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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, 16 Marco Fichera University, 1 Medical Clinic, 6 Marco Fichera, 1 Dhipatimendi reMedical, 16, Caperitanial Clinic. , Catania, 95123, Italy;2 Center for Experimental Oncology and Hematology, AOU Policlinico “G.Rodolico – San Marco”, Catania , 95123, Italy;3 Medical Oncology, AOU Policlinico “G.Rodolico – San Marco”, Catania, 95123, Italy;4 Medical Genetics, ARNAS Garibaldi, Catania, 95123, Italy;5 Medicine Genetics, ASP, Syracuse, 96100, Italy;6 Dhipatimendi reBiomedical uye Biotechnology Sayenzi, Yunivhesiti yeCatania, Medical Genetics, Catania, Italy, 95123;7Oasi Research Institute-IRCS, Troina, 94018, Italy Communications: Stefania Stella, tel +39 095 378 1946, email [email protected];[email yakadzivirirwa] Chinangwa: Germline mutations muBRCA1 uye BRCA2 uye yakatanga kenza yemazamu (BC), ovary (OC) nezvimwe zvinosanganiswa nehupenyu hwehupenyu hwekenza.Kuongororwa kweBRCA gene chinhu chinokosha pakuongorora njodzi yemunhu mumwe nomumwe, pamwe nekutsvaga nzira dzekudzivirira muvatakuri vane utano uye kugadzirisa marapirwo muvarwere vekenza.Kuwanda kweBRCA uye kushanduka kwe data pane gerographic nharaunda. BRCA pathogenic variants mumhuri dzeSicilian, zvidzidzo zvakanangana nevanhu vekumabvazuva kweSicily zviri kushaikwa.Chinangwa chekudzidza kwedu chaiva chekuongorora kuitika uye kuparadzirwa kweBRCA pathogenic germline alterations muboka revarwere veBC vanobva kumabvazuva kweSicily uye kuongorora kushamwaridzana kwavo neBC maitiro chaiwo vachishandisa mutsara wechizvarwa chinotevera chechipiri chekutsvaga kwepamusoro-soro uye 3. Varwere ve5 (9%) vaiva ne BRCA pathogenic variant, 17 (49%) mu BRCA1 uye 18 (51%) mu BRCA2.BRCA1 kuchinja kwakawanda kune katatu-negative BC varwere, nepo BRCA2 kuchinja kunowanzoonekwa mu luminal BC varwere.Kuenzaniswa nevasina-vatakuri, zvidzidzo zvemagiredhi zvine BRCArative zvinyorwa zvinopa zvakanyanya kudarika BRCA1 index. BRCA mutational status muBC varwere vanobva kumabvazuva kweSicily uye inosimbisa basa rekuongorora kweNGS mukuziva varwere vane nhaka BC.Pazvose, idzi data dzinoenderana nehumbowo hwekare hunotsigira BRCA kuongororwa kwekudzivirira kwakakodzera uye kurapwa kwekenza muvatakuri vanochinja.
Kenza yemazamu (BC) ndiyo inonyanya kuipa munyika yose uye kenza inouraya zvikuru muvakadzi.1 Zvisikwa zvehupenyu zvinotarisa BC prognosis uye kliniki maitiro akadzidzwa zvakanyanya uye akajekeswa zvishoma nekufamba kwenguva.Kutaura zvazviri, mazita akawanda ezvinyorwa zvinoshandiswa panguva ino kuisa BC muzvikamu zvakasiyana-siyana zvema molecular subtypes.Idzo isrogen (ER) uye/kana estrogen (ER) uye / kana progesterone yemunhu, epiderification yeprogesterone, epiprogesterone yemunhu. ration index Ki-67 uye tumor grade (G) .2 Kusanganiswa kwezvipembenene izvi zvakaratidza zvinotevera BC zvikamu: 1) Luminal tumors, kuratidza ER uye / kana PgR kutaura, yakaverengera 75% yeBCs. Aya mapundu akawedzera kuparadzaniswa kuva Luminal A, apo Ki-67 yakanga iri pasi pe20% uye HER2 yakaipa, uye Luminal B, iyo yakaenzana ne0% kana ye6plification ye HER 2 kana HER2 , apo 0% kana 6plification ye HER2 , kana HER2 , kana HER2 , 0 kana 2 chiyero chehupenyu. index;2) HER2 + mapundu ari ER uye PgR asina kunaka asi anoratidza HER2 amplification.Iri boka rinotora 10% yemakumbo ose emazamu;3) Triple-negative kenza yemazamu (TNBC), iyo isingaratidzi ER uye PgR kutaura uye HER2 amplification, inotora inenge 15% yekenza yemazamu.2-4
Pakati peiyi BC subtypes, bundu giredhi uye proliferation index inomiririra mhiri-sectional biomarkers iyo yakananga uye yakazvimirira yakabatana nebundu hutsinye uye prognosis.5,6
Mukuwedzera kune zvakataurwa pamusoro pezvinyorwa zvehupenyu, basa rekuchinja kwemajini kunokonzera kukura kweBC rave richinyanya kukosha mumakore mashomanana adarika.7 Inenge 1 mu10 mazamu emazamu anogarwa nhaka nekuda kwekuchinja kwegermline mumajeni chaiwo.8 Zvidzidzo zviviri zvakakura zveepidemiological zvinosanganisira zvinopfuura 180,000 vakadzi genes, BCAARDie, ABR, 180,000 vakadzi munguva pfupi yapfuura TM TM 1BR, BCAARD, A1BR K2, PALB2, RAD51C, uye RAD51D) inonyanya kukonzera nhaka BC.Pakati pemajini aya, BRCA1 uye BRCA2 (inozonzi BRCA1 / 2) yakaratidza kuwirirana kwakasimba nekukura kwezvipembenene zvezamu.9-12 Zvechokwadi, germline BRCA1 / 2 nguva yekuchinja kwemararamiro, pancreatic mutation inowedzera zvakanyanya, pancreatic mutation inowedzera zvakanyanya. ectal, uye melanoma.Kubva pazera re13 kusvika kumakore makumi masere, kuwanda kwechiitiko cheBC i72% muvakadzi vane BRCA1 pathogenic variant (PV) uye 69% muvakadzi vane BRCA2 PV.14
Zvinonyanya kukosha, bhuku rechangobva kubudiswa rinoratidza kuti njodzi yeBC inobva kune rudzi rwePV.Kutaura zvazviri, kana ichienzaniswa nemhando dzakasiyana-siyana dzepathogenic truncating, glaring missense variants, kunyanya mu BRCA1 gene, inobatanidzwa nekuderedza ngozi yeBC, kunyanya kuvakadzi vakwegura.15
Kuvapo kweBRCA1 kana BRCA2 PV kwaibatanidzwa nemhando dzakasiyana-siyana dzehupenyu uye kliniki.16,17 BRCA1-yakabatanidzwa BCs inowanzova yekiriniki yehasha, isina kusiyanisa zvakanaka, uye inopararira zvikuru.Matundu aya anowanzoita katatu asina kunaka uye ane zera rekutanga.Mapundu anoitika muBRCA1-akabatanidzwa BCs anowanzova ane hutsinye muchipatara, asina kunyatsosiyanisa, uye anowedzera zvakanyanya.Izvi zvipembenene zvinowanzoita katatu zvakashata uye zvine zera rekutanga. se tumors inowanzoonekwa mu lumen B uye inowanzoitika kune vakwegura vakuru.16-18 Zvinonyanya kukosha, kuchinja muBRCA1 uye BRCA2 kunowedzera kunzwisisika kune mishonga chaiyo, kusanganisira platinum salts uye zvinodhaka zvinotarisirwa zvakadai sepoly (ADP-ribose) polymerase inhibitors (PARPi) .19,20
Mumakore mashoma apfuura, kushandiswa kwechizvarwa chinotevera sequencing (NGS) mumakiriniki maitiro kwakagonesa kuwedzera kwenhamba yevarwere veBC kuti vaongororwe mamolecular susceptibility syndromes, kusanganisira BRCA1/2.21 Saizvozvowo, tsananguro dzinobva pamaitiro chaiwo ane chekuita nenhoroondo yemhuri , demographic, uye clinicopathological maitiro kuti vaone zviri nani vanhu vakakodzera2322232223222322322232223222222 yekuongorora izvi. BRCA1 / 2 kuongorora muhuwandu hwevanhu, kuratidza misiyano munzvimbo dzakasiyana-siyana.24-27 Kunyange zvazvo kune mishumo pamusoro peBC cohort kumadokero kweSicily, data shoma inowanikwa paBRCA1 / 2 kuongorora munharaunda yeSicily yekumabvazuva.28,29
Isu tinotsanangura pano mhedzisiro yegermline BRCA1/2 yekuongorora muBC varwere vanobva kumabvazuva kweSicily, tichiwedzera kuwiriranisa kuvepo kweBRCA1 kana BRCA2 kuchinja kweiyo klinikipathological maitiro emamota aya.
Ongororo yakadzokororwa yakaitwa pa "Center for Experimental Oncology and Hematology" paPoliclinico Hospital.Rodolico - San Marco muCatania.Kubva muna Ndira 2017 kusvika Kurume 2021, huwandu hwevarwere mazana mana nemakumi mashanu neshanu vane mazamu uye ovarian, melanoma, pancreatic kana prostate cancer vakaendeswa kune yedu molecular diagnostic BRCAratory test with the BRCAratory test. lsinki, uye vese vatori vechikamu vakapa mvumo yakanyorwa yakanyorwa isati yaitwa mamorekuru kuongororwa.
Histological and biological characters (ER, PgR, HER2 status, Ki-67, uye giredhi) yeBC yakaongororwa pa core biopsy kana sampuli yekuvhiya, tichitarisa chete aggressive tumor components.Kubva pane izvi maitiro, BCs akaiswa sezvizvi: luminal A (ER+ uye/kana PgR+, HER2-, HER20 , HER20 , Ki- 6,7) -67≥20%), luminal B-HER2+ (ER uye/kana PgR+, HER2+), HER2+ (ER uye PgR-, HER2+) kana katatu yakaipa (ER uye PgR-, HER2-).
Vasati vaongorora mamiriro ekuchinja kweBRCA1 uye BRCA2, chikwata chemarudzi akawanda chinosanganisira oncologist, geneticist, uye psychologist vakaita bundu genetics kubvunza kumurwere wega wega kuti vaone kuvepo kweBRCA1 uye/kana BRCA1.kana vanhu vane ngozi yakawanda yePV mu BRCA2 gene.Kusarudzwa kwemurwere kwakaitwa maererano neItaly Society of Medical Oncology (AIOM) mirayiridzo uye mazano emunharaunda yeSicilian.30,31 Izvi zvinosanganisira: (i) nhoroondo yemhuri yezvinozivikanwa zvakasiyana-siyana zvepathogenic mumagetsi ekunzwa (eg, BRCA1, BRCA2, TP53, PTEN);(ii) varume vane BC;(iii) avo vane BC neOC;(iv) vakadzi vane BC <36 years, TNBC <60 years, kana bilateral BC <50 years;(v) nhoroondo yezvehutano yeBC <50 makore uye imwe yehama yekutanga-dhigirii: (a) BC <50 makore;(b) isiri-mucinous uye isina-borderline OC yezera ripi zvaro;(c) nyika mbiri BC;(d) murume BC;(e) kenza yepancreatic;(f) kenza yeprostate;(vi) mbiri kana kupfuura Yemunhu nhoroondo yeBC> 50 makore uye nhoroondo yemhuri yeBC, OC, kana pancreatic cancer yehama dziri hama dzekutanga dhigirii kune mumwe nemumwe (kusanganisira hama dzaari dhigirii rekutanga hama);(vii) Nhoroondo yega yeOC uye ingangoita imwe yekutanga-dhigirii hama: (a) BC <50 makore;(b) NOC;(c) nyika mbiri BC;(d) murume BC;(vii) mukadzi ane high-grade serous OC.
A 20 mL peripheral blood sample yakawanikwa kubva kumurwere wega wega uye yakaunganidzwa mumachubhu eEDTA (BD Biosciences).Genomic DNA yakaparadzaniswa kubva ku0.7 mL yese yeropa samples pachishandiswa QIAsymphony DSP DNA Midi kit Isolation Kit (QIAGEN, Hilden, Italy) maererano nemirairo yemugadziri uye yakapfuura ne3. , MA, USA) Ita quantification.Kuvandudza chinangwa uye kugadzirira raibhurari kunoitwa neOncomine™ BRCA Research Assay Chef, yakagadzirira kutakurwa muIon AmpliSeq™ Chef Reagents DL8 Kit yekugadzira otomatiki raibhurari maererano nemirairo yemugadziri.Kiti iyi ine maviri multiplex PCR primer madziva anogona kushandiswa kudzidza ese BRCA7 (3M0030) BRCA7 (N5M0030). Muchidimbu, 15 µL yega yega diluted sample DNA (10 ng) yakawedzerwa kumabarcoded plates ekugadzirira raibhurari uye zvese reagents uye zvinodyiwa zvakaiswa paIon Chef™ chiridzwa.Automated library library and barcoded sample library pooling yakazoitwa paIon Chef™ chiridzwa.Chiverengero chebhiti®rori yakagadziridzwa neFish® yakazoitwa Quore 3 metres. cientific, Waltham, MA, USA) maererano nemirairo yemugadziri.Pakupedzisira, maraibhurari anosanganiswa muequimolar ratios muIon Chef™ library samples chubhu (barcoded tubes) ndokuiswa paIon Chef™ chiridzwa.Kutevedzana kwakaitwa pachishandiswa Ion Torrent S5 (Thermo Fisher Scientific) pachishandiswa Ion Chef™ Chiredzi Scientific).Kuongorora kwedata kwakaitwa neAmplicon Suite (SmartSeq srl) uye Ion Reporter Software.
Mazita ose akasiyana-siyana akatevera mitemo yemazuva ano yeHuman Genome Variation Consortium, inowanikwa paIndaneti (HGVS, http://www.hgvs.org/mutnomen) .Kukosha kwekliniki yeBRCA1/2 zvakasiyana-siyana zvakatsanangurwa pachishandiswa kupatsanurwa kweInternational Consortium ENIGMA (Evidence-Based Network for Interpreting Allemconsline database, https://interpreting Almconsline/ zvakadai seARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, uye UMD.Kuronga kunosanganisira zvikamu zvishanu zvakasiyana-siyana zvengozi: benign (boka I), zvichida benign (boka II), musiyano wekukosha kusinganzwisisiki (VUS, chikwata chechitatu), zvichida pathogenic (boka IV), uye pathogenic (category yeprotein inogadzirisawo V, mutsara weprotein, mutsara weV. kuwana 30 databases.32
Kupa zvingave zvakakosha zvekiriniki kune yega yega VUS, zvinotevera computational protein prediction algorithms yakashandiswa: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/G) uye Align. d_input.php).Misiyano yakarongwa sekirasi 1 ne2 yaionekwa semhando yemusango.
Sanger sequencing yakasimbisa kuvapo kwega kwega pathogenic variant.Muchidimbu, peya yeprimers chaiyo yakagadzirirwa musiyano wega wega wakaonekwa kuburikidza nekushandisa BRCA1 uye BRCA2 gene referensi sequences (NG_005905.2, NM_007294.3 uye NG_012772.3, NM9.00 yakateverwa nePC, NM9.00 yakateedzerwa). ncing.
Varwere vakaongororwa kuti havana BRCA1/2 gene vakaongororwa nemultiplex ligation-dependent probe amplification (MLPA) maererano nemirairo yemugadziri yekuongorora kuvepo kwegenomic rearrangements (LGR) nucleotides pakureba.Probe amplification products, zvinosanganisira yakasarudzika seti yePCR amplicon, zvakabva zvaongororwa necapillary electrophoresis uye neCofalyser.Net software pamwe chete neakakodzera batch-specific Cofalyser tables (www.mrcholland.com).
Kusarudzwa kweklinikipathological variables (histological grade uye Ki-67% proliferation index) yakabatanidzwa nekuvapo kweBRCA1 / 2 PV, yakaverengerwa kushandisa Prism software v. 8.4 vachishandisa Fisher's exact test vachifunga kuti p-value <0.05 inokosha.
Pakati paNdira 2017 naKurume 2021, varwere mazana mana nemakumi mashanu nevashanu vakavhenekwa germline BRCA1/2 mutations.Kuongororwa kwekuchinja kwekuchinja kwakaitwa paPoliclinico Hospital's Center for Experimental Oncology and Hematology.Maererano neSicilian guideline (http://www.gurs.regione.sicilia.it.0h20Indicep-1,0811-Veticep-Indicep, 2020), iyo Rodolico yeCatania - San Marco” zvakazara, varwere mazana matatu nemakumi masere nevapfumbamwe Paive negomarara rezamu, makumi matatu nenomwe kenza ye ovarian, gumi nematanhatu kenza yepancreatic, 8 kenza yeprostate uye 5 melanoma.Kugoverwa kwevarwere zvinoenderana nerudzi rwegomarara uye mhedzisiro yekuongorora inoratidzwa muMufananidzo 1.
Mufananidzo 1 unoratidza kuyerera kwechati inoratidza muchidimbu chekudzidza.Varwere vane mazamu, melanoma, pancreatic, prostate, kana ovarian tumors vakaedzwa kuti vashanduke muBRCA1 uye BRCA2 majini.
Mhedziso: PVs, pathogenic variant;VUS, mutsauko wekusava nechokwadi kukosha;WT, yemusango-mhando BRCA1/2 kutevedzana.
Isu takasarudza takaisa zvidzidzo zvedu pamapoka ekenza yemazamu.Varwere vaive nezera repakati pemakore makumi mana nemapfumbamwe (range 23-89) uye vaive vakadzi vazhinji (n = 376, kana 97%).
Pazvidzidzo izvi, 64 (17%) yakanga ine BRCA1/2 kuchinja uye vose vaiva vakadzi. Makumi matatu neshanu (9%) vaiva nePV uye 29 (7.5%) vaiva neVUS. Gumi nenomwe (48.6%) ye35 pathogenic variants yakaitika muBRCA1 uye 18 (51.4%) muBRCA2, nepo 51.4%) mu. (Mifananidzo 1 uye 2) LGR yakanga isipo mukuongorora kweMLPA.
Mufananidzo 2. Kuongororwa kweBRCA1 uye BRCA2 kuchinja mune varwere vekenza yemazamu 389. (A) Kugoverwa kwepathogenic variants (PV) (tsvuku), zvakasiyana-siyana zvekukosha kusinganzwisisiki (VUS) (orange), uye WT (bhuruu) mune 389 varwere vekenza yemazamu;(B) 389 varwere vekenza yemazamu Makumi matatu neshanu (9%) vaiva neBRCA1 / 2 pathogenic variants (PVs) .Pakati pavo, 17 (48.6%) vaiva BRCA1 PV vatakuri (yakasviba tsvuku) uye 18 (51.4%) vaiva BRCA2 vatakuri (chiedza chitsvuku);(C) 29 (7.5%) yezvidzidzo zve389 ​​zvakatakura VUS, 5 (17.2%) BRCA1 genes (dark orange) uye 24 (82.8%) BRCA2 genes (light orange).
Mhedziso: PVs, pathogenic variant;VUS, mutsauko wekusava nechokwadi kukosha;WT, yemusango-mhando BRCA1/2 kutevedzana.
Takazoongorora kuwanda kweBC molecular subtypes muvarwere vane BRCA1/2 PV. Kugoverwa kwaisanganisira 2 (5.7%) luminal A, 15 (42.9%) luminal B, 3 (8.6%) luminal B-HER2+, 2 (5.7%) HER2+ uye 13 (37.1%) pakati pevarwere veTNBC, 5. , 2 (11.8%) yakanga ine HER2 + chirwere, uye gumi (58.8%) yakanga ine TNBC. Tumors pasina BRCA1 mutations angave luminal A kana luminal B-HER2 + (Figure 3) . Muchikamu cheBRCA2-positive, 10 (55.6%) mapundu akanga ari luminal B, 3 (16) BBC (16%) uye 16 BBC . .1%) yakanga iri luminal A (Mufananidzo 3) .Hapana HER2 + tumors yakanga iripo muboka iri.Saka, kuchinja kweBRCA1 kwakawanda kune varwere veTNBC, asi BRCA2 kuchinja kwakanyanya mu lumen B vanhu.
Mufananidzo 3 Kuwanda kwekenza yemazamu subtypes muvarwere vane pathogenic variants mu BRCA1 uye BRCA2.Histograms inoratidza kugoverwa kweBRCA1- (yakasviba tsvuku) uye BRCA2- (chiedza tsvuku) PVs pakati pemamolecular subtypes evarwere vekenza yemazamu.Nhamba dzakashumwa mukati mebhokisi rimwe nerimwe dzinomiririra chikamu chevarwere vane BRCA1 uye BRCA2 yekenza yemazamu.
Mhedziso: PVs, pathogenic variant;HER2 +, epidermal kukura factor receptor 2 yakanaka;TNBC, kenza yemazamu ine katatu isina kunaka.
Zvadaro, takaongorora rudzi uye gene localization yeBRCA1 uye BRCA2 PVs.Mu BRCA1 PV, takacherechedza 7 single nucleotide variants (SNVs), 6 deletions, 3 duplications uye 1 kuiswa.Kushandura kumwe chete (c.5522delG) kunomiririra kutsva kunowanikwa 553 Vs yakawanikwa 530 yakawanda inowanikwa BRCA50. 9delCTAAT.Kushandura uku kunosanganisira kubviswa kwema nucleotides mashanu (CTAAT) muBRCA1 exon 15, zvichiita kuti kuchinjwa kweamino acid leucine ne tyrosine pacodon 1679, uye nekuda kweshanduro frameshift ine yakafanotaurwa imwe stop codon inotungamirira kune premature protein truncation imwe chete inowanikwa muPtaV imwe chete yakawanikwa muPtaV imwe chete yakaonekwa muPtaV imwe chete yakawanikwa muPtaV. splice site consensus region (c.4357+1G>T) (Table 1).
Nezve BRCA2 PV, takacherechedza 6 deletions, 6 SNVs uye 2 kudzokorora. Hapana chekuchinja kwakawanikwa ibhuku.Matanho matatu akadzoka zvakare muhuwandu hwedu, c.428dup uye c.8487 + 1G>A yakaonekwa muzvidzidzo zve3, inoteverwa ne c.5851_5854kudzokororwa kwechipiri 2AGdup kudzokorora c. 5 yeBRCA2, yakafanotaurwa kuti incode truncated, isiri-functional protein.The c.8487 + 1G>A mutation inoitika munharaunda intronic yeBRCA2 intron 19 (± 1,2) uye inokanganisa splicing consensus sequence, zvichiita kuti kuchinjwa kwezvipembenene kunokonzera absent541protein absent58del absent541protein. kune 4-nucleotide deletion kubva nucleotide positions 5851 kusvika 5854 mu coding exon 10 ye BRCA2 gene uye inoguma nekushandura frameshift ine yakafanotaurwa imwe nzira yekumisa codon (p.S1951WfsTer) . Zvinonyanya kukosha, sezvakambotaurwa, zvose zvakashandurwa c.837G uye C. Kuchinja kwekutanga kunosanganisira kuchinjwa kweadenosine (A) mu BRCA2 exon 7 ine guanine (G) ine nucleotide inokonzera kuchinja kwevaline kune isoleucine pacodon 211, isoleucine Amino acid inonzi amino acid ine zvinhu zvakafanana. 13 yejini encoding BRCA2.The c.7008-2A>T shanduko inogona kuunza zvinyorwa zvakawanda zvehurefu hwakasiyana.Uyezve, muboka reBRCA2 PVs, 4 kubva ku18 shanduko (22.2%) dzaive intronic.
Takabva taronga BRCA1/2 deleterious mutations in functional domains and protein-binding regions (Fig. 4) .Mune BRCA1 gene, 50% yePVs yakanga iri munharaunda yekenza yemazamu (BCCR), nepo 22% yekuchinja kwacho kwaiva munharaunda yekenza ye ovarian cluster region (OCCR) (Fig. BRCA52 BCR munharaunda yePCR 4A 4A 7A). uye 42.8% yekuchinja kwakange kuri muOCCR (Fig. 4B) .Tevere, takaongorora nzvimbo yePV mukati meBRCA1 uye BRCA2 mapuroteni domains.Kune BRCA1 protein, takawana matatu PVs mu loop uye coil coil domains, uye maviri mutations muBRCT domain (For the Fig., mapped to the 4A). intronic uye 3 exonic shanduko dzakaonekwa mune oligo / oligosaccharide-binding (OB) uye shongwe (T) domains (Mufananidzo 4B).
Figure 4 Schematic representation yeBRCA1 uye BRCA2 mapuroteni uye localization of pathogenic variants.Ichi chifananidzo chinoratidza kugoverwa kweBRCA1 (A) uye BRCA2 (B) zvakasiyana-siyana zvepathogenic muvarwere vekenza yemazamu.Exonic mutations inoratidzwa mubhuruu, nepo intronic variants inoratidzwa muorenji.Kureba kwebhari kunomiririra nhamba yezviitiko.The BRCA21 domain ine mapuroteni ekushanda uye BRCA21 yakataurwa. a loop domain (RING) uye yenyukireya localization sequence (NLS), iyo coiled-coil domain, SQ/TQ cluster domain (SCD), uye BRCA1 C-terminal domain (BRCT) .(B) BRCA2 protein ine sere BRC inodzokorora, DNA-binding domain ine helical domain (Helical), matatu oligonucles, OB-Tharide (Oligonucleotide) uye TQAnharide (Oligonucleotide). NLS kudivi reC.Nzvimbo dzinodaidzwa kuti Breast Cancer Cluster Region (BCCR) neOvarian Cancer Cluster Region (OCCR) inoratidzwa pazasi.*Inomiririra kuchinja kunoita ma<em>stop codon.
Takazoongorora BC clinicopathological features inogona kuwirirana nekuvapo kweBRCA1 / 2 PV. Complete kliniki zvinyorwa zvaive zviripo kune 181 BRCA1 / 2-negative varwere (vasiri vatakuri) uye vose vatakuri (n = 35) .
Takaverenga kugoverwa kweKi-67 zvichienderana nepakati peboka redu (25%, range <10-90%). Zvidzidzo zvine Ki-67 <25% zvakatsanangurwa se "low Ki-67", nepo vanhu vane hutsika ≥ 25% vaionekwa se "high Ki-67" vatakuri (Fig. 5A).
Mufananidzo 5 Correlation yeKi-67 ine giredhi kugoverwa mukenza yemazamu vakadzi vane uye vasina BRCA1 uye BRCA2 PVs. varwere vekenza kupinda histological giredhi mapoka (G2 uye G3) zvinoenderana BRCA1 uye BRCA2 mutation mamiriro (WT zvidzidzo, BRCA1 uye BRCA2 PVs vatakuri).
Saizvozvo, takaongorora kana bundu giredhi yakabatana nekuvapo kweBRCA1/2 PV. Sezvo G1 BC yakanga isipo muhuwandu hwedu, takakamura varwere mumapoka maviri (G2 kana G3) .Inoenderana nemhedzisiro yeKi-67, kuongororwa kwakaratidza kuwirirana kwakakosha pakati pebundu giredhi uye BRCA1 mutation, ine yakakwira proports ye05CA ichienzaniswa ne05CA-inonzi tumorcarrier01 BR3CA ichienzaniswa ne01. ) (Mufananidzo 5B).
Kufambira mberi muDNA sequencing tekinoroji kwakagonesa kufambira mberi kusati kwamboitika muBRCA1/2 genetic test, ine zvakakosha kune varwere vane nhoroondo yemhuri yegomarara.Kusvika pari zvino, zvingangoita 20.000 BRCA1/2 zvakasiyana-siyana zvakaonekwa uye zvakarongerwa maererano neAmerican Society of Medical Genetics 35 uye ENIGMA inonyanyozivikanwa iyo BRCA1/36 yakafara system. graphic regions.37 MuItaly, chiyero cheBRCA1/2 PVs chakabva pa8% kusvika ku37%, zvichiratidza kusiyana kwepakati penyika.38,39 Nehuwandu hwevanhu vanosvika mamiriyoni mashanu, Sicily inharaunda yechishanu pakukura muItaly maererano nehuwandu hwevagari vemo.Kunyange zvazvo data iripo pakuparadzirwa kweBRCA1 / 2 chikamu chekumadokero kwechitsuwa chekumadokero hakuna uchapupu hwakadzama.
Kudzidza kwedu ndeimwe yemishumo yekutanga pamusoro pechiitiko che BRCA1 / 2 PV muvarwere veBC kumabvazuva kweSicily.28 Takaisa pfungwa dzedu pakuongorora BC, sezvo ichi ndicho chirwere chinowanzoitika muboka redu.
Paunenge uchiedza varwere ve389 ​​BC, 9% yakatakura BRCA1 / 2 PVs, yakagoverwa zvakaenzana pakati peBRCA1 ne BRCA2.Izvi zvigumisiro zvinopindirana neavo vakambotaurwa muhuwandu hweItaly.28 Zvinofadza, 3% (13 / 389) yeboka redu vaiva varume.Iyi chiyero chakakwirira kudarika chinotarisirwa kune varume vane kenza yemazamu BC (1% 4 BR) kusarudzwa kwechirume BC kusarudzwa kwe2% yeBR. Zvisinei, hapana mumwe wevarume ava akagadzira BRCA1 / 2 PV, saka vakanga vari vanyori vekuwedzera kuongororwa kwema molecular kuti vabvise kuvapo kwekuchinja kusingawanzoitiki kwakadai sePALB2, RAD51C uye D, pakati pevamwe.Kusiyana kwekusakosha kusina chokwadi kwakatorwa mu7% yezvidzidzo umo BRCA2 VUS yakanga iri pachena.Kunyange ichi chigumisiro chiripo,41 inopindirana.
Patakaongorora kugoverwa kweBC molecular subtypes muBRCA1/2 mutant vakadzi, takasimbisa hukama hunozivikanwa pakati peTNBC neBRCA1 PV (58.8%) uye pakati pe luminal B BC ne BRCA2 PV (55.6%).16,43 The luminal A uye HER2 + tumors mu BRCA1 uye BRCA1 uye BRCA1 mutakuri wemabhuku 6 data.
Isu tinobva tatarisa pamhando uye nzvimbo yeBRCA1/2 PV.Muboka redu, BRCA1 PV yakajairika yaiva c.5035_5039delCTAAT.Kunyange zvazvo Incorvaia et al.havana kutsanangura kusiyana uku muboka ravo reSicilian, vamwe vanyori vakazvitaura se germline BRCA1 PV.34 Several BRCA1 PVs yakawanikwa muboka redu - eg c.181T>G, c.514del, c.3253dupA uye c.5266dupC - iyo yakawanikwa 1 BRCA1 muSitaci 2, 28 Mutaci (28 BRCA1) zvakaonekwa. G uye c.5266dupC) inowanzowanikwa muAshkenazi vaJudha vekuEastern neCentral Europe (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian uye German ), 44,45 uye, muUnited States neArgentina, munguva ichangopfuura yakatsanangurwa se "inowanzoitika germline variant" muItaly varwere vane BC uye OC3cant yakambozivikanwa nekenza ye75cant kubva kuchamhembe. muPalermo uye Messina.Zvinofadza, kunyange Incorvaia et al.vakawana iyo c.3253dupA musiyano mune dzimwe mhuri muCatania.28 Iyo inonyanya kumiririra BRCA2 PVs ndeye c.428dup, c.5851_5854delAGTT uye intronic musiyano c.8487+1G>A, izvo zvakashumwa zvakadzama 28 mumurwere muPalerdu ane c.52V8 imba c.52V8 c. kuchamhembe kwakadziva kumadokero kweSicily, kunyanya munzvimbo dzeTrapani nePalermo, nepo c.5851_5854delAGTT PV yakaonekwa mudzimba dziri kuchamhembe kwakadziva kumadokero kweSicily.Iyo 8487 + 1G>Musiyano wainyanya kuwanikwa muzvidzidzo kubva kuMessina, Palermo, uye Caltanissetta.28 Rebbeck et al.yakambotsanangura c.5851_5854delAGTT kuchinjwa muColombia.37 Imwe BRCA2 PV, c.631 + 1G>A, yakawanikwa muBC uye OC varwere vanobva kuSicily (Agrigento, Siracusa uye Ragusa) .28 Zvinonyanya kukosha, takacherechedza kugarisana kweBRCA2 maviri akasiyana-siyana uye 6 c.6 c. , iyo yataifungidzira kuti yakaparadzaniswa mu cis mode, sezvakambotaurwa saizvozvo.34,46 Izvi BRCA2 uble mutations zvechokwadi inowanzoonekwa munharaunda yeItaly uye yakawanikwa ichiunza premature stop codons, inokanganisa mutumwa RNA splicing uye zvichiita kuti BRCA2 protein isakundikana.47,48
Isu takaronga zvakare BRCA1 uye BRCA2 PVs mune putative OCCR uye BCCR matunhu mapuroteni domains uye majini.Matunhu aya akatsanangurwa naRebbeck et al.senzvimbo dzine njodzi yekukura kwekenza yemazamu uye yemazamu, maererano.49 Zvisinei, uchapupu hune chokuita nekubatana pakati penzvimbo yezvipembenene zvakasiyana-siyana uye ngozi yekenza yemazamu kana yevhavha inoramba ichikakavadzana.28,50-52 Muhuwandu hwedu, BRCA1 PVs yainyanya kuwanikwa munharaunda yeBCCR, asi BRCA2 PVs yakanga iri pakati peOCCR yaiwanzowanikwa sei, OCCR yainyanya kuwanikwa. BCCR nzvimbo uye BC features.Izvi zvinogona kunge zvakakonzerwa nenhamba shoma yevarwere vane BRCA1 / 2 mutations.Kubva paprotein domain perspective, BRCA1 PVs inoparadzirwa pamwe chete neprotein yose, uye BRCA2 kuchinja kunonyanya kuwanikwa muBRC kudzokorora domain.
Pakupedzisira, takabatanidza BC clinicopathological features neBRCA1 / 2 PV.Nekuda kwenhamba shoma yevarwere yakabatanidzwa, takangowana kuwirirana kwakakosha pakati peKi-67 uye giredhi rebundu.Kunyange zvazvo kuongorora uye kududzirwa kweKi-67 kunoramba kuchingokakavadzana, ndezvechokwadi kuti huwandu hwehuwandu hwehuwandu hunobatanidza nehuwandu hwehuwandu hwehutachiona hwehutachiona hwehutachiona hwehutachiona uye hutsika hwekudzoka kwechirwere "kuderera" uye kuderera kwechirwere. Ki-67 ndeye 20%.Zvisinei, ichi chikumbaridzo hachishandi kune yedu BRCA1/2 mutation murwere wehuwandu, iyo ine yepakati Ki-67 kukosha kwe25%.Iyi maitiro epamusoro eKi-67 mazinga anogona kutsanangurwa nekupararira mu luminal yedu B uye TNBC cohorts, iyo mashoma luminal A tumors aivepo.Zvisinei, humwe humbowo hwe2-67 hunoita senge huri nani (5-30) humbowo hunoratidza kuti-30 yehumwe humbowo hunoita sezviri nani. kusvika kuprognosis yavo.53,54 Kubva pamigumisiro yekuongorora kwedu, kuwirirana kwakakosha hazvishamisi.Inoitika pakati pepamusoro Ki-67 uye mamakisi uye kuvapo kweBRCA1 PV.Kutaura zvazviri, BRCA1-ane chokuita nemakumbo akafanana neTNBC uye anoratidza mamwe maitiro ane hutsinye.16,17
Mukupedzisa, chidzidzo ichi chinopa mushumo pamusoro pemamiriro ekuchinja kweBRCA1 / 2 muBC cohort kubva kumabvazuva kweSicily.Zvose, zvatinowana zvinopindirana nehumbowo huripo, zvose maererano nekuchinja kwekuchinja uye kliniki yehutano muBC.Zvimwe zvidzidzo muhuwandu hwevanhu ve BRCA1 / 2-mutant BC varwere, vakafanana nePV yakagadziriswa kushandiswa kwevarwere vakawanda, zvakadai sePV yakawedzera kushandiswa kwePV. zvakasiyana uye zvishoma kudarika BRCA1 / 2. Izvi zvichabvumira kuzivikanwa uye kutungamira kwakakodzera kwenhamba inowedzera yezvidzidzo pane kuwedzera kwekenza nekuda kwekuchinja kwemajini.
Takasimbisa kuti varwere vakasaina chibvumirano chekuziva kuti vasunungure mapundu avo vasingazivikanwe nechinangwa chekutsvakurudza.Varwere vose vakasaina chibvumirano chakanyorwa maererano neDeclaration of Helsinki.Maererano nemutemo weAOU Policlinico "G.Rodolico - S.Marco", chidzidzo ichi chakasunungurwa kubva pakuongororwa kwetsika nokuti BRCA1 / 2 kuongororwa kwakaitwa maererano nechinangwa chekutsvakurudza kwakanyorwa kwevarwere uye kubvunzurudzwa kwakanyorwa kwechiremba. .
Tinotenda Prof. Paolo Vigneri nerubatsiro rwake mukuchengeta varwere vegomarara rezamu sezvakakumbirwa neEthics Committee.
Federica Martorana anoshuma honoraria kubva kuIstituto Gentili, Eli Lilly, Novartis, Pfizer.Vamwe vanyori vanozivisa kuti hapana kupesana kwechido mubasa iri.
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