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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, 1 I-Medical Living Clinic1, 16 Umtholampilo we-Maperimental1 University of Catania, Catania, 95123, Italy;2 Centre 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 Umnyango Wesayensi Yezinto Eziphilayo Nezasemvelo, eNyuvesi yaseCatania, I-Medical Genetics, Catania, Italy, 95123; I-7Oasi Research Institute-IRCS, Troina, 94018, Italy Ezokuxhumana: Stefania Stella, ucingo +39 095 378 1946, i-imeyili [i-imeyili ivikelwe]; [i-imeyili ivikelwe] Injongo: Ukuguqulwa kwe-germline ku-BRCA1 ne-BRCA2 kanye nomdlavuza webele osungulwe (BC), i-ovary (OC) nokunye okuhlotshaniswa nobungozi bokuphila impilo yonke yomdlavuza.Ukuhlola isakhi sofuzo se-BRCA kuyisihluthulelo sokuhlola ubungozi bomuntu ngamunye, kanye nokuthola izindlela zokuvimbela kubathwali abanempilo kanye nokuhlanganisa ukwelashwa ezigulini ezinomdlavuza. nakuba idatha ikhona ezinhlobonhlobo ze-BRCA ze-pathogenic emindenini yase-Sicily, izifundo eziqondiswe ngokuqondile kubantu empumalanga yeSicily ziyashoda.Inhloso yocwaningo lwethu kwakuwukuphenya isigameko nokusatshalaliswa kwe-BRCA pathogenic germline alterations eqenjini leziguli ze-BC ezivela empumalanga ye-Sicily kanye nokuhlola ukuhlotshaniswa kwazo nezici ezithile ze-BC kusetshenziswa ukuguqulwa kwesizukulwane esilandelayo kanye nokuhlukaniswa kwe-tumor ukuhlukaniswa. index.RESULTS: Sekukonke, iziguli ezingama-35 (9%) zibe nokuhluka kwe-BRCA pathogenic, 17 (49%) ku-BRCA1 kanye ne-18 (51%) ku-BRCA2.BRCA1 izinguquko zivame kakhulu ezigulini ze-BC eziphindwe kathathu, kanti ukuguqulwa kwe-BRCA2 kuvame kakhulu ezigulini ze-luminal BC. inkomba ye-proliferative.Iziphetho: Okutholakele kwethu kunikeza ukubuka konke kwesimo sokuguquka kwe-BRCA ezigulini ze-BC ezivela empumalanga ye-Sicily futhi ziqinisekisa indima yokuhlaziywa kwe-NGS ekuhlonzeni iziguli ezinofuzo lwe-BC.Sekukonke, le datha ihambisana nobufakazi bangaphambilini obusekela ukuhlolwa kwe-BRCA ukuze kuvinjwe indlela efanele kanye nokwelashwa komdlavuza kubathwali abaguqukayo.
Umdlavuza webele (BC) uyisifo esibulalayo esivame kakhulu emhlabeni wonke kanye nomdlavuza obulala kakhulu kwabesifazane.1 Izici zezinto eziphilayo ezinquma ukubikezelwa kwe-BC kanye nokuziphatha komtholampilo kuye kwacwaningwa kabanzi futhi kwacaciswa kancane ngokuhamba kwesikhathi.Eqinisweni, omaka abambalwa be-surrogate okwamanje basetshenziselwa ukuhlukanisa i-BC ibe yizinhlobo ezihlukene zamangqamuzana.Ziyi-estrogen (ER) kanye/noma i-progesterone yokukhula komuntu (i-Pgder2HER receptor) yomuntu i-amplification, inkomba yokwanda kwe-Ki-67 kanye nebanga le-tumor (G) .2 Ukuhlanganiswa kwalezi ziguquko kuhlonze izigaba ze-BC ezilandelayo: 1) Izimila ze-Luminal, ezibonisa i-ER kanye / noma i-PgR expression, zibalelwa ku-75% we-BCs. Lezi zicubu zaphinde zahlukaniswa zibe i-Luminal A, lapho i-Ki-67 ingaphansi kuka-20% futhi i-HER2 ilingana ne-Ki-62% ilingana ne-Ki-62, kanye ne-Luminal 62. Ukukhulisa i-HER2, kungakhathaliseki ukuthi inkomba yokwanda; 2) amathumba e-HER2+ ane-ER ne-PgR angenayo kodwa abonisa ukukhuliswa kwe-HER2.Leli qembu lihlanganisa u-10% wazo zonke izimila zamabele; I-3) Umdlavuza webele we-Triple-negative (TNBC), ongabonisi inkulumo ye-ER ne-PgR kanye nokukhulisa i-HER2, i-akhawunti cishe ye-15% yomdlavuza webele.2-4
Phakathi kwalezi zinhlobo ezincane ze-BC, ibanga le-tumor kanye ne-proliferation index limelela ama-biomarker e-cross-sectional ahlotshaniswa ngokuqondile nokuzimela nokuhlukunyezwa kwe-tumor kanye ne-prognosis.5,6
Ngaphandle kwezici zezinto eziphilayo ezishiwo ngenhla, indima yokuguqulwa kwezakhi zofuzo eziholela ekuthuthukisweni kwe-BC iye yaba yinto ebalulekile kakhulu eminyakeni embalwa edlule.7 Cishe i-1 kwezingu-10 izimila zesifuba zitholwa njengefa ngenxa yokuguqulwa kwamagciwane ezakhini ezithile zofuzo.8 Izifundo ezimbili ezinkulu ze-epidemiological ezibandakanya ngaphezu kwe-180,000 abesifazane abasanda kuhlonza i-genes ye-TM, i-10, i-A, Iqembu le-TM eyisishiyagalombili, i-ABR, i-B. I-BRCA2, CHK2, PALB2, RAD51C, kanye ne-RAD51D) ngokuyinhloko inesibopho sofuzo lwe-BC.Phakathi kwalezi zakhi zofuzo, i-BRCA1 ne-BRCA2 (ngemuva kwalokhu ebizwa ngokuthi i-BRCA1/2) ibonise ukuhlobana okunamandla kakhulu nokuthuthukiswa kwezicubu zesifuba.9-12 Eqinisweni, ubungozi be-germline kanye nezinye izifo ze-BRCA kwandisa kakhulu impilo ye-BRCA1 / BC kuhlanganisa i-ovarian, prostate, pancreatic, colorectal, kanye ne-melanoma.Kusukela eminyakeni eyi-13 kuye kwengama-80, izehlakalo ezikhulayo ze-BC zingama-72% kwabesifazane abane-BRCA1 pathogenic variant (PV) kanye nama-69% kwabesifazane abane-BRCA2 PV.14
Ngokuphawulekayo, ukushicilelwa kwakamuva kusikisela ukuthi ingozi ye-BC incike ohlotsheni lwe-PV.Eqinisweni, uma kuqhathaniswa nezinhlobonhlobo ze-pathogenic truncating, ukuhlukahluka kwe-glaring missense, ikakhulukazi esakhiweni se-BRCA1, kuhlotshaniswa nengozi encishisiwe ye-BC, ikakhulukazi kwabesifazane asebekhulile.15
Ukuba khona kwe-BRCA1 noma i-BRCA2 PV kwakuhlotshaniswa nezici ezihlukene zebhayoloji nezempilo. Izinkomba ezikhulayo.Lezi zicubu zivame kakhulu ku-lumen B futhi ngokuvamile zenzeka kubantu abadala asebekhulile.16-18 Ngokuphawulekayo, ukuguqulwa kwezinguquko ku-BRCA1 ne-BRCA2 kwandisa ukuzwela ekwelapheni okuthile, okuhlanganisa nosawoti we-platinum nezidakamizwa ezihlosiwe ezifana ne-poly(ADP-ribose) polymerase inhibitors (PARPi) .19,20
Eminyakeni embalwa edlule, ukuqaliswa kokulandelana kwesizukulwane esilandelayo (NGS) ekusebenzeni komtholampilo kuye kwanika amandla inani elandayo leziguli ze-BC ukuthi zihlolwe amangqamuzana ezimpawu zokuthambekela komdlavuza, okuhlanganisa i-BRCA1/2.21 Ngasikhathi sinye, izincazelo ezisekelwe ezimisweni eziqondile eziphathelene nomlando womndeni, izibalo zabantu, kanye nezici ze-clinicopathological ukuze kuhlonzwe kangcono abantu abangabodwana1/23 ku-BRCA22 ukuhlolwa komtholampilo. ukuqongelela ekuhlolweni kwe-BRCA1/2 kubantu abathile, okugqamisa umehluko ezifundeni zezwe.24–27 Nakuba kukhona imibiko ngeqembu le-BC entshonalanga yeSicily, idatha embalwa iyatholakala ekuhlolweni kwe-BRCA1/2 empumalanga yeSicily.28,29
Sichaza lapha imiphumela yokuhlolwa kwe-germline BRCA1/2 ezigulini ze-BC ezivela empumalanga yeSicily, siphinde sihlobanise ubukhona bezinguquko ze-BRCA1 noma ze-BRCA2 nezici eziyinhloko ze-clinicopathological zalezi zimila.
Ucwaningo lwe-retrospective lwenziwa "esikhungweni se-Experimental Oncology and Hematology" esibhedlela sase-Policlinico.Rodolico - San Marco e-Catania.Kusukela ngoJanuwari 2017 kuya ku-March 2021, ingqikithi yeziguli ezingu-455 ezinomdlavuza webele kanye ne-ovarian, melanoma, pancreatic noma i-prostate zadluliselwa ocwaningweni lwethu lwe-molecular diagnostic/lebhu ye-BRCAratory. Isimemezelo se-Helsinki, kanye nabo bonke ababambiqhaza banikeze imvume ebhaliwe enolwazi ngaphambi kokuhlaziywa kwamangqamuzana.
Izici ze-Histological and biological (ER, PgR, HER2 status, Ki-67, and grade) of BC ziye zahlolwa kumasampula ayinhloko e-biopsy noma okuhlinzwa, kucatshangelwa izingxenye zesimila ezinolaka kuphela.Ngokusekelwe kulezi zici, ama-BC ahlukaniswe ngale ndlela elandelayo: i-luminal A (ER+ kanye/noma i-PGR+, HER2-, BG+R6, 7) I-HER2-, Ki-67≥20%), i-luminal B-HER2+ (ER kanye/noma i-PgR+, HER2+), i-HER2+ (ER ne-PgR-, HER2+) noma i-triple negative (ER ne-PgR-, HER2-).
Ngaphambi kokuhlola isimo sokuguqulwa kwe-BRCA1 kanye ne-BRCA2, ithimba lezinhlaka eziningi okuhlanganisa i-oncologist, isazi sofuzo, kanye nodokotela wezengqondo benze ukubonisana kofuzo lwesimila esigulini ngasinye ukuze kutholwe ubukhona be-BRCA1 kanye/noma i-BRCA1. noma abantu abasengozini enkulu ye-PV kufuzo lwe-BRCA2.Ukukhethwa kwesiguli kwenziwa ngokuvumelana neziqondiso ze-Italian Society of Medical Oncology (AIOM) kanye nezincomo zendawo zaseSicilian.30,31 Lezi zindlela zihlanganisa: (i) umlando womndeni wezinhlobonhlobo ezaziwayo ze-pathogenic ezakhini zofuzo ezithintekayo (isb, BRCA1, BRCA2, TP53, PTEN); (ii) abesilisa abanoBC; (iii) labo abano-BC no-OC; (iv) abesifazane abane-BC
Zonke izinhlobo zegama ezihlukile zilandela imihlahlandlela yamanje ye-Human Genome Variation Consortium, etholakala ku-inthanethi (HGVS, http://www.hgvs.org/mutnomen).Ukubaluleka komtholampilo kokuhlukahluka kwe-BRCA1/2 kwachazwa kusetshenziswa ukuhlukaniswa kwe-International Consortium ENIGMA (Inethiwekhi Esekelwe Ebufakazini YokuTolika i-Allimconsline ye-Mutantenium, i-https://www.Mutantenium Allemconor ukubonisana nezizindalwazi ezihlukene ezifana ne-ARUP, BRCAEXCHANGE , ClinVar, IARC_LOVD, kanye ne-UMD. Ukuhlukaniswa kuhlanganisa izigaba eziyisihlanu ezihlukene zengcuphe: i-benign (isigaba I), okungenzeka ibenign (isigaba II), okuhlukile kokubaluleka okungaqinisekile (VUS, isigaba III), okungenzeka kube yi-pathogenic (isigaba IV), kanye nomphumela we-Vallyogenic (isigaba IV), kanye nomphumela we-Vallyogenic). ukwakheka nokusebenza kwamaprotheni, ithuluzi elifundisayo elinokufinyelela kuma-database angama-30.32
Ukunikeza ukubaluleka komtholampilo okungaba khona ku-VUS ngayinye, kusetshenziswe ama-algorithms alandelayo okubikezela amaprotheni ekhompyutha: UKUGUQUKA TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/) kanye ne-Align-G (http://agvgd.hci.utah.edu/agvgd_input.php).Okuhlukile okufakwe kusigaba 1 no-2 kuthathwe njengohlobo lwasendle.
Ukulandelana kwe-Sanger kuqinisekise ubukhona bokwehluka ngakunye kwe-pathogenic. Kafushane, ipheya yeziqalo ezithile zadizayinelwa ukwahluka ngakunye okutholiwe ngokusebenzisa i-BRCA1 kanye ne-BRCA2 yochungechunge lwereferensi yofuzo (NG_005905.2, NM_007294.3 kanye ne-NG_012772.3, NM9. ngokulandelana kwe-Sanger.
Iziguli ezitholwe zingenayo i-BRCA1/2 gene zihlolwe i-multiplex ligation-dependent probe amplification (MLPA) ngokuya ngemiyalo yomkhiqizi ukuze kuhlolwe ubukhona bokuhlelwa kabusha kwe-genomic (LGR). ukulandelana cishe kwama-nucleotide angama-60 ngobude.Imikhiqizo yokukhulisa i-Probe, ehlanganisa isethi eyingqayizivele yamaamplikhoni e-PCR, yabe isihlaziywa nge-capillary electrophoresis kanye nesofthiwe ye-Cofalyser.Net ngokuhlanganyela namatafula afanele e-batch e-Cofalyser (www.mrcholland.com).
Okuguquguqukayo okukhethiwe kwe-clinicopathological (ibanga le-histological kanye ne-Ki-67% proliferation index) kuhlotshaniswa nokuba khona kwe-BRCA1/2 PV, kubalwa kusetshenziswa isofthiwe ye-Prism v. 8.4 kusetshenziswa ukuhlolwa okuyingqophamlando kukaFisher kucatshangwa ukuthi inani le-p <0.05 libalulekile.
Phakathi kukaJanuwari 2017 kanye noMashi 2021, iziguli ezingu-455 zahlolelwa ukuguqulwa kwegciwane le-BRCA1/2. Ukuhlolwa kokuguqulwa kwegciwane kwenziwa Esikhungweni Sesibhedlela Se-Policlinico Se-Experimental Oncology and Hematology.Ngokwesiqondiso sase-Sicilian (http://www.gurs.regione.sicilia.it/0h20m-Indicep. Gennaio 2020), the Rodolico of Catania – San Marco” isiyonke, 389 iziguli Kube nomdlavuza webele, 37 umdlavuza wesibeletho, 16 umdlavuza pancreatic 16, 8 umdlavuza wendlala 8 kanye melanoma 5. Ukusatshalaliswa kweziguli ngokohlobo lomdlavuza kanye nemiphumela yokuhlaziya kukhonjisiwe kuMfanekiso 1.
Umfanekiso 1 ubonisa ishadi eligelezayo elibonisa ukubuka konke kocwaningo.Iziguli ezinebele, i-melanoma, i-pancreatic, i-prostate, noma izimila ze-ovarian zahlolelwa ukuguqulwa kwezakhi zofuzo ze-BRCA1 ne-BRCA2.
Izifinyezo: ama-PV, ukuhluka kwe-pathogenic; I-VUS, okuhlukile kokubaluleka okungaqinisekile; I-WT, ukulandelana kohlobo lwasendle lwe-BRCA1/2.
Sigxile kakhulu ezifundweni zethu kumaqoqo omdlavuza webele.Iziguli zazineminyaka yobudala emaphakathi engu-49 (ububanzi obungu-23-89) futhi kwakungabesifazane kakhulu (n=376, noma 97%).
Kulezi zihloko, ama-64 (17%) abe nezinguquko ze-BRCA1/2 futhi bonke bekungabantu besifazane.Amashumi amathathu nanhlanu (9%) ane-PV futhi angu-29 (7.5%) ane-VUS.Ishumi nesikhombisa (48.6%) lokuhlukahluka okungu-35 kwe-pathogenic kwenzeke ku-BRCA1 no-18 (51.4%) ku-BRCA2, kuyilapho u-51.4%) ku-. ku-BRCA2 (Izibalo 1 kanye no-2).I-LGR yayingekho ekuhlaziyeni kwe-MLPA.
Umfanekiso 2. Ukuhlaziywa kwezinguquko ze-BRCA1 kanye ne-BRCA2 ezigulini zomdlavuza webele we-389. (A) Ukusatshalaliswa kwezinhlobonhlobo ze-pathogenic (PV) (obomvu), ukuhlukahluka kokubaluleka okungaqinisekile (VUS) (iwolintshi), kanye ne-WT (eluhlaza okwesibhakabhaka) ezigulini zomdlavuza webele we-389; (B) Iziguli ze-389 zomdlavuza webele Amashumi amathathu nanhlanu (9%) ayene-BRCA1 / 2 variants pathogenic (PVs) .Phakathi kwabo, i-17 (48.6%) yayiyi-BRCA1 PV carriers (ibomvu emnyama) futhi i-18 (51.4%) yayingabathwali be-BRCA2 (obomvu okhanyayo); (C) Ama-29 (7.5%) wezifundo ezingama-389 aphathe i-VUS, 5 (17.2%) i-BRCA1 yofuzo (iwolintshi elimnyama) kanye nama-24 (82.8%) wofuzo we-BRCA2 (owolintshi okhanyayo).
Izifinyezo: ama-PV, ukuhluka kwe-pathogenic; I-VUS, okuhlukile kokubaluleka okungaqinisekile; I-WT, ukulandelana kohlobo lwasendle lwe-BRCA1/2.
Ngokulandelayo siphenye ukusabalala kwe-BC molecular subtypes ezigulini ezine-BRCA1/2 PV. Ukusatshalaliswa kuhlanganisa i-luminal A engu-2 (5.7%), 15 (42.9%) luminal B, 3 (8.6%) luminal B-HER2+, 2 (5.7%) HER2+ kanye no-13 (37.1%) phakathi kweziguli ezingu-9 ze-TNBC, 5% ze-TNBC, Amaphesenti angu-20 A positive. i-luminal B BC, 2 (11.8%) yayinesifo se-HER2+, futhi i-10 (58.8%) yayine-TNBC.Izimila ezingenakho ukuguqulwa kwe-BRCA1 zaziyi-luminal A noma i-luminal B-HER2+ (Figure 3).Eqenjini elingaphansi le-BRCA2-positive, 10 (55.6%) izimila zaziyi-luminal B.3, 3+ 3%) (16.7%) i-TNBC no-2 (11.1%) bekuyi-luminal A (Umfanekiso 3).Awekho amathumba e-HER2+ abekhona kuleli qembu.Ngakho, ukuguqulwa kwe-BRCA1 kuvame ezigulini ze-TNBC, kanti ukuguqulwa kwe-BRCA2 kuhamba phambili ku-lumen B ngabanye.
Umfanekiso we-3 Ukusabalalisa kwe-subtypes yomdlavuza webele ezigulini ezinokuhlukahluka kwe-pathogenic ku-BRCA1 ne-BRCA2.I-Histograms ebonisa ukusabalalisa kwe-BRCA1- (obomvu obumnyama) kanye ne-BRCA2- (obomvu okhanyayo) ama-PVs phakathi kwama-molecular subtypes eziguli zomdlavuza webele.Izinombolo ezibikiwe ngaphakathi kwebhokisi ngalinye zimelela iphesenti leziguli ezine-BRCA1 subtype PV kanye ne-BRCA2 ngayinye yomdlavuza webele.
Izifinyezo: ama-PV, ukuhluka kwe-pathogenic; I-HER2+, i-epidermal growth factor receptor 2 positive; I-TNBC, umdlavuza webele ongenawo kathathu.
Ngokulandelayo, sihlole uhlobo nofuzo lwendawo lwe-BRCA1 kanye ne-BRCA2 PVs.Ku-BRCA1 PV, siphawule okuhlukile okungu-7 kwe-nucleotide eyodwa (SNVs), ukususwa okungu-6, ukuphindaphinda okungu-3 kanye nokufakwa oku-1. Ukuguqulwa okukodwa kuphela (c.5522delG) kumelele ukutholwa okusha okutholakele kuzo zombili izihloko ezitholakala kakhulu i-BRCA1V. c.5035_5039delCTAAT.Lokhu kuguqulwa kuhilela ukususwa kwama-nucleotide amahlanu (CTAAT) ku-BRCA1 exon 15, okuholela ekushintshweni kwe-amino acid leucine nge-tyrosine ku-codon 1679, futhi ngenxa yokuguqulwa kwefreyimu enenye indlela ebikezelwe yokumisa ikhodoyini enye iprotheni eyodwa kuphela ithola iprotheni eyodwa kuphela. icala.Ngokuphawulekayo, enye yama-PV abikiwe ibitholakala endaweni yokuvumelana yesayithi ye-splice (c.4357+1G>T) (Ithebula 1).
Mayelana ne-BRCA2 PV, siqaphele ukususwa okungu-6, ama-SNV angu-6 nokuphindaphinda okungu-2. Azikho izinguquko ezitholakele eziyinoveli.Izinguquko ezintathu eziphinde zavela kubantu bethu, c.428dup kanye no-c.8487+1G>A okuphawulwe ezihlokweni ezingu-3, kulandelwa u-c.5851_5854ukushintshwa kwe-c. I-C ku-exon 5 ye-BRCA2, ibikezelwe ukuthi izofaka ikhodi yephrotheni encishisiwe, engasebenzi.I-c.8487+1G>Ukuguqulwa kwenzeka endaweni ye-intronic ye-BRCA2 intron 19 (± 1,2) futhi kuthinta ukulandelana kwesivumelwano sokuhlanganisa, okuholela ekuguquguqukeni kwe-splicing noma i-abs. c.5851_5854delAGTT okuhlukile kwe-pathogenic kungenxa yokususwa kwe-4-nucleotide ezindaweni ze-nucleotide 5851 kuya ku-5854 ku-coding exon 10 yofuzo lwe-BRCA2 futhi kuphumela kuhlaka lokuhumusha olune-stop codon ebikezelwe (p.S1951Wf kokubili njengoba kubikiwe ngaphambilini). c.631G>A kanye ne-c.7008-2A>T zitholwe esigulini esifanayo.34 Ukuguqulwa kokuqala kuhilela ukushintshwa kwe-adenosine (A) ku-BRCA2 exon 7 nge-guanine (G) equkethe i-nucleotide okuholela ekushintsheni kwe-valine ku-isoleucine ku-codon 211, i-isole ye-amino acid ithinta kakhulu i-amino acid i-amino acid. ukuhlanganisa.Okuhlukile kwesibili kutholakala endaweni ye-intronic futhi kuholela ekushintsheni okuphindwe kabili kwe-A kuya ku-thymine (T) ngaphambi kwe-exon 13 ye-gene encoding BRCA2.Ushintsho lwe-c.7008-2A>T lungase lukhiqize imibhalo eminingi yobude obuhlukene.Ngaphezu kwalokho, eqenjini le-BRCA2 PVs, izinguquko ezingu-8 zazingaphandle kwe-2% ye-intronic.
Sibe sesifaka imephu yokuguqulwa kwe-BRCA1/2 esusayo ezizindeni ezisebenzayo nasezifundeni ezibophezela amaprotheni (Fig. 4).Kufuzo lwe-BRCA1, u-50% wama-PVs abekwe endaweni yeqoqo lomdlavuza webele (BCCR), kuyilapho u-22% wokuguqulwa atholakala esifundeni seqoqo lomdlavuza we-ovarian (OCCR) (Fig. BRCA5A) ku-vario ye-PCA etholakala kumaphesenti angu-BRCA52. isifunda se-BCCR kanye no-42.8% wezinguquko zitholakala ku-OCCR (Fig. 4B).Okulandelayo, sihlole indawo ye-PV ngaphakathi kwesizinda samaprotheni e-BRCA1 kanye ne-BRCA2.Kuphrotheni ye-BRCA1, sithole ama-PV amathathu kusizinda se-loop kanye nekhoyili ehlanganisiwe, kanye nokuguqulwa okubili kwesizinda se-BRCT4Amaphrotheni, i-BRCT4A2 yesizinda se-mapped. kusizinda sokuphinda se-BRC, kuyilapho izinguquko ezingu-3 ze-intronic kanye ne-3 ze-exonic zitholwe ku-oligo/oligosaccharide-binding (OB) kanye nezizinda zombhoshongo (T) (Umfanekiso 4B).
Umfanekiso 4 Ukumelwa okuhleliwe kwamaprotheni e-BRCA1 kanye ne-BRCA2 kanye nokwenza kwasendaweni kwezinhlobonhlobo ze-pathogenic.Lesi sibalo sibonisa ukusatshalaliswa kwe-BRCA1 (A) ne-BRCA2 (B) okuhlukile kwe-pathogenic ezigulini ezinomdlavuza webele.Ukuguqulwa kwe-Exonic kuboniswa ngoluhlaza okwesibhakabhaka, kuyilapho okuhlukile kwe-intronic kuboniswa ngowolintshi.Ubude bebha bumele inani lamacala.Isizinda sazo se-BRCA21 esisebenzayo.I-BRCA21 Iphrotheni ye-BRCA1 iqukethe isizinda seluphu (RING) kanye nokulandelana kwendawo yenuzi (NLS), isizinda sekhoyili ekhoyiliwe, isizinda seqoqo le-SQ/TQ (SCD), kanye nesizinda se-BRCA1 C-terminal (BRCT).(B) Iphrotheni ye-BRCA2 iqukethe izimpinda eziyisishiyagalombili ze-BRC, isizinda esibopha i-DNA esinesizinda se-helical oligobinding/oligobinding three (Heligobinding three) ukugoqa, isizinda sombhoshongo (T), kanye ne-An NLS ohlangothini lwe-C.Izindawo ezibizwa ngokuthi i-Breast Cancer Cluster Region (BCCR) kanye ne-Ovarian Cancer Cluster Region (OCCR) zikhonjiswe ngezansi.*Imele ukuguqulwa kwezakhi zofuzo ezinquma ama-stop codon.
Sibe sesiphenya izici ze-BC clinicopathological ezingase zihlobane nokuba khona kwe-BRCA1/2 PV. Amarekhodi omtholampilo aphelele atholakalela iziguli eziyi-181 BRCA1/2-negative (ezingezona izithwali) kanye nabo bonke abathwali (n = 35).Kube khona ukuhlobana phakathi kwezinga lokwanda kwesimila kanye nebanga.
Sibale ukusatshalaliswa kwe-Ki-67 ngokusekelwe kumidiyeni yeqembu lethu (25%, ububanzi <10-90%).Izifundo ezine-Ki-67 <25% zichazwe ngokuthi “i-Ki-67″ ephansi, kuyilapho abantu abanamanani ≥ 25% babhekwe “njenge-Ki-67″ ephezulu.Umehluko obalulekile (i-Ki-60) obalulekile (i-1p-carrier) utholwe. BRCA1 PV abathwali (Fig. 5A).
Umfanekiso 5 Ukuhlobana kwe-Ki-67 nokusatshalaliswa kwebanga kwabesifazane abanomdlavuza webele abane-BRCA1 kanye nangenayo i-BRCA2 PVs.(A) Ibhokisi elibonisa amanani amaphakathi e-Ki-67 ezigulini ezingu-181 ezingathwali ze-BC uma ziqhathaniswa ne-BRCA1 (18) noma i-BRCA2 (17) iziguli ze-PV.P. ukwabelwa kweziguli ezinomdlavuza we-BC emaqenjini ebanga le-histological (G2 ne-G3) ngokuya nge-BRCA1 kanye ne-BRCA2 isimo sokuguquka (izihloko ze-WT, i-BRCA1 kanye ne-BRCA2 PVs abathwali).
Ngokufanayo, sihlole ukuthi ingabe ibanga lesimila lihlobene nokuba khona kwe-BRCA1/2 PV.Njengoba i-G1 BC yayingekho emphakathini wethu, sihlukanise iziguli ngamaqembu amabili (G2 noma i-G3). Ngokuvumelana nemiphumela ye-Ki-67, ukuhlaziya kwembule ukuhlobana okubalulekile ngokwezibalo phakathi kwebanga lesimila kanye nokuguqulwa kwe-BRCA1, okunengxenye ephakeme ye-G3 ethwala isimila uma kuqhathaniswa ne-G3 ye-non-tumor-BRCA (p<0.005) (Umfanekiso 5B).
Intuthuko kubuchwepheshe bokulandelana kwe-DNA yenze inqubekelaphambili engakaze ibonwe ekuhlolweni kofuzo kwe-BRCA1/2, okunomthelela obalulekile ezigulini ezinomlando womndeni womdlavuza.Kuze kube manje, cishe i-20.000 ye-BRCA1/2 ehlukahlukene ihlonziwe futhi yahlukaniswa ngokusho kwe-American Society of Medical Genetics 35 kanye nohlelo lwe-ENIGMA lwaziwa kahle nge-BRCA1/36 luyaziwa kahle nge-BRCA1/36. kabanzi ezifundeni zezwe.37 Ngaphakathi kwe-Italy, izinga le-BRCA1/2 PVs lalisuka ku-8% laya ku-37%, libonisa ukuhlukahluka okubanzi kwangaphakathi kwezwe.38,39 Njengoba kunabantu abacishe babe izigidi ezi-5, iSicily iyisifunda sesihlanu ngobukhulu e-Italy ngokwenani labantu abahlala khona. isiqhingi.
Ucwaningo lwethu lungomunye wemibiko yokuqala mayelana nesigameko se-BRCA1/2 PV ezigulini ze-BC empumalanga yeSicily.28 Sigxile ekuhlaziyeni kwethu ku-BC, njengoba lokhu kuyisifo esivame kakhulu eqenjini lethu.
Lapho kuhlolwa iziguli ze-389 BC, i-9% iphethe i-BRCA1/2 PVs, esatshalaliswa ngokulinganayo phakathi kwe-BRCA1 ne-BRCA2.Le miphumela ihambisana naleyo ebibikwe ngaphambilini kubantu base-Italy.28 Kuyathakazelisa ukuthi, i-3% (13/389) yeqembu lethu kwakungamadoda.Leli zinga liphakeme kunalokho okulindelekile kumdlavuza webele wabesilisa (1% ye-4 yabo bonke abantu be-BC) Ingozi yokuguqula i-BRCA1/2. Nokho, akekho kulawa madoda owakha i-BRCA1/2 PV, ngakho babengamakhandidethi okuhlaziya okwengeziwe kwamangqamuzana ukuze kukhishwe ukuba khona kokuguqulwa kwezakhi zofuzo okungajwayelekile okufana ne-PALB2, i-RAD51C kanye no-D, phakathi kokunye. Izinhlobonhlobo ezinokubaluleka okungaqinisekile zitholwe ku-7% wezifundo lapho i-BRCA2 ekhona le VUS yayikhona. ubufakazi.28,41,42
Lapho sihlaziya ukusatshalaliswa kwe-BC molecular subtypes kwabesifazane abaguqukile be-BRCA1/2, siqinisekise izinhlangano ezaziwayo phakathi kwe-TNBC ne-BRCA1 PV (58.8%) naphakathi kwe-luminal B BC kanye ne-BRCA2 PV (55.6%).16,43 I-luminal A ne-HER2+ izimila ku-BRCA1 kanye ne-BRCA1 nenkampani yenethiwekhi1 yidatha ekhona ye-6 PV2.
Bese sigxila ohlotsheni nendawo ye-BRCA1/2 PV.Eqenjini lethu, i-BRCA1 PV ejwayeleke kakhulu bekuyi-c.5035_5039delCTAAT.Nakuba u-Incorvaia et al. abazange bakuchaze lokhu okwehlukile eqenjini labo lase-Sicilian, abanye ababhali bakubike njengegciwane i-BRCA1 PV.34 Ama-PV amaningana e-BRCA1 atholwe eqenjini lethu - isb c.181T>G, c.514del, c.3253dupA kanye no-c.5266dupC - okutholwe okubili kwe-BRCA1 ku-Sicier. (c.181T>G no-c.5266dupC) zivame ukutholakala kumaJuda ase-Ashkenazi aseMpumalanga naseYurophu Ephakathi (iPoland, Czech), isiSlovenia, i-Austrian, isiHungary, isiBelarusian nesiJalimane), i-44,45 futhi, e-United States nase-Argentina, isanda kuchazwa ngokuthi "i-germline variant" echazwe ngaphambilini BCdel 4 iziguli ezine-OCdel 4 ngaphambili. ezigulini zomdlavuza webele we-8 ezivela enyakatho yeSicily ePalermo naseMessina.Ngokuthakazelisayo, ngisho no-Incorvaia et al. ithole okuhlukile kwe-c.3253dupA kweminye imindeni e-Catania.28 Ama-BRCA2 PV amele kakhulu yi-c.428dup, c.5851_5854delAGTT kanye nokwehluka oku-intronic c.8487+1G>A, okubikwe ngemininingwane eyengeziwe 28 esigulini sase-Palermo esine-c.52AG5, P52V, C. ibonwe ezindlini ezisenyakatho-ntshonalanga yeSicily, ikakhulukazi ezifundeni zaseTrapani nasePalermo, kanti i-c.5851_5854delAGTT PV yabonwa emakhaya asenyakatho-ntshonalanga yeSicily.Okuhlukile okungu-8487+1G>A kuvame kakhulu ezifundweni zaseMessina, Palermo, naseCaltanissetta.28 al. Rebbeck et al. ichaze ngaphambilini ukuguqulwa kwe-c.5851_5854delAGTT e-Colombia.37 Enye i-BRCA2 PV, c.631+1G>A, itholwe ezigulini ze-BC kanye ne-OC ezivela e-Sicily (Agrigento, Siracusa and Ragusa).28 Ngokuphawulekayo, siqaphele ukuphilisana kwezinhlobo ezimbili ze-BRCA2 kanye ne-31G2>A (BRCA2>A) ezimbili (BRCA2>A). c.7008-2A>T) esigulini esifanayo, ebesicabanga ukuthi sihlukaniswe ngemodi ye-cis, njengoba kubikwe kanjalo ngaphambilini.34,46 Lezi zinguquko ze-BRCA2 uble zivame ukubonwa ngempela esifundeni sase-Italy futhi zitholwe zethula ama-codon okumisa ngaphambi kwesikhathi, okuthinta i-RNA yesithunywa ehlanganayo futhi ibangela ukuthi iphrotheni ye-BRCA2,8 ihluleke.
Siphinde futhi senze imephu ye-BRCA1 kanye ne-BRCA2 PVs ezindaweni ezibekayo ze-OCCR kanye ne-BCCR yezizinda zamaprotheni nezakhi zofuzo.Lezi zifunda zichazwe ngu-Rebbeck et al. njengezindawo eziyingozi zokuthuthukisa umdlavuza we-ovarian nowebele, ngokulandelana.49 Nokho, ubufakazi obuphathelene nokuhlangana phakathi kwendawo yokuhlukahluka kwegciwane kanye nengozi yomdlavuza webele noma we-ovarian kusalokhu kuyimpikiswano. izifunda ezibekayo ze-OCCR ne-BCCR kanye nezici ze-BC.Lokhu kungase kube ngenxa yenani elilinganiselwe leziguli ezinezinguquko ze-BRCA1/2. Ngokombono wesizinda samaprotheni, ama-BRCA1 PVs asatshalaliswa kuwo wonke amaprotheni, futhi ukuguqulwa kwe-BRCA2 kutholakala ngokukhethekile kusizinda sokuphinda se-BRC.
Okokugcina, sihlobanise izici ze-BC clinicopathological ne-BRCA1/2 PV.Ngenxa yenani elilinganiselwe leziguli ezifakiwe, sithole kuphela ukuhlobana okubalulekile phakathi kwe-Ki-67 nebanga lesimila.Nakuba ukuhlolwa nokuchazwa kwe-Ki-67 kusalokhu kuyimpikiswano ngandlela thile, kuqinisekile ukuthi amazinga aphezulu okukhula ahlotshaniswa nengozi eyandayo yokuncipha kokubuya kwesifo, ukuhlukaniswa kokubuya kwesifo. I-Ki-67 “ephezulu” kanye “nephansi” ingu-20%.Nokho, lo mkhawulo awusebenzi esigungwini sethu sesiguli se-BRCA1/2, esinenani elimaphakathi le-Ki-67 elingu-25%.Lo mkhuba wamazinga aphezulu we-Ki-67 ungachazwa ukwanda kweqembu lethu le-luminal B kanye ne-TNBC, lapho okukhanyayo okumbalwa ku-A kusikisela ukuthi kukhona ubufakazi obuphezulu be-Ki-7. (25–30%) ingase ihlukanise kangcono iziguli ngokuvumelana nokubikezela kwazo.53,54 Kusukela emiphumeleni yokuhlaziya kwethu, ukuhlobana okuphawulekayo akumangazi.Kuvela phakathi kwe-Ki-67 ephezulu kanye namamaki kanye nokuba khona kwe-BRCA1 PV.Eqinisweni, izimila ezihlobene ne-BRCA1 zivamile ku-TNBC futhi zibonisa izici ezinonya kakhulu.16,17,17.
Sengiphetha, lolu cwaningo luhlinzeka ngombiko mayelana nesimo sokuguqulwa kwe-BRCA1/2 eqenjini le-BC kusukela empumalanga ye-Sicily. Sekukonke, okutholakele kwethu kuhambisana nobufakazi obukhona ngaphambili, kokubili mayelana nokusakazeka kokuguqulwa kwezakhi zofuzo kanye nezici ze-clinicopathological ku-BC. Ucwaningo olwengeziwe emiphakathini emikhulu ye-BRCA1 / 2-mutant BC iziguli, ukuhlaziya okuguquguqukayo okunwetshiwe kusetshenziswa iziguli ze-BC ezihlukahlukene yama-PV ahlukile futhi angavamile kakhulu kune-BRCA1/2. Lokhu kuzovumela ukuhlonza nokuphathwa ngendlela efanele kwenani elikhulayo lezifundo ezisengozini enkulu yomdlavuza ngenxa yokuguqulwa kofuzo.
Siqinisekise ukuthi iziguli zisayine imvume enolwazi ukuze zikhiphe amasampula azo isimila ngokungaziwa ngezinhloso zocwaningo.Zonke iziguli zisayine imvume ebhaliwe enolwazi ngokweSimemezelo sase-Helsinki.Ngokwenqubomgomo ye-AOU Policlinico "G.Rodolico - S.Marco", lolu cwaningo lukhishwe ekubuyekezweni kwezimiso zokuziphatha ngoba ukuhlaziya kwe-BRCA1/2 kwenziwa zonke iziguli ngokuvumelana nemvume yazo ebhaliwe yokusetshenziswa komtholampilo. idatha ngezinjongo zocwaningo.
Sibonga uProf. Paolo Vigneri ngosizo lwakhe ekunakekeleni iziguli ezinomdlavuza webele njengoba kucelwe iKomidi Lokuziphatha.
U-Federica Martorana ubika i-honoraria evela ku-Istituto Gentili, u-Eli Lilly, uNovartis, uPfizer.Abanye ababhali bamemezela ukuthi akukho ukungqubuzana kwezintshisekelo kulo msebenzi.
1. Sung H, Ferlay J, Siegel RL, et al.Global Cancer Statistics 2020: I-GLOBOCAN ilinganisela izehlakalo nokufa kwabantu abanomdlavuza abangama-36 emazweni angu-185 emhlabeni jikelele.CA Cancer J Clin.2021;71(3):209-249.303:10/249.
Isikhathi sokuthumela: Apr-15-2022
