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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 Machera, 1 Maperimental Clinic, 1 Dhipatimendi reMaperimental uye Maperinze Clinic1 University of Catania, 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) uye zvimwe zvinosanganiswa nehupenyu hwehupenyu hwekenza.Kuongororwa kweBRCA gene chinhu chinokosha pakuongorora njodzi yega yega, pamwe nekutsvaga nzira dzekudzivirira muvatakuri vane hutano uye kugadzirisa marapirwo muvarwere vekenza. kunyange zvazvo data iripo paBRCA pathogenic variants mumhuri dzeSicilian, zvidzidzo zvakanangana nevanhu vekumabvazuva kweSicily hazvisipo.Chinangwa chekudzidza kwedu chaiva chekuongorora kuitika nekuparadzirwa kweBRCA pathogenic germline alterations muboka revarwere veBC kubva kumabvazuva kweSicily uye kuongorora kushamwaridzana kwavo neBC maitiro chaiwo vachishandisa kushandura chizvarwa chekuwedzera uye kuwedzera kwekukura kwechirwere chinotevera. index.RESULTS: Pakazara, varwere makumi matatu nevashanu (9%) vaive neBRCA pathogenic variant, 17 (49%) muBRCA1 uye 18 (51%) muBRCA2.BRCA1 shanduko dzakanyanya mune triple-negative BC varwere, nepo BRCA2 kuchinja kunowanzoitika mu luminal BC varwere. proliferative index.Mhedziso: Zvatikawana zvinopa mhedziso yeBRCA mutational status muBC varwere vanobva kumabvazuva kweSicily uye inosimbisa basa rekuongorora kweNGS mukuziva varwere vane nhaka BC.Pakazhinji, 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, zviratidzo zvakati wandei zvinoshandiswa kuisa BC muzvikamu zvakasiyana-siyana zvema molecular subtypes.Idzo isrogen (ER) uye/kana progesterone yemunhu (Pgder2 receptor) receptor (Pgder2HER) amplification, proliferation index Ki-67 uye tumor grade (G) .2 Kubatanidzwa kwezvipembenene izvi zvakaratidza zvinotevera BC zvikamu: 1) Luminal tumors, kuratidza ER uye / kana PgR kutaura, yakaverengera 75% yeBCs. Aya mazamu akaparadzaniswa zvakare kuva Luminal A, apo Ki-67 yakanga iri pasi pe20% uye HER2 yakanga yakaenzana kana 60% yakaenzana, uye 60 yeB-62 yaivapo, uye 60-62. HER2 kukwidziridzwa, zvisinei nekuwedzera 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 mumhando dzakasiyana-siyana.8 Zvidzidzo zviviri zvakakura zveepidemiological zvinosanganisira zvinopfuura 180,000 vakadzi genes ichangobva kuonekwa, BCAARDie, A 1000 vakadzi vachangobva kuonekwa TM TM 1, A, A. BRCA2, CHK2, PALB2, RAD51C, uye RAD51D) inonyanya kukonzera nhaka BC.Pakati pemajini aya, BRCA1 uye BRCA2 (inozonzi BRCA1 / 2) yakaratidza kuwirirana kwakasimba nekusimudzirwa kwemazamu emuzamu.9-12 Zvechokwadi, germline zvakanaka sehupenyu hwehutachiona hunowedzera zvakanyanya BRCA / life BRCA1. kusanganisira ovarian, prostate, pancreatic, colorectal, uye melanoma.Kubva pazera re13 kusvika kumakore makumi masere, chiitiko chekuwedzera kweBC 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 kwaisanganiswa nemhando dzakasiyana-siyana dzehupenyu uye kliniki.16,17 BRCA1-yakabatana BCs inowanzova yekiriniki yechisimba, isina kunyatsosiyanisa, uye yakawanda kwazvo.Izvi zvipembenene zvinowanzoita katatu zvisina kunaka uye zvine zera rekutanga.Mapundu anoitika muBRCA1-akabatanidzwa BCs anowanzova ane hutsinye muchipatara, asina kunyatsosiyanisa, uye anowedzera zvakanyanya.Matumbu aya anowanzoita katatu asina kunaka uye ane zera rekutanga. proliferative indices.Izvi zvipembenene zvinowanzoonekwa mu lumen B uye zvinowanzoitika kune vanhu vakuru.16-18 Zvinonyanya kukosha, kuchinja muBRCA1 uye BRCA2 kunowedzera kunzwisisika kune mamwe marapirwo, 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 for cancer susceptibility syndromes, kusanganisira BRCA1 / 2.21 Saizvozvo, tsananguro dzinobva pamaitiro chaiwo ane chekuita nenhoroondo yemhuri , demographic, uye clinicopathological maitiro kuti vaone zviri nani vanhu veCA1/222222222222222222 yekuongorora iyi. kuunganidza paBRCA1 / 2 kuongorora muhuwandu hwevanhu, kuratidza misiyano munzvimbo dzakasiyana-siyana.24-27 Kunyange zvazvo kune mishumo yeBC cohort kumadokero kweSicily, data shoma inowanikwa paBRCA1 / 2 kuongorora kumabvazuva kweSicily.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 ongororo. Declaration yeHelsinki, uye vese vatori vechikamu vakapa mvumo yakanyorwa yakanyorwa isati yaitwa mamorekuru kuongororwa.
Histological and biological features (ER, PgR, HER2 mamiriro, Ki-67, uye giredhi) yeBC yakaongororwa pa core biopsy kana kuvhiyiwa samples, tichitarisa chete aggressive tumor components.Kubva pane izvi hunhu, BCs dzakarongedzerwa sezvizvi: luminal A (ER+ uye/kana PgR+, HER2-, BIG+R), HER2- (ER20, Ki-R-6,7) HER2-, Ki-67≥20%), luminal B-HER2+ (ER uye/kana PgR+, HER2+), HER2+ (ER uye PgR-, HER2+) kana katatu negative (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 ndokuunganidzwa mumachubhu eEDTA (BD Biosciences).Genomic DNA yakaparadzaniswa kubva pa0.7 mL yese yeropa samples pachishandiswa QIAsymphony DSP DNA Midi kit Isolation Kit (QIAGEN, Hilden, Italy) maererano nemirairo yemugadziri uye yakapfuura ne3rometer yeFish. Scientific, Waltham, 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. (NM_000059.3) majini Qubit® 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) maererano nemirairo yemugadziri.Pakupedzisira, maraibhurari anosanganiswa muequimolar ratios muIon Chef™ library samples chubhu (barcoded chubhu) ndokuiswa paIon Chef™ chiridzwa.Kutevedzana kwakaitwa pachishandiswa Fisher Scient (Thermo Fisher Scientific) uchishandisa Ion 510 Chip (Thermo Fisher Scientific) .Data kuongororwa kwakaitwa neAmplicon Suite (SmartSeq srl) uye Ion Reporter Software.
Zvose zvakasiyana-siyana zvezita zvakatevera 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, https://Interpreting Allemconsline/ kubvunza dhatabhesi dzakasiyana dzakadai seARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, uye UMD.Kuronga kunosanganisira zvikamu zvishanu zvakasiyana zvengozi: benign (category I), ingangove benign (category II), musiyano wekukosha kusingazivikanwe (VUS, category III), ingangoita pathogenic (category IV), uyezve pathogenic (category IV), uye analyogenic effect. mapuroteni maitiro uye basa, chigadziro chekudzidzisa nekuwana 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/) uye Align-G (http://agvgd.hci.utah.edu/agvgd_input.php).Misiyano inoiswa mukirasi 1 ne2 yaitorwa semhando yemusango.
Sanger sequencing yakasimbisa kuvepo kwega kwega pathogenic variant.Muchidimbu, peya yeprimers chaiyo yakagadzirirwa musiyano wega wega wakaonekwa nekushandisa BRCA1 uye BRCA2 gene referensi sequences (NG_005905.2, NM_007294.3 uye NG_012772.3, NM9.000 yakateedzerwa). neSanger kutevedzana.
Varwere vakaongororwa kuti havana BRCA1/2 gene vakaongororwa nemultiplex ligation-dependent probe amplification (MLPA) maererano nemirairo yemugadziri yekuongorora kuvepo kwemahombe genomic rearrangements (LGR).Muchidimbu, maDNA samples anodhindwa uye anosvika makumi matanhatu BRCA1 uye BRCA2 anoshandiswa gene-protectorspecific. kutevedzana dzinenge 60 nucleotides pakureba.Probe amplification products, zvinosanganisira rakasiyana 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.0h20m-Indicep. Gennaio 2020), iyo Rodolico yeCatania - San Marco” zvakazara, varwere mazana matatu nemakumi masere nevapfumbamwe Paive negomarara rezamu, kenza yekenza makumi matatu nenomwe, kenza yepancreatic 16, kenza yeprostate 8 uye melanoma 5. 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%).
Pakati pezvidzidzo izvi, 64 (17%) yakanga ine BRCA1 / 2 kuchinja uye vose vaiva vakadzi. Makumi 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 5 VUS 5 (2%) uye . muBRCA2 (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%. luminal B BC, 2 (11.8%) vaiva neHER2+ chirwere, uye gumi (58.8%) vaiva neTNBC. Tumors pasina BRCA1 mutations angave luminal A kana luminal B-HER2+ (Figure 3) .Muchikamu cheBRCA2-positive, 10 (55.6%) mapundu aiva luminal B. 3, 3% + 3% ye luminal B. (16.7%) TNBC uye 2 (11.1%) yaiva luminal A (Mufananidzo 3) .Hapana HER2 + tumors yaivapo muboka iri. Nokudaro, kuchinja kweBRCA1 kunowanikwa muTNBC varwere, asi BRCA2 kuchinja kunonyanya 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 mune zvose zviri zviviri zvakawanikwa BRCA1V. c.5035_5039delCTAAT.Kuchinja uku kunosanganisira kudzima nucleotides (CTAAT) shanu muBRCA1 exon 15, zvichikonzera kutsiviwa kweamino acid leucine ne tyrosine pacodon 1679, uye nokuda kweshanduro frameshift ine akafanorongedzerwa imwe nzira inomira codon inotungamira kune imwe prema trun inoshanduka. nyaya.Notably, imwe yePVs yakashumwa yaive munzvimbo ye splice site consensus region (c.4357+1G>T) (Table 1).
Nezve BRCA2 PV, takacherechedza 6 deletions, 6 SNVs uye 2 kudzokorora. Hapana shanduko yakawanikwa ibhuku.Kuchinja katatu kwakadzokororwa muhuwandu hwedu, c.428dup uye c.8487 + 1G>A yakaonekwa muzvidzidzo zve 3, inoteverwa ne c.5851_5854kudzokororwa kwechipiri 2AGdup kudzokorora. C in exon 5 ye BRCA2, yakafanotaurwa kuti incode truncated, isiri-functional protein.The c.8487 + 1G> A mutation inoitika munharaunda intronic ye BRCA2 intron 19 (± 1,2) uye inokanganisa splicing consensus sequence, zvichiita kuti kuchinjwa kweprotein kunokonzera absplicing. c.5851_5854delAGTT pathogenic variant inokonzerwa ne 4-nucleotide deletion kubva nucleotide positions 5851 kusvika 5854 mu coding exon 10 ye BRCA2 gene uye inoguma mushanduro frameshift ine yakafanotaurwa imwe stop codon (p.S1951W yakashumwa kare,tasTf yakashumwa kare). c.631G> A uye c.7008-2A> T zvakaonekwa mumurwere mumwe chete.34 Kuchinja kwekutanga kunosanganisira kuchinjwa kweadenosine (A) mu BRCA2 exon 7 ine guanine (G) ine nucleotide inokonzera kuchinja kwevaline kune isoleucine pacodon 211, isoleal inoshandura amino acid inofanana neAmino acid inofanana neAmino acid. splicing.Kusiyana kwechipiri kunowanikwa munharaunda ye intronic uye kunoguma neA double ku thymine (T) substitution before exon 13 ye gene encoding BRCA2.The c.7008-2A>T shanduko inogona kuunza zvinyorwa zvakawanda zvehurefu hwakasiyana.Uyezve, muboka reBRCA2 PVs, 4 yaiva intronic 2%).
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. BRCA5A 4A% mu PV , mu 3% ye PV). nharaunda yeBCCR uye 42.8% yekuchinja kwakange iri muOCCR (Fig. 4B) .Text, takaongorora nzvimbo yePV mukati meBRCA1 uye BRCA2 mapuroteni domains.Kune BRCA1 protein, takawana maPV matatu mu loop uye coil coil domains, uye maviri mutations muBRCT4 mapped mapuroteni, For mapped domains BRCAV2. kune BRC inodzokorora domain, nepo 3 intronic uye 3 exonic shanduko dzakaonekwa mune oligo / oligosaccharide-binding (OB) uye tower (T) domains (Mufananidzo 4B).
Mufananidzo 4 Schematic representation yeBRCA1 uye BRCA2 mapuroteni uye localization of pathogenic variants.Ichi chifananidzo chinoratidza kugoverwa kweBRCA1 (A) uye BRCA2 (B) pathogenic variants muvarwere vekenza yemazamu.Exonic mutations inoratidzwa mubhuruu, nepo intronic variants inoratidzwa muorenji.Kureba kwebhari kunomiririra nhamba yezviitiko.The BRCA21 domains yakashuma.The BRCA21 domains yakashumwa. BRCA1 protein ine loop domain (RING) uye yenyukireya localization sequence (NLS), iyo coiled-coil domain, an SQ/TQ cluster domain (SCD), uye BRCA1 C-terminal domain (BRCT) .(B) BRCA2 protein ine sere BRC inodzokorora, DNA-binding domain ine helical domain oligobinding (Heligobinding) katatu oligobinding (Heligobinding) matatu (Heligobinding) matatu kupeta, a tower domain (T), uye An NLS kudivi reC.Nzvimbo dzinonzi Breast Cancer Cluster Region (BCCR) neOvarian Cancer Cluster Region (OCCR) dzinoratidzwa pazasi.*Inomiririra kuchinja kunoita mastop 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 neKi-67 <25% zvakatsanangurwa se "low Ki-67", asi vanhu vane hutsika ≥ 25% vaionekwa se "high Ki-67" BRCA1 PV vatakuri (Fig. 5A).
Mufananidzo 5 Correlation yeKi-67 ine giredhi kugoverwa mukenza yemazamu vakadzi vane uye vasina BRCA1 uye BRCA2 PVs. kugoverwa kweBC cancer varwere muhistological giredhi mapoka (G2 uye G3) zvinoenderana BRCA1 uye BRCA2 mutation mamiriro (WT zvidzidzo, BRCA1 uye BRCA2 PVs vatakuri).
Saizvozvo, takaongorora kana bundu giredhi rakabatana nekuvapo kweBRCA1/2 PV.Sezvo G1 BC yakanga isipo muhuwandu hwedu, takakamura varwere mumapoka maviri (G2 kana G3) .Zvichienderana nemhedzisiro yeKi-67, ongororo yakaratidza kuwirirana kwakakosha pakati pebundu giredhi uye BRCA1 mutation, ine yakakwira chikamu cheBRCA-inotakura G3 (p<0.005) (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 Iyo inozivikanwa kwazvo BRCA1rum system.35,36. 37 MuItaly, chiyero cheBRCA1/2 PVs chakabva pa8% kusvika pa37%, zvichiratidza kusiyana kwakasiyana-siyana munyika.38,39 Nehuwandu hwevanhu vanosvika mamiriyoni mashanu, Sicily inzvimbo yechishanu pakukura muItaly maererano nehuwandu hwevagari vemo.Kunyange zvazvo data iripo pakuparadzirwa kwemuganhu we BRCA/2 kune humbowo hwakadzama kumavirira kweSisi. chitsuwa.
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 neBRCA2. Izvi zvinoguma zvinoenderana neavo vakambotaurwa muhuwandu hweItaly.28 Zvinofadza, 3% (13 / 389) yeboka redu vaiva varume.Iyi chiyero chakakwirira kudarika inotarisirwa kuvarume vekenza yemazamu (1% ye0% yevose vanosarudza kenza yemazamu BC) BRCA1 / 2 mutation risk.Zvisinei, hapana wevarume ava akagadzira BRCA1/2 PV, saka vakanga vari vanyori vekuwedzera kuongorora kwema molecular kuti vabvise kuvapo kwekuchinja kusingawanzoitiki kwakadai sePALB2, RAD51C uye D, pakati pevamwe.Kusiyana kwekukosha kusina chokwadi kwakadzoserwa mu7% yezvidzidzo umo BRCA2 inoramba iripo nechikonzero ichi chaivapo. uchapupu.28,41,42
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 musiyano uyu 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 mbiri BRCA1 muSiti (c.181T> G uye c.5266dupC) inowanzowanikwa muAshkenazi vaJudha vekuEastern neCentral Europe (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian uye German), 44,45 uye, muUnited States neArgentina, ichangobva kutsanangurwa se "inowanzoitika yakasiyana-siyana yegermline" muItaly BC 4 varwere vaiva neC4. mu8 varwere vekenza yemazamu kubva kuchamhembe kweSicily muPalermo uye Messina.Zvinofadza, kunyange Incorvaia et al. yakawana c.3253dupA musiyano mune dzimwe mhuri muCatania.28 Iyo yakanyanya kumiririra BRCA2 PVs ndeye c.428dup, c.5851_5854delAGTT uye intronic musiyano c.8487+1G>A, izvo zvakashumwa zvakadzama 28 mumurwere muPalermo ane c.52AG5_52AG5 C. yakaonekwa mudzimba dziri kuchamhembe kwakadziva kumadokero kweSicily, kunyanya munzvimbo dzeTrapani nePalermo, nepo c.5851_5854delAGTT PV yakaonekwa mudzimba dziri kuchamhembe kwakadziva kumadokero kweSicily.Iyo 8487 + 1G>Musiyano waive wakajairika muzvidzidzo kubva kuMessina, Palermo, uye Caltanissetta.28 Rebbeck et al. yakambotsanangura c.5851_5854delAGTT shanduko muColombia.37 Imwe BRCA2 PV, c.631+1G>A, yakawanikwa muBC uye OC varwere kubva kuSicily (Agrigento, Siracusa uye Ragusa) .28 Zvinonyanya kukosha, takacherechedza kugarisana kweviri BRCA2 c.6 uye 31GA yakasiyana (BRCA2>A) c.7008-2A> T) mumurwere mumwe chete, 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 iparadze, 47 protein.
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 kwegomarara uye kenza 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 pakati penzvimbo ipi neipi yataive tisingawanikwi. putative OCCR uye BCCR nzvimbo uye BC features.Izvi zvinogona kunge zvakakonzerwa nenhamba shoma yevarwere vane BRCA1 / 2 mutations. Kubva pane mapuroteni domain maonero, BRCA1 PVs inoparadzirwa pamwe chete neprotein yose, uye BRCA2 kuchinja kunonyanya kuwanikwa muBRCA inodzokorora domain.
Pakupedzisira, takabatanidza BC clinicopathological features neBRCA1 / 2 PV.Nekuda kwenhamba shoma yevarwere vakabatanidzwa, takangowana kuwirirana kwakakosha pakati peKi-67 uye giredhi rebundu.Kunyange zvazvo kuongorora uye kududzirwa kweKi-67 kunoramba kuchingokakavadzana, ndeyechokwadi kuti kukwirira kwepamusoro kunobatanidza nehuwandu hwehuwandu hwehutachiona hwehutachiwana hwemazuva ekudzoka uye kusiyanisa kudzoka kwechirwere. "yakakwirira" uye "yakaderera" Ki-67 ndeye 20%.Zvisinei, ichi chikumbaridzo hachishandi kune yedu BRCA1/2 mutation murwere wehuwandu, iyo ine yepakati Ki-67 kukosha kwe 25%.Iyi maitiro epamusoro eKi-67 mazinga anogona kutsanangurwa nekupararira mu luminal yedu B uye TNBC cohorts, izvo zvishomanana luminal A inoratidzika kuti 6 humbowo hwakanga huripo-humwe huchapupu huripo hweKi-67. (25-30%) inogona kugadzirisa zviri nani varwere maererano nekufungidzira kwavo.53,54 Kubva pamigumisiro yekuongorora kwedu, kuwirirana kwakakosha hazvishamisi.Kunoitika pakati peKi-67 yepamusoro uye makirasi uye kuvapo kweBRCA1 PV.Kutaura zvazviri, BRCA1-inoenderana nemararamiro 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 BRCA1 / 2-mutant BC varwere, vakawedzera kuongororwa kushandiswa kwehuwandu hwehuwandu hwehutachiona hweBC, hwakadai sehupo hwakasiyana-siyana hunoita kuti huvepo. yePVs iyo yakasiyana uye isingawanzoitiki kupfuura BRCA1 / 2. Izvi zvichabvumira kuzivikanwa uye kutungamirirwa kwakakodzera kwenhamba inowedzera yezvidzidzo pane kuwedzera kwekenza nekuda kwekuchinja kwemajini.
Takasimbisa kuti varwere vakasaina chibvumirano chekuzivisa 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 pakuongorora kwehutsika nokuti BRCA1 / 2 kuongororwa kwakaitwa maererano nemvumo yekushandiswa kwakanyorwa kwevarwere vose vakapa mvumo yekushandiswa kwekliniki. data yezvinangwa zvekutsvaga.
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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