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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, 6, Waaxda Caafimaadka ee Liviazella a, 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, Talyaaniga;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 ee la aasaasay (BC), ugxan-sidaha (OC) iyo kuwa kale ee la xidhiidha khatarta nolosha kansarka Kala duwanaanshaha pathogenic ee qoysaska Sicily, daraasado si gaar ah loogu beegsanayo dadka ku nool bariga Sicily ayaa ka maqan. Ujeedada daraasaddeennu waxay ahayd in la baaro dhacdooyinka iyo qaybinta BRCA pathogenic germline beddelka koox ka mid ah bukaannada BC ee ka soo jeeda bariga Sicily iyo si loo qiimeeyo ururkooda sifooyin gaar ah oo BC ah iyadoo la adeegsanayo isku xigxiga-jiilka soo socda, joogitaanka isbeddellada isbeddellada 3 ee bukaannada. (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-laaban, halka isbeddellada BRCA2 ay aad ugu badan yihiin bukaannada BC ee iftiinka. dulmar guud oo ku saabsan heerka 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 habboon iyo daaweynta kansarka ee sidayaal isu beddelka.
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 sii qeexay 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 progesterone (Ph. index ration index Ki-67 iyo buro fasalka (G) .2 Isku darka doorsoomayaashan ayaa aqoonsaday qaybaha BC ee soo socda: 1) Burooyinka Luminal, oo muujinaya ER iyo / ama muujinta PgR, ayaa lagu xisaabiyay 75% ee BCs. Burooyinkan ayaa loo sii kala qaybiyay Luminal A, marka Ki-67 uu ka hooseeyo 20% iyo HER2 oo ka hooseeya joogitaanka HER2, iyo ka sarreeya joogitaanka HER2, iyo Luminal B2. iyada oo aan loo eegin index of proliferation;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 nafleyda ee aan soo sheegnay, doorka isbeddellada hidde-sidaha 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 naasaha ayaa la dhaxlo sababtoo ah isbeddellada jeermiska ee hiddo-wadaha khaaska ah 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. abuurka, mindhicirka, iyo melanoma. Laga bilaabo da'da 13 ilaa 80 sano, dhacdooyinka isugaynta 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 sarreeya. Burooyinkan badanaa waa saddex laab taban waxayna leeyihiin da' hore oo bilaw ah. es. Burooyinkani 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 daroogooyinka la beegsanayo sida poly (ADP-ribose) polymerase inhibitors (PARPi).19,20
Dhawrkii sano ee la soo dhaafay, hirgelinta taxanaha jiilka soo socda (NGS) ee ku-dhaqanka bukaan-socodka ayaa u suurtageliyay tiro sii kordheysa oo bukaannada BC ah inay maraan baaritaanka molecular ee xanuunka u nugulaanta 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 CABR2. /2 baaritaan dad gaar ah, oo muujinaya kala duwanaanshiyaha guud ahaan gobollada juqraafiga.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, wadarta 455 bukaan oo qaba naaska iyo ugxan-sidaha, melanoma, pancreatic ama qanjirka 'prostate' ayaa loo gudbiyay baaritaanka unugyada DNA-ga ee DNA-ga. saamiga Helsinki, iyo dhammaan ka qaybgalayaashu waxay bixiyeen ogolaansho qoraal ah ka hor falanqaynta molecular.
Sifooyinka taariikhiga ah iyo bayoolojiga (ER, PgR, heerka HER2, Ki-67, iyo darajada) ee BC ayaa lagu qiimeeyay biopsy xudunta u ah ama shaybaarada qalliinka, iyadoo la tixgelinayo 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%) 7≥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 soo mariyey Qubitmo, Filucient USA, Qubitmo 3. ) Samee qiyaasid.Xoojinta bartilmaameedka iyo diyaarinta maktabadda waxaa sameeya Oncomine™ BRCA Research Assay Chef, oo diyaar u ah in lagu shubo Ion AmpliSeq Si kooban, 15 µL oo muunad kasta oo la qaso DNA (10 ng) ayaa lagu daray taarikada barcodeed ee loogu talagalay diyaarinta maktabadda, dhammaan reagents iyo alaabtii waxaa lagu raray qalabka Ion Chef™. Diyaarinta maktabadda otomaatig ah iyo isu-ururinta muunada maktabadda ayaa lagu sameeyay aaladda Ion Chef™. Tirada maktabadaha la diyaariyay ayaa markaas lagu qiimeeyay 3.0Ficient Firimo. , USA) marka loo eego tilmaamaha soo saaraha Suite (SmartSeq srl) iyo Ion Reporter Software.
Dhammaan noocyada kala duwanaanshiyaha waxay raaceen tilmaamaha hadda jira ee Dallada Kala Duwanaanshaha Genome, ee laga heli karo onlayn (HGVS, http://www.hgvs.org/mutnomen) . Sida ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, iyo UMD. Kala soocida waxaa ka mid ah shan qaybood oo khatar ah oo kala duwan: benign (category I), u badan tahay benign (category II), kala duwanaansho aan la hubin muhiimada (VUS, category III), suurto gal ah pathogenic (category IV), iyo pathogenic (qaybta IV), iyo sidoo kale pathogenic (qaybta VARS saamayn ku yeelan karaan qaab-dhismeedka borotiinka). 0 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-GVag.puta .php) Kala duwanaanshiyaha loo kala saaray sida fasalka 1 iyo 2 waxa loo tixgeliyey nooca duurjoogta ah.
Isku xigxiga Sanger ayaa xaqiijiyay jiritaanka kala duwanaansho kasta oo cudur-sidaha ah.Si kooban, lammaane asal gaar ah ayaa loogu talagalay kala duwanaansho kasta oo la ogaado iyadoo la adeegsanayo BRCA1 iyo BRCA2 taxanaha tixraaca hidda-wadaha (NG_005905.2, NM_007294.3 iyo NG_012772.3, NM_0300re) ayaa la raacay. damin
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) . noqdaan alaab-weyneyn, oo ka kooban qalab PCR gaar ah, ka dib waxaa lagu falanqeeyay kombuyuutarrada koofiyadda iyo Cofalyser.Net software iyadoo lala kaashanayo miisaska Cofalyser-ga 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 o 2020), the Rodolico of Catania – San Marco” guud ahaan, 389 bukaan 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 muujiyey 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%).
Mawduucyadan, 64 (17%) waxay lahaayeen BRCA1/2 isbeddellada 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% V1US. 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 baaritaannada 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%) luminal B-HER2 +, 2 (5.7%) HER2 + iyo 13 (bukaannada 37.1%) Tmopositive BC2. 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) .Koox-hoosaadka BRCA2-positive, 10 (55.6%), 3% luminal B, Burooyinka 10 (55.6%) waxay ahaayeen luminal B. 6.7%) TNBC iyo 2 (11.1%) waxay ahaayeen luminal A (Jaantus 3).
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 nuqul iyo 1 gelin. Kaliya hal mutation (c.5522delBR) waxay u taagan tahay daahfurka cusub. Beddelkaani wuxuu ku lug leeyahay tirtirka shan nucleotides (CTAAT) ee BRCA1 exon 15, taasoo keentay beddelka amino acid leucine ee tyrosine ee codon 1679, iyo iyadoo ay ugu wacan tahay qaab tarjumaad ah oo leh codon joojin kale oo la saadaaliyay inay horseed u tahay goynta borotiinka ee PV. Dhammaan isbeddellada kale ayaa laga helay hal goob oo keliya 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 ayaa ku soo noqnoqday dadkeenna, c.428dup iyo c.8487+1G>A lagu arkay 3 maaddooyinka, oo ay ku xigto c.5851_5854delAG in C.5851.8 on 5 of BRCA2, saadaaliyay in ay encode a la jarjaray, protein aan shaqaynayn.C.8487+1G>Isbeddelku waxa uu ka dhacaa gobolka intronic ee BRCA2 intron 19 (± 1,2) oo saameeya isku xigxiga consensus ee splicing, taasoo keentay in splicing isbedelay taasoo keentay in protein aan caadi ahayn ama c.5. si loo tirtiro 4-nucleotide oo ka soo jeeda boosaska nucleotide 5851 ilaa 5854 ee codeing exon 10 ee hidda-wadaha BRCA2 iyo natiijooyinka qaab tarjumaad ah oo leh codon joojin kale oo la saadaaliyay (p.S1951WfsTer) Waxay ku lug leedahay 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 oo leh sifooyin aad u eg 2.Isbeddelka c.7008-2A>T wuxuu dhalin karaa qoraallo badan oo dhererkoodu kala duwan yahay. Intaa waxaa dheer, kooxda BRCA2 PVs, 4 ka mid ah 18 isbeddel (22.2%) waxay ahaayeen kuwo gudaha ah.
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 (OCCR) (Jaantus. 32A7) gobolka iyo 42.8% isbeddellada waxay ku yaalliin OCCR (Jaantus. 4B) .Marka xigta, waxaan qiimeynay meesha PV ee gudaha BRCA1 iyo BRCA2 borotiinka. Isbeddellada gudaha iyo 3 exonic ayaa lagu ogaaday oligo/oligosaccharide-binding (OB) iyo munaaradda (T) domains (Jaantus 4B).
Jaantuska 4 Qaabka qaabaynta borotiinka BRCA1 iyo BRCA2 iyo deegaanaynta noocyada cudurada. Tiradani waxa ay muujinaysaa qaybinta BRCA1 (A) iyo BRCA2 (B) kala duwanaanshaha pathogenic ee bukaanada kansarka naasaha borotiinku waxa uu ka kooban yahay domain loop (RING) iyo isku xigxiga deegaanaynta nukliyeerka (NLS), gariiradda duuban, domain SQ/TQ cluster domain (SCD), iyo BRCA1 C-terminal domain (BRCT) . iyo NLS dhanka C. Meelaha lagu magacaabo Gobolka Kooxda Kansarka Naasaha (BCCR) iyo Gobolka Kooxda Kansarka Ugxan-sidaha (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%, xadka <10-90%). Mawduucyada Ki-67 <25% waxaa lagu qeexay "Ki-67" hoose, halka shakhsiyaadka leh qiyamka ≥ 25% loo tixgeliyey "Ki-67 sare" . Sawirka 5A).
Jaantuska 5 Xidhiidhka Ki-67 oo leh darajada qaybinta kansarka naasaha dumarka leh iyo kuwa aan lahayn BRCA1 iyo BRCA2 PVs. galay kooxaha darajada histological (G2 iyo G3) marka loo eego BRCA1 iyo BRCA2 heerka beddelka (madooyinka WT, BRCA1 iyo BRCA2 PVs sideyaal).
Sidoo kale, waxaan baarnay in heerka burada uu xiriir la leeyahay joogitaanka BRCA1 / 2 PV. Maadaama G1 BC ay ka maqan tahay dadkeena, waxaan u qaybinay bukaanada laba kooxood (G2 ama G3) 005) (Jaantuska 5B).
Horumarka laga sameeyay tignoolajiyada isku xigxiga DNA-da ayaa suurtageliyay horumar aan horay loo arag oo laga sameeyay BRCA1/2 baaritaanka hidda-socodka, oo leh saameyn muhiim ah bukaannada leh taariikhda qoyska ee kansarka 37 gudaha Talyaaniga, heerka BRCA1 / 2 PVs wuxuu u dhexeeyay 8% ilaa 37%, taasoo muujinaysa kala duwanaansho ballaaran oo gudaha ah.
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, si siman loo qaybiyay inta u dhaxaysa BRCA1 iyo BRCA2. Natiijooyinkani waxay la socdaan kuwii hore loogu soo sheegay dadweynaha Talyaaniga. weligood, nimankan midkoodna ma soo saarin BRCA1/2 PV, sidaa darteed waxay ahaayeen musharraxiinta falanqaynta molecular ee dheeraadka ah si meesha looga saaro joogitaanka isbeddellada aan caadiga ahayn sida PALB2, RAD51C iyo D, iyo kuwo kale. Kala duwanaanshaha muhiimada aan la hubin ayaa lagu soo celiyay 7% maadooyinka BRCA2 VUS ay caddahay.
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 lagu arkay 1.1. T> G iyo c.5266dupC) ayaa caadi ahaan laga helaa Yuhuuda Ashkenazi ee Bariga iyo Bartamaha Yurub (Poland, Czech), Slovenia, Australiya, Hungarian, Belarusian iyo Jarmal ), 44,45 iyo, Maraykanka iyo Argentina, ayaa dhawaan lagu qeexay " kala duwanaansho jeermiska soo noqnoqda" ee bukaannada Talyaaniga ee bukaanka BC iyo 4 OC. ee Palermo iyo Messina. Waxa xiiso leh, xitaa Incorvaia et al.laga helay kala duwanaanshaha c.3253dupA ee qoysaska qaar 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 loo soo sheegay 28 bukaan ku sugan Palermo oo leh c.4555 Qoysaska ku nool waqooyi-galbeed ee Sicily, badi ahaan gobollada Trapani iyo Palermo, halka c.5851_5854delAGTT PV lagu arkay guryaha waqooyi-galbeed ee Sicily. 8487+1G>Ka duwanaanshiyaha ayaa aad ugu badnaa maadooyinka Messina, Palermo, iyo Caltanissetta.28 Rebbeck et al.Horey loogu sharaxay 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) Taas oo aan u maleynay in lagu kala soocay habka cis, sidii hore loo sheegay sidaas oo kale.
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 ugxan-sidaha 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. Gobollada OCCR iyo BCCR iyo astaamaha BC.Tani waxaa sabab u ah tirada xaddidan ee bukaannada leh isbeddellada BRCA1/2. Marka laga eego aragtida domain-ka borotiinka, BRCA1 PVs 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 kiliinikada 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. Inkastoo qiimeynta iyo tarjumaadda Ki-67 ay weli tahay mid muran leh, waxaa hubaal ah in heerarka sare ee sare u kaca ay la xiriiraan khatarta sii kordheysa ee soo noqoshada cudurka " iyo hoos u dhigista taariikhda Ki-67. 7 waa 20%, si kastaba ha ahaatee, xadkani ma khuseeyo bukaankeena BRCA1 / 2 isbeddelka bukaan-socodka, kaas oo leh dhexdhexaad Ki-67 qiimaha 25%. gnosis.53,54 Natiijooyinka falanqayntayada, isku xidhka muhiimka ah maaha wax la yaab leh. Waxay ku dhacdaa inta u dhaxaysa Ki-67 sare iyo darajooyinka iyo joogitaanka BRCA1 PV. Dhab ahaantii, burooyinka BRCA1 ee la xidhiidha TNBC waxay muujinayaan sifooyin badan oo gardarro ah.16,17
Gebogebadii, daraasaddan ayaa bixisa warbixin ku saabsan heerka is-beddelka ee BRCA1 / 2 ee kooxda BC ee bariga Sicily. Guud ahaan, natiijooyinkayagu waxay la socdaan caddaynta hore, labadaba marka la eego isbeddelka isbeddelka iyo sifooyinka bukaan-socodka ee BC. Daraasado badan oo dad badan oo BRCA1 / 2-mutant BC ah oo bukaanno ah, sida isticmaalka joogtada ah ee falanqaynta mutagenome ee bukaannada BC, sida isticmaalka joogtada ah ee falanqaynta kala duwan 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 dhaafey dib-u-eegis anshaxeed sababtoo ah BRCA1/2 bukaanada ayaa sidoo kale la siiyay falanqayn qoraal ah oo ku saabsan bukaanada loo isticmaalo si waafaqsan falanqeynta bukaanada. ee xogtooda ujeeddooyin 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