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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 reSainzi dzeBiomedical neBiotechnology, Yunivhesiti yeCatania, Medical Genetics, Catania, Italy, 95123; 7Oasi Research Institute-IRCCS, Troina, 94018, Italy Kutaurirana: Stefania Stella, nhare +39 095 378 1946, email [email protected]; [email protected] Chinangwa: Kuchinja kwemarudzi embeu muBRCA1 neBRCA2 uye kwakaratidza kenza yemazamu (BC), ovary (OC) nezvimwe zvine chekuita nenjodzi yekenza yehupenyu hwese. Kuongororwa kwegene reBRCA kwakakosha pakuongorora njodzi yemunhu mumwe nemumwe, pamwe nekutsvaga nzira dzekudzivirira muvanhu vane hutano uye kugadzirisa marapirwo muvarwere vekenza. Kuwanda kwekuchinja kweBRCA1 neBRCA2 kunosiyana zvakanyanya munzvimbo dzakasiyana-siyana, uye kunyangwe data riripo pamarudzi akasiyana eBRCA mumhuri dzeSicilian, zvidzidzo zvakanangana nevanhu vari kumabvazuva kweSicily hazvipo. Chinangwa chechidzidzo chedu chaive chekuongorora kuwanda uye kupararira kwekuchinja kwemarudzi embeu muBRCA muboka revarwere veBC vanobva kumabvazuva kweSicily uye kuongorora hukama hwavo nehunhu hweBC hwakati uchishandisa kutevedzana kwechizvarwa chinotevera. Kuvapo kwekuchinja kwakabatana negiredhi regomarara uye indekisi yekupararira. Mhedzisiro: Pakazara, varwere makumi matatu nevashanu (9%) vaive nerudzi rweBRCA pathogenic, 17 (49%) muBRCA1 uye 18 (51%) muBRCA2. Kuchinja kweBRCA1 kwakawanda muvarwere veBC vane triple-negative, nepo kuchinja kweBRCA2 kwakajairika muvarwere veluminal BC. Zvichienzaniswa Nevasina kutakura chirwere ichi, vanhu vane mhando dzeBRCA1 vaiva nerudzi rwegomarara rwakakwira zvakanyanya uye huwandu hwechirwere ichi hunowedzera. Mhedziso: Zvatakawana zvinopa ruzivo rwemamiriro ekuchinja kweBRCA muvarwere veBC vanobva kumabvazuva kweSicily uye zvinosimbisa basa rekuongorora kweNGS mukuziva varwere vane BC inogarwa nhaka. Kazhinji, data iri rinoenderana nehumbowo hwekare hunotsigira kuongororwa kweBRCA kuti pave nekudzivirira nekurapa kenza zvakanaka muvanhu vane hutachiona hwekuchinja.
Kenza yemazamu (BC) ndiyo inonyanya kukonzera kenza pasi rose uye ndiyo inonyanya kukonzera kenza muvakadzi.1 Zvinhu zvehupenyu zvinosarudza fungidziro yeBC uye maitiro ekiriniki zvakadzidzwa zvakanyanya uye zvakajekeswa zvishoma nekufamba kwenguva. Kutaura zvazviri, zviratidzo zvakawanda zvinoshandiswa kuisa BC muzvikamu zvakasiyana zvemamorekuru. Izvi zvinosanganisira estrogen (ER) uye/kana progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) amplification, proliferation index Ki-67 uye tumor grade (G).2 Kubatanidzwa kwezvimiro izvi kwakaratidza zvikamu zvinotevera zveBC: 1) Luminal tumors, inoratidza ER uye/kana PgR expression, yakaita 75% yeBCs. Matumbu aya akakamurwa kuita Luminal A, apo Ki-67 yaive pasi pe20% uye HER2 negative, uye Luminal B, apo Ki-67 yaive yakaenzana kana kupfuura 20% uye pamberi peHER2 amplification, zvisinei neproliferation index; 2) Matumbu eHER2+ asina ER nePgR asi anoratidza HER2 amplification. Boka iri rinoita 10% yematumbu ese emazamu; 3) Kenza yemazamu ine katatu (TNBC), iyo isingaratidze ER nePgR expression uye HER2 amplification, inoumba inenge 15% yematumbu emazamu.2-4
Pakati pemhando idzi dzeBC, giredhi regomarara uye indekisi yekupararira kwegomarara zvinomiririra zviratidzo zve cross-sectional zvinobatanidzwa zvakananga uye zvakazvimiririra nekurwisa kwegomarara uye fungidziro yaro.5,6
Kuwedzera kune zvataurwa pamusoro apa, basa rekuchinja kwemajini kwakagarwa nhaka kunotungamira mukukura kweBC rave richikosha zvikuru mumakore mashoma apfuura.7 Inenge 1 pa10 bundu rezamu rinogarwa nhaka nekuda kwekuchinja kwemajini mumajini chaiwo.8 Zvidzidzo zviviri zvikuru zve epidemiological zvinosanganisira vakadzi vanopfuura 180,000 munguva pfupi yapfuura zvakawana boka remajini masere (kureva, ATM, BARD1, BRCA1, BRCA2, CHK2, PALB2, RAD51C, uye RAD51D) zvinonyanya kukonzera BC inogarwa nhaka. Pakati pemajini aya, BRCA1 neBRCA2 (zvinozonzi BRCA1/2) zvakaratidza hukama hwakasimba nekukura kwemabundu emazamu.9-12 Kutaura zvazviri, germline BRCA1/2 mutations inowedzera zvakanyanya njodzi yehupenyu hwese hweBC pamwe nedzimwe kenza, kusanganisira ovarian, prostate, pancreatic, colorectal, uye melanoma. Kubva pazera remakore 13 kusvika 80, kuwanda kweBC kuri 72% muvakadzi vane BRCA1 pathogenic variant (PV) uye 69% muvakadzi vane BRCA2 PV.14
Zvinonyanya kukosha kuti bhuku razvino rinoratidza kuti njodzi yeBC inoenderana nerudzi rwePV. Kutaura zvazviri, zvichienzaniswa nemarudzi anokonzera kuputika kwemasero, marudzi akasiyana-siyana akajeka, kunyanya mujini reBRCA1, ane chekuita nenjodzi shoma yeBC, kunyanya kuvakadzi vakuru.15
Kuvapo kweBRCA1 kana BRCA2 PV kwakabatana nezviratidzo zvakasiyana zvehupenyu uye zvekiriniki.16,17 MaBC ane chekuita neBRCA1 anowanzova akasimba mukurapa, haana kusiyana zvakanaka, uye anopararira zvakanyanya. Mabundu aya anowanzova ne triple negative uye ane zera rekutanga. Mabundu anowanikwa muvarwere vane BRCA2-mutation anowanzo kuratidza magiredhi ari pakati nepakati kusvika akanaka uye zviratidzo zvinopararira zvakasiyana. Mabundu aya anowanzoonekwa mu lumen B uye anowanzoonekwa muvakuru.16-18 Zvinonyanya kukosha kuti, kuchinja muBRCA1 neBRCA2 kunowedzera kunzwa kune mamwe marapirwo, kusanganisira platinum salts nemishonga inotarirwa senge poly(ADP-ribose) polymerase inhibitors (PARPi).19,20
Mumakore mashoma apfuura, kuiswa kwe "next-generation sequencing" (NGS) mukiriniki kwakabvumira huwandu huri kuwedzera hwevarwere veBC kuongororwa kwemamorekuru ezvirwere zvegomarara, kusanganisira BRCA1/2.21 Panguva imwe chete, tsananguro dzakavakirwa pamatanho chaiwo maererano nenhoroondo yemhuri, huwandu hwevanhu, uye hunhu hwekiriniki kuti vaone zviri nani vanhu vakakodzera kuongororwa BRCA1/2.22,23 Mumamiriro ezvinhu aya, humbowo huri kuunganidzwa pakuongororwa kweBRCA1/2 muvanhu vakasiyana, zvichiratidza mutsauko munzvimbo dzakasiyana.24–27 Kunyangwe paine mishumo pamusoro peboka reBC kumadokero kweSicily, data shoma riripo pakuongororwa kweBRCA1/2 muvanhu vekumabvazuva kweSicily.28,29
Pano tinotsanangura mhedzisiro yekuongororwa kwe germline BRCA1/2 muvarwere veBC vanobva kumabvazuva kweSicily, zvichiwedzera kubatanidza kuvapo kwekuchinja kweBRCA1 kana BRCA2 nezviratidzo zvikuru zvekiriniki zvemamota aya.
Chidzidzo chekare chakaitwa pa "Center for Experimental Oncology and Hematology" paPoliclinico Hospital.Rodolico - San Marco muCatania. Kubva muna Ndira 2017 kusvika munaKurume 2021, varwere vanosvika 455 vane kenza yemazamu neyeovarian, melanoma, pancreatic kana prostate vakaendeswa kumolecular diagnostic laboratory yedu kuti vaongororwe majini eBRCA/2. Chidzidzo ichi chakaitwa zvichienderana neDeclaration of Helsinki, uye vese vatori vechikamu vakapa mvumo yakanyorwa vasati vaongorora mamorekuru.
Hunhu hweHistological uye hweBiological (ER, PgR, HER2 status, Ki-67, uye giredhi) yeBC yakaongororwa pa biopsy kana ma surgery samples chete, tichifunga nezvezvikamu zvegomarara zvine simba. Zvichibva pahunhu uhwu, maBC akarongwa seizvi: luminal A (ER+ uye/kana PgR+, HER2-, Ki-67<20%), luminal B (ER+ uye/kana PgR+, HER2-, Ki-67≥20%), luminal B-HER2+ (ER uye/kana PgR+, HER2+), HER2+ (ER uye PgR-, HER2+) kana triple negative (ER uye PgR-, HER2-).
Vasati vaongorora mamiriro ekuchinja kweBRCA1 neBRCA2, timu yemapoka akasiyana-siyana anosanganisira chiremba wekenza, nyanzvi yezvemajini, uye nyanzvi yezvepfungwa vakaita kubvunzana nezvemajini egomarara kumurwere wega wega kuti vaone kuvapo kweBRCA1 uye/kana BRCA1. kana vanhu vane njodzi yakakura yePV mujini reBRCA2. Kusarudzwa kwevarwere kwakaitwa zvichienderana nenhungamiro dzeItalian Society of Medical Oncology (AIOM) uye mazano emunharaunda yeSicilian.30,31 Izvi zvinosanganisira: (i) nhoroondo yemhuri yemarudzi anozivikanwa ezvirwere mumajini ekudzivirira chirwere (semuenzaniso, BRCA1, BRCA2, TP53, PTEN); (ii) varume vane BC; (iii) avo vane BC neOC; (iv) vakadzi vane BC <36 years, TNBC <60 years, kana BC <50 years; (v) nhoroondo yekurapa yeBC <50 years uye hama imwe chete yedhigiri rekutanga: (a) BC <50 years; (b) non-mucinous uye non-borderline OC yezera ripi zvaro; (c) bilateral BC; (d) murume BC; (e) kenza yepancreas; (f) kenza yeprostate; (vi) mbiri kana kupfuura nhoroondo yemunhu weBC ane makore anopfuura makumi mashanu uye nhoroondo yemhuri yeBC, OC, kana kenza yepancreas kune hama dziri hama dzedanho rekutanga (kusanganisira hama dzaari hama dzedanho rekutanga); (vii) Nhoroondo yeOC uye hama imwe chete yedanho rekutanga: (a) BC pasi pemakore makumi mashanu; (b) NOC; (c) BC mbiri; (d) murume BC; (vii) mukadzi ane serous OC yepamusoro.
Sample yeropa re20 mL yakawanikwa kubva kumurwere wega wega ndokuunganidzwa mumachubhu eEDTA (BD Biosciences). DNA yeGenomic yakabviswa kubva mumasampuli eropa rese e0.7 mL uchishandisa QIAsymphony DSP DNA Midi kit Isolation Kit (QIAGEN, Hilden, Italy) zvichienderana nemirairo yemugadziri uye yakapfuudzwa kuburikidza neQubit® 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA). Kuvandudza chinangwa uye kugadzirira raibhurari kunoitwa neOncomine™ BRCA Research Assay Chef, yakagadzirira kuiswa muIon AmpliSeq™ Chef Reagents DL8 Kit yekugadzirira raibhurari otomatiki zvichienderana nemirairo yemugadziri. Kit iyi ine mapuru maviri ePCR primer anogona kushandiswa kudzidza majini ese eBRCA1 (NM_007300.3) uye BRCA2 (NM_000059.3). Muchidimbu, 15 µL yeDNA yega yega yakaderedzwa (10 ng) yakawedzerwa kumaplate ane barcoded kuti igadzirirwe raibhurari uye ma reagents ese nezvinhu zvinoshandiswa zvakaiswa paIon Chef™ instrument. Kugadzirira raibhurari otomatiki uye kuunganidza raibhurari ine barcoded sample pooling zvakazoitwa paIon Chef™ instrument. Huwandu hwemaraibhurari akagadzirwa hwakazoongororwa neQubit® 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) zvichienderana nemirairo yemugadziri. Pakupedzisira, maraibhurari anosanganiswa mu equimolar ratios mumachubhu emuenzaniso eraibhurari eIon Chef™. (machubhu ane barcode) uye akaiswa paIon Chef™ instrument. Kutevedzana kwakaitwa pachishandiswa Ion Torrent S5 (Thermo Fisher Scientific) instrument (Thermo Fisher Scientific) pachishandiswa Ion 510 Chip (Thermo Fisher Scientific). Kuongororwa kwedata kwakaitwa neAmplicon Suite (SmartSeq srl) neIon Reporter Software.
Mazita ese akasiyana aitevera gwara razvino reHuman Genome Variation Consortium, rinowanikwa online (HGVS, http://www.hgvs.org/mutnomen). Kukosha kwekiriniki kwemarudzi eBRCA1/2 kwakatsanangurwa uchishandisa kupatsanurwa kweInternational Consortium ENIGMA (Evidence-Based Network for Interpreting Germline Mutant Alleles, https://enigmaconsortium.org/) uye kubvunza madhatabhesi akasiyana akadai seARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, uye UMD. Kupatsanurwa uku kunosanganisira mapoka mashanu akasiyana enjodzi: benign (chikamu I), benign (chikamu II), variant of uncertain significant significant (VUS, chikamu III), benign pathogenic (chikamu IV), uye pathogenic (chikamu V).VarVamwe vakaongororawo mhedzisiro yekuchinja kwemapuroteni pachimiro nebasa, chishandiso chinopa ruzivo chine mukana wekuwana madhatabhesi makumi matatu.32
Kuti tipe VUS imwe neimwe kukosha kwekiriniki, maalgorithms anotevera ekufungidzira mapuroteni ekuverenga akashandiswa: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/) uye Align-GVGD (http://agvgd.hci.utah.edu/agvgd_input.php). Mhando dzakarongwa sekirasi 1 ne2 dzaionekwa semhando yemusango.
Kutevedzana kweSanger kwakasimbisa kuvapo kwemhando yega yega yezvirwere. Muchidimbu, maprimer maviri chaiwo akagadzirwa kune yega yega mhando yakawanikwa nekushandisa BRCA1 neBRCA2 gene reference sequences (NG_005905.2, NM_007294.3 uye NG_012772.3, NM_000059.3, zvichiteerana). Saka, PCR yakatarwa yakaitwa ichiteverwa neSanger sequencing.
Varwere vakaongororwa vasina gene reBRCA1/2 vakaongororwa ne multiplex ligation-dependent probe amplification (MLPA) zvichienderana nemirairo yemugadziri kuti vaongorore kuvapo kwe large genomic rearrangements (LGR). Muchidimbu, DNA samples dzakabviswa uye ma gene-specific probes anosvika makumi matanhatu eBRCA1 neBRCA2 anoshandiswa, imwe neimwe ichiona DNA sequence chaiyo inosvika makumi matanhatu e nucleotides muhurefu. Zvigadzirwa zve probe amplification, zvinosanganisira seti yakasiyana yePCR amplicons, zvakazoongororwa ne capillary electrophoresis uye neCofalyser.Net software pamwe chete nematafura eCofalyser akakodzera (www.mrcholland.com).
Zvimwe zvinhu zvakasarudzwa zvekiriniki (histological grade uye Ki-67% proliferation index) zvakabatana nekuvapo kweBRCA1/2 PV, zvakaverengerwa uchishandisa Prism software v. 8.4 uchishandisa bvunzo chaiyo yaFisher zvichitora p-value <0.05 seyakakosha.
Pakati paNdira 2017 naKurume 2021, varwere 455 vakaongororwa germline BRCA1/2 mutations. Kuongororwa kwekuchinja kwemasero kwakaitwa paPoliclinico Hospital's Center for Experimental Oncology and Hematology. Zvichienderana negwara reSicilian (http://www.gurs.regione.sicilia.it/Indicep1.htm, N. 02-Venerdì 10 Gennaio 2020), Rodolico weCatania - San Marco”, varwere 389 vaive nekenza yemazamu, 37 kenza yemazamu, 16 kenza yepancreatic, 8 kenza yeprostate uye 5 melanoma. Kugoverwa kwevarwere zvichienderana nerudzi rwekenza uye mhedzisiro yekuongororwa kunoratidzwa muMufananidzo 1.
Mufananidzo 1 unoratidza chati inoratidza ongororo yeongororo iyi. Varwere vane bundu rezamu, melanoma, pancreatic, prostate, kana ovarian vakaongororwa kuti vaone kana paine shanduko mumajini eBRCA1 neBRCA2.
Zvidimbu: PVs, pathogenic variant; VUS, variant isina chokwadi kukosha; WT, wild-type BRCA1/2 sequence.
Takanyatsotarisa zvidzidzo zvedu pamapoka evanhu vane kenza yemazamu. Varwere vaiva nemakore anosvika makumi mana nemapfumbamwe (pakati pe23-89) uye vazhinji vavo vaiva vakadzi (n=376, kana 97%).
Pavanhu ava, 64 (17%) vaiva nekuchinja kweBRCA1/2 uye vese vaiva vakadzi. Makumi matatu nevashanu (9%) vaiva nePV uye 29 (7.5%) vaiva neVUS. Gumi nemanomwe (48.6%) kubva pamarudzi makumi matatu nemashanu ezvirwere akaitika muBRCA1 uye 18 (51.4%) muBRCA2, nepo 5 VUS yakaitika muBRCA1 (17.2%) uye 24 (82.8%) muBRCA2 (Mifananidzo 1 ne2). LGR yakanga isipo muongororo yeMLPA.
Mufananidzo 2. Kuongororwa kwekuchinja kweBRCA1 neBRCA2 muvarwere vekenza yemazamu 389. (A) Kupararira kwemarudzi akasiyana-siyana ezvirwere (PV) (tsvuku), akasiyana asina chokwadi (VUS) (orenji), uye WT (bhuruu) muvarwere vekenza yemazamu 389; (B) varwere vekenza yemazamu 389 Makumi matatu nevashanu (9%) vaiva nemarudzi akasiyana-siyana ezvirwere (PVs) eBRCA1/2. Pakati pavo, 17 (48.6%) vaiva vatakuri veBRCA1 PV (tsvuku yakasviba) uye 18 (51.4%) vaiva vatakuri veBRCA2 (tsvuku yakasviba); (C) 29 (7.5%) yevanhu 389 vaiva neVUS, majini mashanu (17.2%) eBRCA1 (orenji yakasviba) uye majini makumi maviri nemana (82.8%) eBRCA2 (orenji yakasviba).
Zvidimbu: PVs, pathogenic variant; VUS, variant isina chokwadi kukosha; WT, wild-type BRCA1/2 sequence.
Takazoongorora kuwanda kweBC molecular subtypes muvarwere vane BRCA1/2 PV. Kupararira kwacho 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%) varwere veTNBC. Pakati pevarwere vane BRCA1-positive, 5 (29.4%) vaiva neluminal B BC, 2 (11.8%) vaiva nechirwere cheHER2+, uye 10 (58.8%) vaiva neTNBC. Matumbu asina BRCA1 mutations aive luminal A kana luminal B-HER2+ (Mufananidzo 3). Muboka reBRCA2-positive, 10 (55.6%) tumors dzaive luminal B, 3 (16.7%) dzaive luminal B-HER2+, 3 (16.7%) TNBC uye 2 (11.1%) dzaive luminal A (Mufananidzo 3). Kwete. Mabundu eHER2+ aivepo muboka iri. Saka, shanduko dzeBRCA1 dzakanyanya kuwanda muvarwere veTNBC, nepo shanduko dzeBRCA2 dzichinyanya kuwanda muvanhu vane lumen B.
Mufananidzo 3 Kuwanda kwemhando dzekenza yemazamu muvarwere vane mhando dzakasiyana dzekenza muBRCA1 neBRCA2. MaHistogram anoratidza kupararira kweBRCA1- (tsvuku yakasviba) neBRCA2- (tsvuku yakapfava) PV pakati pemhando dzakasiyana dzekenza yemazamu. Nhamba dzakataurwa mukati mebhokisi rega rega dzinomiririra huwandu hwevarwere vane BRCA1 neBRCA2 PV yemhando yega yega yekenza yemazamu.
Zvidimbu: PVs, pathogenic variant; HER2+, human epidermal growth factor receptor 2 positive; TNBC, triple-negative breast cancer.
Zvadaro, takaongorora mhando uye nzvimbo yemajini eBRCA1 neBRCA2 PVs. MuBRCA1 PV, takaona ma single nucleotide variants manomwe (SNVs), 6 deletions, 3 duplications uye 1 insertion. Kuchinja kumwe chete (c.5522delG) kunomiririra kuwanikwa kutsva. BRCA1 PV yakajairika yakawanikwa muvanhu vese yaive c.5035_5039delCTAAT. Kuchinja uku kunosanganisira kubviswa kwema nucleotides mashanu (CTAAT) muBRCA1 exon 15, zvichikonzera kutsiviwa kweamino acid leucine netyrosine pacodon 1679, uye nekuda kweshanduko yekushandura ine imwe nzira yekumira codon inofungidzirwa inotungamira kukucheka kwemapuroteni nguva isati yakwana. Dzimwe shanduko dzese dzinoonekwa mune imwe chete nyaya. Zvinonyanya kukosha, imwe yemaPV akataurwa yaive munzvimbo ye splice site consensus (c.4357+1G>T) (Tafura 1).
Nezve BRCA2 PV, takaona kubviswa katanhatu, maSNV matanhatu uye kudzokororwa kaviri. Hapana kana chimwe chezvishanduko zvakawanikwa chiri chitsva. Kuchinja katatu kwakadzokororwa muhuwandu hwedu, c.428dup uye c.8487+1G>A zvakaonekwa muvanhu vatatu, zvichiteverwa ne c.5851_5854delAGTT yakatorwa muzviitiko zviviri. Kuchinja kwe c.428dup kunosanganisira kudzokororwa kweC mu exon 5 yeBRCA2, inofungidzirwa kuti ichanyora puroteni yakachekwa, isingashande. Kuchinja kwe c.8487+1G>A kunoitika munzvimbo yeBRCA2 intron 19 (± 1,2) uye kunokanganisa kutevedzana kwekubatana, zvichikonzera kuchinja kwekubatanidza zvichikonzera puroteni isina kujairika kana kuti isipo. Kusiyana kwe c.5851_5854delAGTT kunokonzerwa nekubviswa kwe 4-nucleotide kubva panzvimbo dze nucleotide 5851 kusvika 5854 mu coding exon 10 ye Gene reBRCA2 uye rinoguma nekuchinja kweframe ne codon inomira (p.S1951WfsTer). Zvinonyanya kukosha, sezvakambotaurwa, shanduko dzese dziri c.631G>A uye c.7008-2A>T dzakaonekwa mumurwere mumwe chete.34 Kuchinja kwekutanga kunosanganisira kutsiviwa kwe adenosine (A) mu BRCA2 exon 7 ne guanine (G) ine nucleotide zvichikonzera shanduko ye valine kuita isoleucine pa codon 211, isoleucine Amino acid i amino acid ine hunhu hwakafanana zvikuru. Shanduko iyi inokanganisa kupatsanurwa kwe mRNA kwakajairika. Mhando yechipiri iri munzvimbo ye intronic uye inokonzera kuchinjana kwe A kaviri kune thymine (T) pamberi pe exon 13 yegene inokodha BRCA2. Shanduko ye c.7008-2A>T inogona kugadzira zvinyorwa zvakawanda zvehurefu hwakasiyana. Uyezve, muboka re BRCA2 PVs, 4 kubva pa18 shanduko (22.2%) dzaive intronic.
Takabva taongorora ma "BRCA1/2 defectious mutations" munzvimbo dzinoshanda uye nzvimbo dzinosunga mapuroteni (Mufananidzo 4). Mugene reBRCA1, 50% yemaPV aive munzvimbo yeboka rekenza yemazamu (BCCR), nepo 22% yema "mutations" aive munzvimbo yeboka rekenza ye ovarian (OCCR) (Mufananidzo 4A). MuBRCA2 PV, 35.7% yema "variants" aive munzvimbo yeBCCR uye 42.8% yema "mutations" aive muOCCR (Mufananidzo 4B). Tevere, takaongorora nzvimbo yePV mukati meBRCA1 neBRCA2 protein domains. Kune BRCA1 protein, takawana maPV matatu mu "loop" uye "coiled coil domains", uye maviri mu "BRCT domain" (Mufananidzo 4A). Kune BRCA2 protein, maPV mana akabatanidzwa kune BRC repeat domain, nepo matatu "intronic" uye matatu "exonic changes" akaonekwa munzvimbo ye oligo/oligosaccharide-binding (OB) uye "tower" (T) (Mufananidzo 4B).
Mufananidzo 4. Mufananidzo wekuongorora mapuroteni eBRCA1 neBRCA2 uye nzvimbo yemarudzi akasiyana-siyana ezvirwere. Mufananidzo uyu unoratidza kupararira kwemarudzi akasiyana-siyana ezvirwere eBRCA1 (A) neBRCA2 (B) muvarwere vekenza yemazamu. Kuchinja kwekunze kunoratidzwa mubhuruu, nepo marudzi akasiyana-siyana emukati anoratidzwa muorenji. Kureba kwebha kunomiririra huwandu hwezviitiko. Mapuroteni eBRCA1 neBRCA2 nenzvimbo dzawo dzinoshanda zvinoshumwa. (A) Puroteni yeBRCA1 ine nzvimbo ye loop (RING) uye nuclear localization sequence (NLS), nzvimbo ye coiled-coil, nzvimbo ye SQ/TQ cluster (SCD), uye nzvimbo yeBRCA1 C-terminal (BRCT). (B) Puroteni yeBRCA2 ine BRC repeats sere, nzvimbo yeDNA-binding ine nzvimbo yehelical (Helical), matatu oligonucleotide/oligosaccharide-binding (OB) folds, nzvimbo ye tower (T), uye An NLS kudivi reC. Nzvimbo dzinonzi Breast Cancer Cluster Region (BCCR) uye Ovarian Cancer Cluster Region (OCCR) dzinoratidzwa pa pasi.*Inomiririra shanduko dzinoona ma "stop codons".
Takazoongorora zvinhu zveBC clinicopathological zvinogona kunge zvine chekuita nekuvapo kweBRCA1/2 PV. Zvinyorwa zvekiriniki zvakakwana zvaivepo kune varwere 181 vasina BRCA1/2 (vasiri ivo) uye vese vane chirwere ichi (n = 35). Paive nehukama pakati pehuwandu hwegomarara uye giredhi.
Takaverenga kugoverwa kweKi-67 zvichibva papakati peboka redu (25%, range <10-90%). Vanhu vane Ki-67 <25% vakatsanangurwa se "low Ki-67″, nepo vanhu vane kukosha ≥ 25% vaionekwa se "high Ki-67″". Musiyano mukuru weKi-67 (p<0.01) wakawanikwa pakati pevasingatakuri uye vatakuri veBRCA1 PV (Mufananidzo 5A).
Mufananidzo 5 Kubatana kweKi-67 nekugoverwa kwemagiredhi muvakadzi vane kenza yemazamu vane uye vasina BRCA1 neBRCA2 PVs.(A) Bhokisi rinoratidza huwandu hwepakati hweKi-67 muvarwere 181 vasiri vatakuri veBC vachienzaniswa nevarwere veBRCA1 (18) kana BRCA2 (17) vePV. Huwandu hweP huri pasi pe0.5 hwakaonekwa sehwakakosha muhuwandu.(B) Histogram inomiririra kugoverwa kwevarwere vekenza yeBC mumapoka egiredhi rehistological (G2 neG3) zvichienderana nemamiriro ekuchinja kweBRCA1 neBRCA2 (vanhu vane WT, vatakuri veBRCA1 neBRCA2 PVs).
Saizvozvowo, takaongorora kana giredhi regomarara rakabatana nekuvapo kweBRCA1/2 PV. Sezvo G1 BC yakanga isipo muvanhu vedu, takakamura varwere mumapoka maviri (G2 kana G3). Zvichienderana nemhedzisiro yeKi-67, ongororo iyi yakaratidza hukama hwakakosha pakati pegiredhi regomarara nekuchinja kweBRCA1, nehuwandu hwakawanda hwegomarara reG3 muvanhu vanotakura BRCA1 zvichienzaniswa nevasina kutakura (p<0.005) (Mufananidzo 5B).
Kufambira mberi muDNA sequencing technology kwakagonesa kufambira mberi kusati kwamboitika mukuongorora majini eBRCA1/2, zvine zvazvinoreva kune varwere vane nhoroondo yemhuri yekenza. Kusvika pari zvino, mhando dzeBRCA1/2 dzinosvika 20,000 dzakawanikwa uye dzakarongwa zvichienderana neAmerican Society of Medical Genetics 35 uye ENIGMA system.35,36 Zvinozivikanwa kuti BRCA1/2 mutational spectrum inosiyana zvakanyanya munzvimbo dzakasiyana-siyana.37 MuItaly, mwero weBRCA1/2 PVs waive kubva pa8% kusvika pa37%, zvichiratidza kusiyana kukuru kwemukati menyika.38,39 Nehuwandu hwevanhu vanosvika mamiriyoni mashanu, Sicily ndiyo nzvimbo yechishanu pakukura muItaly maererano nehuwandu hwevagari.Kunyangwe data riripo pakupararira kweBRCA1/2 kumadokero kweSicily, hapana humbowo hwakawanda kumabvazuva kwechitsuwa ichi.
Chidzidzo chedu ndechimwe chezviziviso zvekutanga pamusoro pekuwanda kweBRCA1/2 PV muvarwere veBC kumabvazuva kweSicily.28 Takanyanya kutarisa ongororo yedu paBC, sezvo ichi chiri chirwere chinowanzoonekwa muboka redu.
Pakuyedza varwere 389 BC, 9% vaive neBRCA1/2 PVs, dzakagoverwa zvakaenzana pakati peBRCA1 neBRCA2. Mhedzisiro iyi inoenderana neyakambotaurwa muvanhu vekuItaly.28 Zvinofadza kuti, 3% (13/389) veboka redu vaive varume. Chiyero ichi chakakwira kupfuura zvaitarisirwa kune kenza yemazamu yevarume (1% yeBCs dzese),40 zvichiratidza kusarudzwa kwedu kwevanhu zvichibva panjodzi yekuchinja kweBRCA1/2. Zvisinei, hapana kana mumwe wevarume ava akagadzira BRCA1/2 PV, saka vaive vachitsvaga kuongororwa kwakawanda kwemamorekuru kuti vabvise kuvapo kwekuchinja kusingawanzoitika senge PALB2, RAD51C neD, pakati pezvimwe. Mhando dzisina kukosha kwakawanikwa mu7% yevanhu umo BRCA2 VUS yaive pachena. Kunyangwe mhedzisiro iyi inoenderana nehumbowo huripo.28,41,42
Patakaongorora kupararira kweBC molecular subtypes muvakadzi vane BRCA1/2 mutant, takasimbisa hukama hunozivikanwa pakati peTNBC neBRCA1 PV (58.8%) uye pakati peluminal B BC neBRCA2 PV (55.6%).16,43 Matumbu eluminal A neHER2+ muBRCA1 neBRCA2 PV carriers anoenderana nedata riripo remabhuku.16,43
Tinobva tatarisa parudzi nenzvimbo yeBRCA1/2 PV. Muboka redu, BRCA1 PV yainyanya kuwanikwa yaive c.5035_5039delCTAAT. Kunyangwe Incorvaia et al. Havana kutsanangura shanduko iyi muboka ravo reSicilian, vamwe vanyori vakaitaura se germline BRCA1 PV.34 Ma BRCA1 PV akati wandei akawanikwa muboka redu - semuenzaniso c.181T>G, c.514del, c.3253dupA uye c.5266dupC - ayo akaonekwa muSicily.28 Paaya, maviri ma BRCA1 founder mutations (c.181T>G uye c.5266dupC) anowanikwa muAshkenazi Jews ekuEastern neCentral Europe (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian neGerman), 44,45 uye, muUnited States neArgentina, munguva pfupi yapfuura yakatsanangurwa se "recurrent germline variant" muvarwere vekuItaly vane BC neOC. Iyo 34c.514del variant yakamboonekwa muvarwere vasere vekenza yemazamu vanobva kuchamhembe kweSicily muPalermo neMessina. Zvinofadza kuti, kunyangwe Incorvaia et al. vakawana c.3253dupA variant mune dzimwe mhuri muCatania.28 Ma BRCA2 PV anonyanya kuratidzwa ndeaya c.428dup, c.5851_5854delAGTT uye intronic variant c.8487+1G>A, ayo akataurwa zvakadzama 28 mumurwere muPalermo ane c.428dup, c.5851_5854delAGTT PV yakaonekwa mumhuri dziri kuchamhembe kwakadziva kumadokero kweSicily, kunyanya munzvimbo dzeTrapani nePalermo, nepo c.5851_5854delAGTT PV yakaonekwa mumhuri dziri kuchamhembe kwakadziva kumadokero kweSicily. Iyo 8487+1G>A variant yaiwanzoonekwa muvanhu vanobva kuMessina, Palermo, neCaltanissetta.28 Rebbeck et al. yakambotsanangura nezvekuchinja kwe c.5851_5854delAGTT muColombia.37 Imwe BRCA2 PV, c.631+1G>A, yakawanikwa muvarwere veBC neOC vanobva kuSicily (Agrigento, Siracusa naRagusa).28 Zvinonyanya kukosha, takaona kubatana kwemarudzi maviri eBRCA2 (BRCA2 c.631G>A uye c.7008-2A>T) mumurwere mumwe chete, watakafunga kuti akaparadzaniswa mu cis mode, sezvakambotaurwa kare saizvozvo.34,46 Aya ma BRCA2 mutations anowanzoonekwa munharaunda yeItaly uye akawanikwa achiunza ma codons ekumira asati asvika nguva, zvichikanganisa kusanganiswa kwemessenger RNA uye zvichiita kuti protein yeBRCA2 ikundikane.47,48
Takanyorawo BRCA1 neBRCA2 PV munzvimbo dzinofungidzirwa kuti OCCR neBCCR dzemapuroteni nemajini. Nzvimbo idzi dzakatsanangurwa naRebbeck nevamwe senzvimbo dzine njodzi dzekukura kwekenza yemazamu neyemazamu, zvichiteerana.49 Zvisinei, humbowo hune chekuita nehukama huripo pakati penzvimbo yemarudzi akasiyana-siyana embeu uye njodzi yekenza yemazamu kana yemazamu huchiri kukakavadzana.28,50-52 Muvanhu vedu, BRCA1 PV dzaive dziri munzvimbo yeBCCR, nepo BRCA2 PV dzaive dziri munzvimbo yeOCCR. Zvisinei, hatina kukwanisa kuwana hukama huripo pakati penzvimbo dzinofungidzirwa kuti OCCR neBCCR nenzvimbo dzine zviratidzo zveBC. Izvi zvinogona kunge zvichikonzerwa nehuwandu hushoma hwevarwere vane BRCA1/2 mutations. Kubva pamaonero enzvimbo yeprotein, BRCA1 PVs dzinopararira pamwe chete neprotein yese, uye shanduko dzeBRCA2 dzinowanikwa zvakanyanya munzvimbo inodzokororwa yeBRC.
Pakupedzisira, takabatanidza maitiro eBC clinicopathological neBRCA1/2 PV. Nekuda kwehuwandu hushoma hwevarwere vakabatanidzwa, takangowana hukama hwakakosha pakati peKi-67 negiredhi rebundu. Kunyangwe kuongororwa nekududzirwa kweKi-67 kuchiramba kune gakava, zvine chokwadi kuti huwandu hwakawanda hwekupararira hunobatanidzwa nekuwedzera kwengozi yekudzoka kwechirwere uye kudzikira kwekurarama. Kusvika pari zvino, kuguma kwekusiyanisa pakati peKi-67 "yakakwira" ne "yakaderera" i20%. Nekudaro, chiyero ichi hachishande kune huwandu hwedu hwevarwere veBRCA1/2 mutation, iyo ine chiyero chepakati cheKi-67 che25%. Iyi nzira yehuwandu hweKi-67 yakakwira inogona kutsanangurwa nekuwanda kwemapoka edu eluminal B neTNBC, ayo mashoma eluminal A bundu aivepo. Nekudaro, humwe humbowo hunoita sehunoratidza kuti Ki-67 cutoff yakakwira (25-30%) inogona kupatsanura varwere zviri nani zvichienderana nekufungidzira kwavo.53,54 Kubva mumhedzisiro yekuongorora kwedu, hukama hwakakosha hahushamisi. Hunoitika pakati peKi-67 yakakwira nemagiredhi uye kuvapo kweBRCA1 PV. Kutaura zvazviri, bundu rine chekuita neBRCA1 rinowanzoonekwa muTNBC uye rinoratidza zviratidzo zvehasha.16,17
Mukupedzisa, chidzidzo ichi chinopa mushumo pamusoro pemamiriro ekuchinja kweBRCA1/2 muboka reBC rinobva kumabvazuva kweSicily. Zvose zvatakawana zvinoenderana nehumbowo huripo, zvese maererano nekuwanda kwekuchinja kwemuviri uye zviratidzo zvekiriniki muBC. Zvimwe zvidzidzo muhuwandu hwakawanda hwevarwere veBRCA1/2-mutant BC, zvakaita sekushandisa multigenome extended mutational analysis, zvinofanirwa kuongororwa kuvapo kwePV dzakasiyana uye dzisingawanzoitiki pane BRCA1/2. Izvi zvichabvumira kuzivikanwa uye kutarisirwa kwakakodzera kwehuwandu huri kuwedzera hwevanhu vari panjodzi yakawedzera yekenza nekuda kwekuchinja kwemajini.
Takasimbisa kuti varwere vakasaina chibvumirano chekuzivisa kuti vaburitse masampuli avo egomarara vasingazivikanwe kuti vawane ruzivo rwekutsvaga. Varwere vese vakasaina chibvumirano chakanyorwa maererano neChiziviso cheHelsinki. Zvichienderana nemutemo weAOU Policlinico "G.Rodolico - S.Marco", chidzidzo ichi chakasunungurwa pakuongorora tsika nekuti ongororo yeBRCA1/2 yakaitwa zvichienderana nekiriniki uye varwere vese vakapa chibvumirano chakanyorwa. Varwere vanobvumawo kushandiswa kwedata ravo pakutsvaga.
Tinotenda Purofesa Paolo Vigneri nerubatsiro rwavo mukutarisira varwere vegomarara remazamu sezvakakumbirwa neKomiti yeMaitiro.
Federica Martorana anotaura nezvemabasa ekuremekedza kubva kuna Istituto Gentili, Eli Lilly, Novartis, Pfizer. Vamwe vanyori vanoti hapana kusawirirana kwebasa iri.
1. Sung H, Ferlay J, Siegel RL, nevamwe. Global Cancer Statistics 2020: GLOBOCAN inofungidzira kuwanda kwekenza uye kufa kwevanhu makumi matatu nematanhatu munyika 185 pasi rose.CA Cancer J Clin.2021;71(3):209-249.doi: 10.3322/caac.21660