reporter Software.
Dhammaan noocyada kala duwanaanshiyaha waxay raaceen habraaca hadda jira ee Dallada Kala Duwanaanshaha Genome, ee laga heli karo onlayn (HGVS, http://www.hgvs.org/mutnomen) . Kala talinta xogaha kala duwan sida ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, iyo UMD. Kala soocida waxaa ka mid ah shan qaybood oo halis ah oo kala duwan: benign (category I), malaha benign (category II), kala duwanaanshaha aan la hubin (VUS, category III), u badan tahay pathogenic (category IV), iyo VES saamaynta ku leh qaab-dhismeedka borotiinka. function, qalab macluumaad leh oo heli kara 30 database.32
Si loo qoondeeyo muhiimada caafimaad ee suurtagalka ah ee VUS kasta, algorithms saadaalinta borotiinka xisaabinta ee soo socota ayaa la isticmaalay: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/) iyo Align-GVGD (http://agvgd.hci.utah.edu/agvgd_input.php) . Kala duwanaanshiyaha loo kala saaray fasalka 1 iyo 2 ayaa loo tixgeliyey nooca duurjoogta ah.
Isku xigxiga Sanger ayaa xaqiijiyay jiritaanka kala duwanaansho kasta. oo ay ku xigto taxanaha Sanger.
Bukaannada tijaabiyey diidmada hidda-wadaha BRCA1/2 waxaa lagu tijaabiyey Multiplex ligation-dependent probe amplification (MLPA) sida ku cad tilmaamaha soo saaraha si loo qiimeeyo joogitaanka dib-u-habaynta genomic ee waaweyn (LGR) . Nucleotides oo dherer ah. Badeecadaha kor u qaadida, oo ka kooban qayb gaar ah oo amplicons PCR ah, ayaa dabadeed lagu falanqeeyay kombuyuutarrada kombuyuutarrada iyo Cofalyser.Net software iyada oo la socota miisaska Cofalyser-ka gaarka ah ee ku habboon (www.mrcholland.com).
Doorsoomayaasha bukaan-socod ee la xushay (darajada taariikhiga ah iyo Ki-67% tusmada fidinta) ayaa lala xiriiriyay joogitaanka BRCA1/2 PV, la xisaabiyay iyadoo la adeegsanayo software-ka Prism v. 8.4 iyadoo la adeegsanayo tijaabada saxda ah ee Fisher iyadoo loo maleynayo p-qiimaha <0.05 inay muhiim tahay.
Intii u dhaxaysay Janaayo 2017 iyo Maarso 2021, 455 bukaan ayaa laga baadhay jeermiska BRCA1/2. Tijaabada isbeddelka ayaa lagu sameeyay Xarunta Tijaabada Oncology iyo Hematology ee Cisbitaalka Policlinico. Sida ku cad tilmaamaha Sicilian 10 Gennaio 2020), Rodolico ee Catania - San Marco "guud ahaan, bukaanada 389 Waxaa jiray kansarka naasaha, 37 kansarka ugxansidaha, 16 kansarka ganaca, 8 kansarka qanjirka 'prostate' iyo 5 melanoma. Qaybinta bukaannada iyadoo loo eegayo nooca kansarka iyo natiijooyinka falanqaynta ayaa lagu muujiyay sawirka 1.
Jaantuska 1 wuxuu muujinayaa jaantuska socodka oo muujinaya dulmar guud ee daraasadda.Bukaanada qaba naasaha, melanoma, pancreatic, prostate, ama burooyinka ugxan-sidaha ayaa lagu tijaabiyay isbeddellada hiddo-wadaha BRCA1 iyo BRCA2.
Soo gaabinta: PV-yada, kala duwanaanshaha cudur-sidaha; VUS, kala duwanaansho aan la hubin; WT, nooca duurjoogta ah ee BRCA1/2.
Waxaan si gooni ah diiradda u saarnay daraasaddayada kooxaha kansarka naasaha. Bukaanadu waxay lahaayeen da' dhexdhexaad ah 49 sano (qiyaastii 23-89) waxayna ahaayeen dumar u badan (n=376, ama 97%).
Maaddooyinkaas, 64 (17%) waxay lahaayeen BRCA1/2 isku-beddelasho waxayna ahaayeen dhammaan dumar. Soddon iyo shan (9%) waxay lahaayeen PV iyo 29 (7.5%) waxay lahaayeen VUS.Toddobo iyo toban (48.6%) ee 35 nooc oo cudur-sidaha ah ayaa ka dhacay BRCA1 iyo 18 (51.4%) ee BRCA2, halka 5.2% CABRUS ay ka dhaceen BRCA2. (82.8%) gudaha BRCA2 (Jaantus 1 iyo 2).LGR kuma jirin falanqaynta MLPA.
Jaantus 2. Falanqaynta isbeddellada BRCA1 iyo BRCA2 ee 389 bukaannada kansarka naasaha. (B) 389 bukaanada kansarka naasaha Soddon iyo shan (9%) waxay lahaayeen BRCA1/2 kala duwanaanshiyaha cudur-sidaha (PVs). (C) 29 (7.5%) 389 maado ayaa sitay VUS, 5 (17.2%) BRCA1 hiddo-wadaha (liimi madow) iyo 24 (82.8%) BRCA2 hiddo-wadaha (liimi khafiif ah).
Soo gaabinta: PV-yada, kala duwanaanshaha cudur-sidaha; VUS, kala duwanaansho aan la hubin; WT, nooca duurjoogta ah ee BRCA1/2.
Waxaan soo xiganay baaritaan ku saabsan bararka BC molecular subtypes ee bukaanada qaba BRCA1 / 2 PV. Qaybinta waxaa ka mid ah 2 (5.7%) luminal A, 15 (42.9%) luminal B, 3 (8.6%) B-HER2 +, 2 (5.7%) HER2 + iyo 13 (Bukaanada BRA 37.1%) Tmopositive (29.4%) waxay lahaayeen luminal B BC, 2 (11.8%) waxay lahaayeen cudurka HER2 +, iyo 10 (58.8%) waxay lahaayeen TNBC. Burooyinka aan lahayn isbeddellada BRCA1 waxay ahaayeen luminal A ama luminal B-HER2 + (Jaantus 3) .In BRCA2-koox-hoosaadka togan, 10, 53% 6 ahaayeen luminal. luminal B-HER2 +, 3 (16.7%) TNBC iyo 2 (11.1%) waxay ahaayeen luminal A (Jaantus 3) .Ma jiraan burooyin HER2 + ah oo ku jira kooxdan. Sidaa darteed, isbeddellada BRCA1 waxay ku badan yihiin bukaannada TNBC, halka isbeddellada BRCA2 ay ku badan yihiin shakhsiyaadka lumen B.
Jaantus 3 Baaxadda noocyada kansarka naasaha ee bukaanada leh noocyada pathogenic ee BRCA1 iyo BRCA2.Histograms muujinaya qaybinta BRCA1- (casaanka madow) iyo BRCA2- (casaan khafiif ah) PVs ka mid ah noocyada hoose ee unugyada unugyada kansarka naasaha. Tirooyinka lagu soo warramey santuuq kasta waxay u taagan yihiin boqolleyda bukaanada qaba BRCA1 iyo BRCA2 ee naasaha kasta.
Soo gaabinta: PV-yada, kala duwanaanshaha cudur-sidaha; HER2 +, receptor factor koritaanka epidermal aadanaha 2 positive; TNBC, kansarka naasaha oo saddex-laab ah.
Ka dib, waxaanu qiimeynay nooca iyo deegaanaynta hidda-wadaha BRCA1 iyo BRCA2 PVs. BRCA1 PV, waxaan ku aragnay 7 kala duwanaansho nucleotide ah (SNVs), 6 tirtirid, 3 nuqulo iyo 1 gelin. Hal mutation (c.5522delBR) kaliya ayaa ka dhigan daahfur cusub. C.5035_5039delCTAAT PV-yada la soo sheegay waxay ku yaalliin gobolka la isku raacsan yahay ee goobta kala qaybsan (c.4357+1G>T) (Shaxda 1).
Marka la eego BRCA2 PV, waxaan aragnay 6 tirtirid, 6 SNVs iyo 2 nuqullo ah. Midkoodna isbeddellada la helay maaha mid cusub. Saddex isbeddel oo ku soo noqnoqday dadkeena, c.428dup iyo c.8487+1G>A lagu arkay 3 maado, oo ay ku xigto c.5851_5854delAG 2TT . ku celi C ee exon 5 ee BRCA2, oo la saadaaliyay in lagu dhajiyo borotiinka la jarjaray, oo aan shaqaynayn. c.5851_5854delAGTT kala duwanaanshiyaha pathogenic waxaa sabab u ah 4-nucleotide tirtirka ka boosaska nucleotide 5851 in 5854 in codeing exon 10 ee hiddo BRCA2 iyo natiijooyinka in qaab tarjumaad ah la saadaaliyay ah joojinta joojinta codon ah (p.S1951Wfs labada hore, 6) . iyo c.7008-2A>T ayaa laga helay isla bukaan.34 Isbeddelka ugu horreeya wuxuu ku lug leeyahay beddelka adenosine (A) ee BRCA2 exon 7 oo leh guanine (G) oo ka kooban nucleotide taasoo keentay isbeddelka valine ilaa isoleucine ee codon 211, isoleucine Amino acid waa amino acid leh isbeddelka labaad ee isku midka ah. gobolka intronic iyo natiijada in laban A to thymine (T) beddelka ka hor exon 13 ee hidda-sidaha encoding BRCA2. Isbedelka c.7008-2A>T ayaa laga yaabaa in ay abuuraan qoraallo badan oo dhererka kala duwan. Intaa waxaa dheer, in kooxda BRCA2 PVs, 4 ka mid ah 18 isbedel (22.2%) ahaayeen intronic.
Waxaan markaa ku dhejinay BRCA1 / 2 isbeddellada tirtirka ah ee qaybaha shaqada iyo gobollada borotiinka-xidha (Jaantus. 4) .In hidda-wadaha BRCA1, 50% PV-yada waxay ku yaalliin gobolka kooxda kansarka naasaha (BCCR), halka 22% isbeddellada ay ku yaalliin qaybta kansarka ugxan-sidaha ee gobolka PV (OCCR) ee gobolka BCCR iyo 42.8% isbeddellada waxay ku yaalliin OCCR (Sawir 4B) .Marka xigta, waxaan qiimeynay meesha PV ku taal gudaha BRCA1 iyo BRCA2 borotiinka. BRC ku celi domainka, halka 3 is-beddelo gudaha ah iyo 3 exonic laga helay oligo/oligosaccharide-binding (OB) iyo munaaradda (T) (Jaantuska 4B).
Jaantus 4 Qaabka qaabaynta borotiinka BRCA1 iyo BRCA2 iyo deegaanaynta noocyada cudurada. Tiradani waxay muujinaysaa qaybinta BRCA1 (A) iyo BRCA2 (B) kala duwanaanshaha pathogenic ee bukaanada kansarka naasaha. Isbeddellada qaawan ayaa lagu muujiyay buluug, halka kala duwanaansho gudaha ah ayaa lagu muujiyay orange. Dhererka barku wuxuu u taagan yahay tirada kiisaska iyo borotiinka CA2 Borotiinka BRCA1 waxa uu ka kooban yahay xayndaab loop (RING) iyo isku xigxiga deegaanaynta nukliyeerka (NLS), gariiradda duuban, domain SQ/TQ cluster domain (SCD), iyo BRCA1 C-terminal domain (BRCT). laalaabka, a Tower domain (T), iyo An NLS oo ku taal dhinaca C. Meelaha lagu magacaabo Gobolka Kooxda Kansarka Naasaha (BCCR) iyo Gobolka Cluster Kansarka Ovarian (OCCR) ayaa lagu muujiyey xagga hoose.
Waxaan ka dib baarnay sifooyinka bukaan-socodka BC ee laga yaabo inay la xiriiraan joogitaanka BRCA1/2 PV. Diiwaanada bukaan-socodka oo dhameystiran ayaa loo heli karaa 181 BRCA1 / 2-bukaannada taban (aan sidayaal) iyo dhammaan sideyaasha (n = 35) Waxaa jiray xiriir ka dhexeeya heerka kororka burooyinka iyo darajada.
Waxaan xisaabinay qaybinta Ki-67 iyadoo lagu saleynayo dhexdhexaadinta kooxdayada (25%, qiyaasta <10-90%). Mawduucyada Ki-67 <25% waxaa lagu qeexay "Ki-67" hoose, halka shakhsiyaadka leh qiimaha ≥ 25% loo tixgeliyey "Ki-67 sare" . Sidayaal PV (Jaantus. 5A).
Jaantuska 5 Xidhiidhka Ki-67 oo leh darajo qaybinta kansarka naasaha dumarka leh iyo kuwa aan lahayn BRCA1 iyo BRCA2 PVs. Bukaanjiifka kansarka BC ee kooxaha darajada taariikhiga ah (G2 iyo G3) marka loo eego BRCA1 iyo BRCA2 heerka beddelka (madooyinka WT, BRCA1 iyo BRCA2 PVs).
Sidoo kale, waxaan baarnay in heerka burada uu xiriir la leeyahay joogitaanka BRCA1 / 2 PV. Maadaama G1 BC ay ka maqan tahay dadkeena, waxaan bukaannada u qaybinay laba kooxood (G2 ama G3) . Iyadoo la raacayo natiijooyinka Ki-67, falanqayntu waxay muujisay isku-xirnaansho tirakoob oo muhiim ah oo u dhexeeya heerka burooyinka iyo isbeddellada BRCA1, oo leh saamiga sare ee burooyinka BRCA1. (p<0.005) (Jaantuska 5B).
Horumarka laga sameeyay tignoolajiyada isku xigxiga DNA-da ayaa awood u siisay horumar aan horay loo arag oo ku saabsan BRCA1/2 baaritaanka hidda-socodka, oo leh saameyn muhiim ah bukaannada leh taariikhda qoyska ee kansarka Guud ahaan gobollada juqraafiyeed.37 Gudaha Talyaaniga, heerka BRCA1/2 PV wuxuu u dhexeeyay 8% ilaa 37%, taasoo muujinaysa kala duwanaansho ballaaran oo gudaha dalka ah. jasiiradda.
Daraasaddeenu waa mid ka mid ah warbixinnada ugu horreeya ee ku saabsan dhacdooyinka BRCA1/2 PV ee bukaannada BC ee bariga Sicily.28 Waxaan diiradda saarnay falanqaynta BC, maadaama kani yahay ilaa hadda cudurka ugu badan ee kooxdeena.
Marka la baarayo bukaanada 389 BC, 9% waxay qaadeen BRCA1/2 PVs, oo si siman loo qaybiyay inta u dhaxaysa BRCA1 iyo BRCA2. Natiijooyinkani waxay la socdaan kuwii hore loogu soo sheegay dadweynaha Talyaaniga. Si kastaba ha ahaatee, nimankan midkoodna ma soo saarin BRCA1 / 2 PV, sidaas darteed waxay u sharaxnaayeen falanqaynta molecular dheeraad ah si meesha looga saaro joogitaanka isbeddellada aan caadiga ahayn sida PALB2, RAD51C iyo D, iyo kuwo kale. Kala duwanaansho muhiim ah oo aan la hubin ayaa lagu soo celiyay 7% maadooyinka BRCA2 VUS, taas oo caddaynaysa 2 caddaynta 2.
Markii aan falanqeynay qaybinta BC molecular subtypes ee BRCA1 / 2 haweenka mutant, waxaan xaqiijinay ururada la yaqaan ee u dhexeeya TNBC iyo BRCA1 PV (58.8%) iyo inta u dhaxaysa luminal B BC iyo BRCA2 PV (55.6%) .16,43 The luminal A iyo HER2 + burooyinka PV ee BRCA1 iyo BRers46 xogta joogtada ah ee BRCA1 iyo BRers46.
Waxaan markaas diirada saareynaa nooca iyo goobta BRCA1/2 PV. Kooxdayada, BRCA1 PV ugu caansan waxay ahayd c.5035_5039delCTAAT. Inkastoo Incorvaia et al. kuma sifayn kala duwanaanshahan kooxdooda Sicilian, qorayaasha kale waxay u sheegeen inay tahay germline BRCA1 PV.34 Dhowr BRCA1 PVs ayaa laga helay kooxdayada - tusaale c.181T>G, c.514del, c.3253dupA iyo c.5266dupC - kuwaas oo la arkay 8. (c.181T>G iyo c.5266dupC) ayaa caadi ahaan laga helaa Yuhuuda Ashkenazi ee Bariga iyo Bartamaha Yurub (Poland, Czech), Slovenia, Australiyaanka, Hungarian, Belarusian iyo Jarmal), 44,45 iyo, Maraykanka iyo Argentina, ayaa dhawaan lagu qeexay sida "variant jeermiska soo noqnoqda" ee bukaannada Talyaani.5 in 8 bukaanada kansarka naasaha ee waqooyiga Sicily ee Palermo iyo Messina. Waxa xiiso leh, xitaa Incorvaia et al. laga helay kala duwanaanshaha c.3253dupA ee qoysaska qaarkood ee Catania.28 Wakiilka ugu badan ee BRCA2 PVs waa c.428dup, c.5851_5854delAGTT iyo kala duwanaanshaha intronic c.8487+1G>A, kuwaas oo si faahfaahsan 28 looga sheegay bukaan ku sugan Palermo oo leh c.458 PV waxaa lagu arkay qoysaska waqooyi-galbeed ee Sicily, gaar ahaan gobollada Trapani iyo Palermo, halka c.5851_5854delAGTT PV lagu arkay qoysaska waqooyi-galbeed ee Sicily. The 8487+1G>Ka duwanaanshiyaha ayaa aad ugu badan maaddooyinka Messina, Palermo, iyo Caltanissetta.28 Rebbeck et al. Horey ayaa loogu sharraxay isbeddelka c.5851_5854delAGTT ee Colombia.37 kale BRCA2 PV, c.631+1G>A, ayaa laga helay BC iyo bukaanada OC ee Sicily (Agrigento, Siracusa iyo Ragusa) .28 Waxaa xusid mudan, waxaan aragnay wada-noolaanshaha laba nooc oo BRCA2 ah (BRCA2) (BRCA2) Isla bukaan, kaas oo aan u maleynay in lagu kala soocay habka cis, sida hore loo soo sheegay sidaas oo kale.34,46 Isbeddelladan BRCA2 ayaa runtii si joogta ah loogu arkay gobolka Talyaaniga waxaana la ogaaday in ay soo bandhigaan codons joogsi degdeg ah, saameynaya kala-baxa Messenger RNA oo keenaya borotiinka BRCA2 inuu ku guuldareysto.47,48
Waxaan sidoo kale khariidadeynay BRCA1 iyo BRCA2 PV-yada OCCR iyo BCCR ee qaybaha borotiinka iyo hiddo-wadaha. Gobolladan waxaa lagu tilmaamay Rebbeck et al. sida meelaha halista u ah horumarinta kansarka ugxansidaha iyo naasaha, siday u kala horreeyaan.49 Si kastaba ha ahaatee, caddaynta ku saabsan xidhiidhka ka dhexeeya meesha kala duwanaanshaha jeermiska iyo khatarta kansarka naasaha ama ugxan-sidaha ayaa weli ah muran. xiriirka ka dhexeeya gobollada OCCR iyo BCCR ee la geliyey iyo astaamaha BC. Tani waxaa laga yaabaa inay sabab u tahay tirada xaddidan ee bukaannada leh isbeddellada BRCA1/2. Marka laga eego aragtida domainka borotiinka, BRCA1 PV-yada waxaa loo qaybiyaa borotiinka oo dhan, iyo isbeddellada BRCA2 ayaa doorbidaya in laga helo qaybta soo noqnoqda ee BRC.
Ugu dambeyntii, waxaan isku xirnay sifooyinka bukaan-socodka ee BC ee BRCA1 / 2 PV. Sababtoo ah tirada xaddidan ee bukaannada lagu daray, waxaan kaliya helnay xiriir weyn oo u dhexeeya Ki-67 iyo heerka burada. Inkasta oo qiimeynta iyo tarjumaadda Ki-67 ay weli tahay mid muran leh, waxaa hubaal ah in heerarka sare ee taranka ay la xiriiraan khatarta sii kordheysa ee soo noqoshada cudurka, hoos u dhigista taariikhda sare ee soo noqoshada iyo hoos u dhaca. "hoose" Ki-67 waa 20% si kastaba ha ahaatee, marinkan ma khuseeyo our BRCA1/2 bukaan-socodka isbeddelka, kaas oo leh dhexdhexaad ah Ki-67 qiimaha 25%. (25-30%) ayaa laga yaabaa inay si fiican u habeeyaan bukaanada marka loo eego saadaashadooda.53,54 Laga soo bilaabo natiijooyinka falanqayntayada, isku xirnaanta muhiimka ah maaha mid la yaab leh. Waxay dhacdaa inta u dhaxaysa Ki-67 sare iyo darajooyinka iyo joogitaanka BRCA1 PV. Dhab ahaantii, burooyinka BRCA1 ee la xidhiidha TNBC waxay muujinayaan sifooyin dagaal badan.16,17
Gebogebadii, daraasaddan ayaa bixisa warbixin ku saabsan heerka is-beddelka ee BRCA1 / 2 ee kooxda BC ee ka soo jeeda bariga Sicily. Guud ahaan, natiijooyinkayagu waxay la socdaan caddaynta hore, labadaba marka la eego isbeddelka isbeddelka iyo sifooyinka bukaan-socodka ee BC. Daraasado dheeraad ah oo ku saabsan dadweynaha waaweyn ee BRCA1 / 2-mutant BC bukaannada, sida isticmaalka dammaanadda mutagenome ee bukaannada BC, sida isticmaalka dammaanadda mutagenome ee bukaannada BC ayaa la qiimeeyay. ka duwan oo ka yar BRCA1/2. Tani waxay ogolaan doontaa aqoonsiga iyo maaraynta saxda ah ee tirada sii kordheysa ee maadooyinka khatarta sii kordheysa ee kansarka sababtoo ah isbeddellada hidde-sideyaasha.
Dhammaan bukaannada waxay saxeexeen oggolaansho qoraal ah oo qoraal ah sida ku cad Baaqa Helsinki. Sida laga soo xigtay siyaasadda AOU Policlinico "G.Rodolico - S.Marco", daraasaddan ayaa laga saaray dib-u-eegis anshaxeed sababtoo ah bukaannada BRCA1/2 ayaa sidoo kale lagu wargeliyay falanqaynta bukaan-socodka iyadoo la raacayo dhammaan falanqaynta bukaan-socodka. ogolaanshaha isticmaalka xogtooda ujeedooyin cilmi baaris.
Waxaan u mahadcelineynaa Prof. Paolo Vigneri caawintiisa daryeelka bukaanka kansarka naasaha sida ay codsadeen Guddiga Anshaxa.
Federica Martorana ayaa ka warbixisay sharafta Istituto Gentili, Eli Lilly, Novartis, Pfizer.
1. Sung H, Ferlay J, Siegel RL, et al.Global Cancer Statistics 2020: GLOBOCAN waxay qiyaastay dhacdooyinka iyo dhimashada 36 kansar ee 185 wadan oo aduunka ah.CA Cancer J Clin.2021;71(3):209-249.doi: 10.33222