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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
UStefania 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 Ikliniki yeLizwe yeLizwe, 1 yeMaperimental, iMaperimental 7 iMaperimental, iMaperimental Clinic IYunivesithi yaseCatania, Catania, 95123, Italy;2 Iziko le-2 ye-Experimental Oncology kunye ne-Hematology, i-AOU Policlinico "G.Rodolico - San Marco", Catania, 95123, Italy; I-3 ye-Oncology yezoNyango, i-AOU Policlinico "G. Rodolico - San Marco", Catania, 95123, Italy; 4 iGenetics yezoNyango, ARNAS Garibaldi, Catania, 95123, Italy; 5 Medicine Genetics, ASP, Syracuse, 96100, Italy; I-6 iSebe le-Biomedical kunye ne-Biotechnology Sciences, iYunivesithi yaseCatania, i-Genetics yezoNyango, eCatania, e-Italy, 95123; I-7Oasi Research Institute-IRCS, Troina, 94018, Italy Unxibelelwano: Stefania Stella, umnxeba +39 095 378 1946, i-imeyile [i-imeyile ekhuselweyo]; [i-imeyile ekhuselweyo] Injongo: Ukuguqulwa kwe-germline kwi-BRCA1 kunye ne-BRCA2 kunye nokusekwa komhlaza webele (BC), i-ovary (OC) kunye nezinye ezihambelana nobungozi bokuphila komhlaza.Uvavanyo lwe-BRCA gene lungundoqo ekuhloleni umngcipheko womntu ngamnye, kunye nokufumana iindlela zokuthintela kubathwali abaphilileyo kunye nokulungelelanisa unyango kwizigulane zomhlaza. nangona idatha ikhona kwiintlobo ze-BRCA ze-pathogenic kwiintsapho zaseSicily, izifundo ezijolise ngokukodwa kubantu basempuma yeSicily zinqongophele. index.RESULTS: Ngokubanzi, izigulane ezingama-35 (9%) zine-BRCA pathogenic variant, 17 (49%) kwi-BRCA1 kunye ne-18 (51%) kwi-BRCA2.BRCA1 iinguqu zixhaphake kwi-triple-negative BC izigulane, kanti ukuguqulwa kwe-BRCA2 kuxhaphake kakhulu kwi-luminal BC izigulane. I-proliferative index.Izigqibo: Iziphumo zethu zibonelela ngombono we-BRCA ye-mutation status kwizigulane ze-BC ezivela empuma yeSicily kwaye ziqinisekisa indima yohlalutyo lwe-NGS ekuchongeni izigulane ezine-hereditary BC. Ngokubanzi, ezi nkcukacha zihambelana nobungqina obudlulileyo obuxhasa ukuhlolwa kwe-BRCA ekukhuseleni ngokufanelekileyo kunye nokunyangwa komhlaza kwi-mutation carriers.
Umhlaza wamabele (BC) yeyona nto ixhaphakileyo emhlabeni jikelele kunye nomhlaza obulala kakhulu kubasetyhini.1 Iimpawu zebhayoloji ezimisela i-BC prognosis kunye nokuziphatha kweklinikhi kuye kwafundwa ngokubanzi kwaye kwacaciswa ngokuyinxenye ngokuhamba kwexesha.Enyanisweni, amanqaku amaninzi e-surrogate asetyenziswa ngoku ukuhlula i-BC kwii-subtypes ezahlukeneyo ze-molecular.Ziyi-estrogen (ER) kunye/okanye i-receptor2 yabantu (i-PgR2 receptor) i-receptor yabantu. i-amplification, i-proliferation index ye-Ki-67 kunye ne-tumor grade (G) .2 Ukudibanisa kwezi ziguquko zichonge ezi zintlu ze-BC zilandelayo: 1) I-Luminal tumors, ebonisa i-ER kunye / okanye i-PgR ibonakaliso, ibalwa kwi-75% ye-BCs. Ezi zicubu zahlulwa kwakhona kwi-Luminal A, xa i-Ki-67 yayingaphantsi kwe-20% kunye ne-HER2 i-negative xa i-60 ilingana ne-62, kunye ne-62 ye-B. Ukwandiswa kwe-HER2, kungakhathaliseki ukuba i-proliferation index; I-2) i-HER2 + i-tumor e-ER kunye ne-PGR engalunganga kodwa ibonisa i-HER2 yokukhulisa. I-3) Umhlaza webele we-Triple-negative (TNBC), engabonakali i-ER kunye ne-PgR intetho kunye ne-HER2 yokukhulisa, i-akhawunti malunga ne-15% ye-cancer yebele.2-4
Phakathi kwezi subtypes ze-BC, ibakala le-tumor kunye ne-proliferation index imele i-biomarkers ye-cross-sectional ehambelana ngokuthe ngqo kwaye ngokuzimeleyo ne-tumor aggressiveness kunye ne-prognosis.5,6
Ukongeza kwiimpawu zebhayoloji ezikhankanywe ngasentla, indima yokuguqulwa kwemfuza ekhokelela ekuphuhlisweni kwe-BC ibaluleke kakhulu kwiminyaka embalwa edlulileyo.7 Ngokumalunga ne-1 kwi-10 ye-tumor yesifuba ifunyenwe njengefa ngenxa yokuguqulwa kwe-germline kwiigenes ezithile.8 Izifundo ezimbini ezinkulu ze-epidemiological ezibandakanya ngaphezu kwe-180,000 yabasetyhini baye bachonga i-genes ye-TM 1, i-10, i-1, i-1, i-A , i-B, i-A, i-80000 yabasetyhini, i-Genes ye-80,000 kutshanje I-BRCA2, i-CHK2, i-PALB2, i-RAD51C, kunye ne-RAD51D) eyona nto ijongene ne-hereditary BC.Phakathi kwezi zakhi zofuzo, i-BRCA1 kunye ne-BRCA2 (emva koku kuthiwa yi-BRCA1 / 2) ibonise ukulungelelaniswa okunamandla kunye nophuhliso lwebele. kuquka i-ovarian, i-prostate, i-pancreatic, i-colorectal, kunye ne-melanoma.Ukususela kwiminyaka eyi-13 ukuya kwi-80 iminyaka, iziganeko ezikhulayo ze-BC yi-72% kubasetyhini abane-BRCA1 variant pathogenic (PV) kunye ne-69% kubasetyhini abane-BRCA2 PV.14
Ngokucacileyo, ukupapashwa kwamva nje kubonisa ukuba ingozi ye-BC ixhomekeke kuhlobo lwe-PV. Enyanisweni, xa kuthelekiswa neentlobo ze-pathogenic truncating variants, i-glaring missense variants, ngokukodwa kwi-BRCA1 gene, idibene nomngcipheko oncitshisiweyo we-BC, ngakumbi kubasetyhini abadala.15
Ubukho be-BRCA1 okanye i-BRCA2 PV yayinxulunyaniswa neempawu ezahlukeneyo zebhayoloji kunye nezonyango. i-indices proliferative.Ezi zicubu zixhaphake kakhulu kwi-lumen B kwaye ngokuqhelekileyo zivela kubantu abadala abadala.16-18 Ngokucacileyo, ukuguqulwa kwe-BRCA1 kunye ne-BRCA2 kwandisa uvakalelo kunyango oluthile, kubandakanywa neetyuwa zeplatinum kunye neziyobisi ezijoliswe kuzo ezifana ne-poly (ADP-ribose) i-polymerase inhibitors (PARPi) .19,20
Kwiminyaka embalwa edlulileyo, ukuphunyezwa kolandelelwano lwesizukulwana esilandelayo (NGS) ekusebenzeni kwezonyango kwenze ukuba inani elonyukayo lezigulane ze-BC zenze uvavanyo lwe-molecular syndromes ye-cancer susceptibility syndromes, kubandakanywa i-BRCA1 / 2.21 Ngaxeshanye, iinkcazo ezisekelwe kwiikhrayitheriya ezichanekileyo malunga nembali yentsapho , i-demographic, kunye neempawu ze-clinicopathological ukuchonga ngcono abantu abangabodwa23 kumxholo we-BR22 . ukuqokelela kwi-BRCA1 / 2 ukuhlolwa kuluntu oluthile, ukugqamisa ukungafani kwimimandla yelizwe.
Sichaza apha iziphumo zovavanyo lwe-germline BRCA1/2 kwizigulane ze-BC ezivela empuma yeSicily, ukulungelelanisa ngakumbi ubukho be-BRCA1 okanye ukuguqulwa kwe-BRCA2 kunye neempawu eziphambili zeklinikhi zala mathumba.
Uphononongo olwenziwayo lwenziwa kwi-"Center for Experimental Oncology and Hematology" kwiSibhedlele sasePoliclinico.Rodolico - San Marco eCatania.Ukususela ngoJanuwari 2017 ukuya kuMatshi 2021, izigulane ezingama-455 ezinesifuba kunye ne-ovarian, i-melanoma, i-pancreatic okanye i-prostate yomhlaza zaye zathunyelwa kwi-molecular diagnostic test / BRCAratory. Isibhengezo seHelsinki, kunye nabo bonke abathathi-nxaxheba banikezela imvume ebhaliweyo enolwazi ngaphambi kohlalutyo lwe-molecular.
Iimpawu ze-Histological kunye ne-biological (ER, PgR, isimo se-HER2, i-Ki-67, kunye ne-grade) ye-BC yavavanywa kwi-core biopsy okanye iisampulu zotyando, kuqwalaselwa kuphela amacandelo e-tumor enobudlova.Ngokusekelwe kwezi mpawu, i-BCs yahlelwa ngolu hlobo lulandelayo: i-luminal A (ER + kunye / okanye i-PGR +, HER2-, i-Pg + 6, i-luminal <, i- ER2-, i- PERG + , i- 7) I-HER2-, i-Ki-67≥20%), i-luminal B-HER2 + (ER kunye / okanye i-PgR +, i-HER2 +), i-HER2 + (i-ER kunye ne-PgR-, i-HER2 +) okanye i-triple negative (ER kunye ne-PgR-, i-HER2-).
Ngaphambi kokuvavanya i-BRCA1 kunye ne-BRCA2 yokuguqula isimo, iqela lezinto ezininzi ezibandakanya i-oncologist, i-geneticist, kunye nesayikholoji yengqondo yenza i-tumor genetics consultation kwisigulane ngasinye ukumisela ubukho be-BRCA1 kunye / okanye i-BRCA1. okanye abantu abanomngcipheko ophezulu we-PV kwi-gene ye-BRCA2. Ukukhethwa kwesigulane kwenziwa ngokuhambelana nezikhokelo ze-Italian Society of Medical Oncology (AIOM) kunye neengcebiso zendawo yaseSicilian.30,31 Ezi ndlela ziquka: (i) imbali yentsapho yeentlobo ze-pathogenic ezaziwayo kwiintlobo ze-susceptibility (umzekelo, i-BRCA1, i-BRCA2, i-TP53, i-TP53); (ii) amadoda anoBC; (iii) abo bano-BC no-OC; (iv) abasetyhini abaneBC <36 iminyaka, TNBC <60 iminyaka, okanye amacala amabini BC <50 iminyaka; (v) Imbali yempilo yobuqu ka-BC
Yonke i-nomenclature eyahluka-hlukeneyo ilandele izikhokelo zangoku ze-Human Genome Variation Consortium, ekhoyo kwi-intanethi (HGVS, http://www.hgvs.org/mutnomen) .Ukubaluleka kwekliniki ye-BRCA1/2 eyahlukileyo yachazwa ngokusebenzisa ukuhlelwa kwe-International Consortium ENIGMA (Ubungqina-Based Network for Interpreting Alglelesline, https://www.Mutanteniting Alglelesline). ukubonisana noovimba beenkcukacha ezahlukeneyo ezifana ne-ARUP, i-BRCAEXCHANGE, i-ClinVar, i-IARC_LOVD, kunye ne-UMD.Uluhlu lubandakanya iindidi ezintlanu ezinobungozi obuhlukeneyo: i-benign (udidi I), mhlawumbi i-benign (udidi II), ukwahluka kokubaluleka okungaqinisekanga (VUS, udidi III), kunokwenzeka ukuba i-pathogenic (i-category IV) kunye ne-anazegen pathogenic (udidi lwe-IV), kunye ne-anazegen pathogenic (udidi lwe-IV) kunye ne-anazegen pathogenic. ubume beprotheyini kunye nomsebenzi, isixhobo esinolwazi ngokufikelela kuma-database angama-30.32
Ukwabela ukubaluleka okunokubakho kweklinikhi kwi-VUS nganye, oku kulandelayo kusetyenziswe i-algorithms yeprotheyini yokuqikelela iprotheyini: IMUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/G) kunye noAlign-GVG (http://agvgd.hci.utah.edu/agvgd_input.php).Iintlobo ngeentlobo ezihlelwa njengeklasi 1 kunye no-2 zazithathwa njengodidi lwasendle.
Ulandelelwano lwe-Sanger luqinisekisile ubukho be-pathogenic variant nganye.Ngokufutshane, iperi ye-primers ethile yenzelwe ukwahluka nganye echongiweyo ngokusebenzisa i-BRCA1 kunye ne-BRCA2 yolandelelwano lwereferensi yemfuza (NG_005905.2, NM_007294.3 kunye ne-NG_012772.3, NM9.000 ilandelwe ngokulandelelana kwe-PC). ngolandelelwano lweSanger.
Izigulana eziye zavavanya zingenayo i-BRCA1/2 gene zavavanywa nge-multiplex ligation-dependent probe amplification (MLPA) ngokwemiyalelo yomenzi yokuvavanya ubukho be-genomic rearrangements (LGR) ngokufutshane, iisampulu ze-DNA zidenatured kwaye ukuya kuthi ga kwi-60 BRCA1 kunye ne-BRCA2 kusetyenziswa i-genespecificbe i-DNA nganye ulandelelwano malunga nama-nucleotide angama-60 ngobude.Imveliso yokukhulisa i-probe, equka iseti eyodwa yee-amplicon ze-PCR, zaye zahlalutywa nge-capillary electrophoresis kunye ne-software ye-Cofalyser.Net ngokubambisana ne-batch-specific Cofalyser tables (www.mrcholland.com).
Iinguqu ezikhethiweyo zeklinikhi (ibakala le-histological kunye ne-Ki-67% ye-proliferation index) zidibene nobukho be-BRCA1 / 2 PV, zibalwe ngokusebenzisa i-software ye-Prism v. 8.4 usebenzisa uvavanyo oluchanekileyo lwe-Fisher oluthatha ixabiso le-p-value <0.05 ebalulekileyo.
Phakathi kukaJanuwari 2017 kunye no-Matshi 2021, izigulane ze-455 zahlolelwa i-germline BRCA1/2 ukuguqulwa kwenguqu. Uvavanyo lokuguqulwa lwenziwa kwiziko leSibhedlele se-Policlinico kwi-Experimental Oncology and Hematology. Ngokuhambelana nesikhokelo saseSicilian (http://www.gurs.regione.sicilia.t.it/Indicep.it/It Gennaio 2020), iRodolico yaseCatania - San Marco "ibonke, izigulane ezingama-389 Kwakukho umhlaza webele, umhlaza we-ovarian angama-37, umhlaza we-pancreatic 16, umhlaza we-prostate osi-8 kunye ne-melanoma eyi-5. Ukusasazwa kwezigulane ngokohlobo lomhlaza kunye neziphumo zohlalutyo kuboniswe kuMfanekiso 1.
Umzobo we-1 ubonisa i-flow chart ebonisa umboniso wokufunda.Izigulane ezinebele, i-melanoma, i-pancreatic, i-prostate, okanye i-ovarian tumors zavavanywa ukuguqulwa kwe-BRCA1 kunye ne-BRCA2 yofuzo.
Izifinyezo: ii-PVs, i-pathogenic variant; I-VUS, ukwahluka kokubaluleka okungaqinisekanga; I-WT, i-wild-type BRCA1/2 ulandelelwano.
Sikhethe ngokukhethekileyo izifundo zethu kumaqela omhlaza webele.Izigulane zazineminyaka engama-49 ubudala (uluhlu lwama-23-89) kwaye ubukhulu becala yayingabasetyhini (n = 376, okanye 97%).
Kwezi zifundo, i-64 (i-17%) ine-BRCA1 / 2 yokuguqulwa kwaye bonke babesetyhini.Amashumi amathathu anesihlanu (9%) ane-PV kunye ne-29 (7.5%) ene-VUS. Ishumi elinesixhenxe (48.6%) ye-35 ye-pathogenic variants yenzeke kwi-BRCA1 kunye ne-18 (51.4%) kwi-BRCA2, ngelixa i-51.4% ye-BRCA2 (i-BRCA18%) kunye ne-2%) yenzeke kwi-BRCA2. kwi-BRCA2 (Amanani 1 kunye ne-2) .I-LGR yayingekho kuhlalutyo lwe-MLPA.
Umzobo 2. Uhlalutyo lwe-BRCA1 kunye ne-BRCA2 utshintsho kwizigulane ze-389 zomhlaza webele. (A) Ukuhanjiswa kweentlobo ze-pathogenic (PV) (obomvu), ukuhlukahluka kokubaluleka okungaqinisekanga (VUS) (i-orange), kunye ne-WT (blue) kwi-389 izigulane zomhlaza webele; (B) I-389 izigulane zomhlaza wesifuba Amashumi amathathu anesihlanu (9%) ane-BRCA1 / 2 i-pathogenic variants (PVs) .Phakathi kwabo, i-17 (48.6%) yayiyi-BRCA1 PV abathwali (obomvu obomvu) kunye ne-18 (51.4%) yabathwali be-BRCA2 (obomvu obomvu); (C) I-29 (7.5%) yezifundo ezingama-389 zithwele i-VUS, i-5 (17.2%) i-BRCA1 yofuzo (i-orenji emnyama) kunye ne-24 (82.8%) ye-BRCA2 yofuzo (i-orenji ekhanyayo).
Izifinyezo: ii-PVs, i-pathogenic variant; I-VUS, ukwahluka kokubaluleka okungaqinisekanga; I-WT, i-wild-type BRCA1/2 ulandelelwano.
Ngokulandelayo siphande ukuxhaphaka kwe-BC i-molecular subtypes kwizigulane ezine-BRCA1/2 PV. Usasazo lubandakanya i-2 (5.7%) luminal A, 15 (42.9%) luminal B, 3 (8.6%) luminal B-HER2+, 2 (5.7%) HER2+ kunye ne-13 (37.1%) phakathi kwezigulane ze-TNBC ezi-2. I-luminal B BC, i-2 (11.8%) yayinesifo se-HER2 +, kwaye i-10 (58.8%) yayine-TNBC.Ii-Tumors ngaphandle kwe-BRCA1 ukuguqulwa kwe-BRCA1 yayiyi-luminal A okanye i-luminal B-HER2+ (Figure 3) .Kwi-BRCA2-positive subgroup, i-10 (55.6%) i-tumors yayiyi-luminal B. 3+72% ye-luminal B. 3+72%) (16.7%) i-TNBC kunye ne-2 (11.1%) yayiyi-luminal A (Figure 3) .Akukho zicubu ze-HER2 + ezikhoyo kweli qela. Ngaloo ndlela, ukuguqulwa kwe-BRCA1 kuxhaphake kwizigulane ze-TNBC, kanti ukuguqulwa kwe-BRCA2 kuninzi kwi-lumen B ngabanye.
Umzobo we-3 Ukuxhaphaka kwe-subtypes yomhlaza wesifuba kwizigulane ezineenguqu ze-pathogenic kwi-BRCA1 kunye ne-BRCA2.I-Histograms ebonisa ukuhanjiswa kwe-BRCA1- (obomvu obomvu) kunye ne-BRCA2- (obomvu obomvu) i-PVs phakathi kwee-molecular subtypes zezigulane zomhlaza webele.Amanani achazwe ngaphakathi kwebhokisi ngalinye amele ipesenteji yezigulane ezine-BRCA1 kunye ne-BRCA2 yomhlaza webele nganye.
Izifinyezo: ii-PVs, i-pathogenic variant; I-HER2 +, i-epidermal growth factor receptor 2 positive; I-TNBC, umhlaza webele one-triple-negative.
Emva koko, sivavanye uhlobo kunye ne-gene ye-gene ye-BRCA1 kunye ne-BRCA2 PVs.Kwi-BRCA1 PV, siye saqaphela i-7 single nucleotide variants (SNVs), ukususwa kwe-6, ukuphindaphinda kwe-3 kunye nokufakwa kwe-1. Kuphela ukuguqulwa okukodwa (c.5522delG) kubonisa ukufunyanwa okutsha kwi-BRCA1 kwisifundo esixhaphakileyo. c.5035_5039delCTAAT.Olu tshintsho lubandakanya ukucinywa kweenucleotides ezintlanu (CTAAT) kwi-BRCA1 exon 15, okukhokelela ekufakweni endaweni ye-amino acid leucine nge-tyrosine kwi-codon 1679, kwaye ngenxa yefreyimshift eqikelelweyo yokumisa enye iprotein ekhokelela kwiprotheni enye kuphela. imeko.Ngokuqaphelekayo, enye yee-PVs ezixeliweyo ibekwe kwindawo yemvumelwano yendawo ye-splice (c.4357+1G>T) (Itheyibhile 1).
Ngokumalunga ne-BRCA2 PV, siye saqaphela ukususwa kwe-6, i-6 SNVs kunye nokuphindaphinda kwe-2. Akukho nalunye utshintsho olufunyenweyo lunoveli.Izinguqu ezintathu eziphindaphindiweyo kuluntu lwethu, i-c.428dup kunye ne-c.8487 + 1G>A ibonwe kwizifundo ze-3, ilandelwa yi-c.5851_5854 i-recovery ye-c. I-C kwi-exon 5 ye-BRCA2, iqikelelwe ukuba ifake i-protein ene-truncated, engasebenziyo.I-c.8487 + 1G>Ukuguquka kwenzeka kwingingqi ye-intronic ye-BRCA2 intron 19 (± 1,2) kwaye ichaphazela ukulandelelana kokuvumelana kwe-splicing, okubangelwa ukuguqulwa kwe-splicing ye-protein okanye i-protein ye-altermal. c.5851_5854delAGTT ukwahluka kwe-pathogenic kungenxa yokususwa kwe-4-nucleotide ukusuka kwizikhundla ze-nucleotide 5851 ukuya ku-5854 kwikhowudi ye-exon 10 yemfuza ye-BRCA2 kwaye iphumela kwi-frameshift yoguqulelo kunye ne-codon exelwe kwangaphambili yokuyeka (p.S1951W) zombini njengoko kuxelwe ngaphambili, i-tasbT. c.631G> A kunye ne-c.7008-2A>T zifunyenwe kwisigulane esifanayo.34 Ukuguqulwa kokuqala kubandakanya ukutshintshwa kwe-adenosine (A) kwi-BRCA2 exon 7 kunye ne-guanine (G) equkethe i-nucleotide ebangela ukuguqulwa kwe-valine kwi-isoleucine kwi-codon 211, i-isoleum ye-amino acid ichaphazela kakhulu i-amino acid i-amino acid. I-splicing.I-variant yesibini ifumaneka kwingingqi ye-intronic kwaye iphumela kwi-double A ukuya kwi-thymine (T) endaweni yokutshintshwa ngaphambi kwe-exon 13 ye-gene encoding BRCA2.I-c.7008-2A>T utshintsho lunokuvelisa izicatshulwa ezininzi zobude obuhlukeneyo.Ngaphezu koko, kwiqela le-BRCA2 PVs, i-8 ishintshile kwi-2% ye-intro1.
Emva koko senza imephu ye-BRCA1 / 2 yeenguqu ezinobungozi kwiindawo ezisebenzayo kunye nemimandla ebophezelayo kwiprotheni (umzobo 4) .Kwi-gene ye-BRCA1, i-50% ye-PVs ibekwe kwingingqi ye-cancer cluster region (BCCR), ngelixa i-22% yeenguqu yayifumaneka kwi-ovarian cancer cluster region (OCCR) (Fig. 30 BRCA5A) ibekwe kwi-PCA 42A. ummandla we-BCCR kunye ne-42.8% yeenguqu eziguquguqukayo zibekwe kwi-OCCR (umzobo 4B) . Emva koko, sivavanye indawo ye-PV ngaphakathi kwe-BRCA1 kunye ne-BRCA2 iprotheni domains. Kwiprotheni ye-BRCA1, sifumene i-PVs ezintathu kwi-loop kunye ne-coil coil domains, kunye neenguqu ezimbini kwi-BRCT4 domains ye-BRCAV, i-protein ye-BRCAV2. kwi-domain ye-BRC ephindayo, ngelixa i-3 intronic kunye ne-3 utshintsho lwe-exonic lufunyenwe kwi-oligo / oligosaccharide-binding (OB) kunye ne-tower (T) domains (Figure 4B).
Umzobo we-4 Ukubonakaliswa kweSchematic ye-BRCA1 kunye ne-BRCA2 iiprotheni kunye neendawo ezihlukeneyo ze-pathogenic.Lo mzobo ubonisa ukuhanjiswa kwe-BRCA1 (A) kunye ne-BRCA2 (B) i-pathogenic variants kwizigulane zomhlaza wesifuba.Ukuguqulwa kwe-Exonic kuboniswe nge-blue, ngelixa ukuhluka kwe-intronic kuboniswe kwi-orange.Ubude bebha bumele inani lamatyala.I-BRCA21 ye-domain esebenzayo. Iprotheyini ye-BRCA1 iqulethe i-loop domain (RING) kunye ne-nuclear localization sequence (NLS), i-coiled-coil domain, i-SQ/TQ cluster domain (SCD), kunye ne-BRCA1 C-terminal domain (BRCT) .(B) Iprotheni ye-BRCA2 iqulethe i-BRCA ephindaphinda ezisibhozo, i-DNA-binding domain kunye ne-helical domain (Heligobinding) ezintathu ze-oligobinding (Heligobinding) ezintathu ukugotywa, idomeyini yenqaba (T), kunye ne-NLS kwicala le-C. Iingingqi ezibizwa ngokuba yiBreast Cancer Cluster Region (BCCR) kunye neOvarian Cancer Cluster Region (OCCR) ziboniswe ezantsi.*Imele iinguqulelo ezigqiba iicodons zokuyeka.
Emva koko siye saphanda iimpawu ze-BC clinicopathological ezinokuthi zihambelane nobukho be-BRCA1 / 2 PV. Iirekhodi zeklinikhi ezipheleleyo zazifumaneka kwi-181 BRCA1 / 2-negative izigulane (ezingekho abathwali) kunye nabo bonke abathwali (n = 35) .Kwakukho ulungelelwaniso phakathi kwezinga lokunyuka kwe-tumor kunye nebakala.
Sibale ukusabalalisa kwe-Ki-67 ngokusekelwe kwi-median yeqela lethu (25%, uluhlu <10-90%).Izifundo ezine-Ki-67 <25% zichazwe njenge "low Ki-67", ngelixa abantu abanexabiso ≥ 25% babhekwa "kwi-Ki-67" ephezulu. Ukwahlukana okuphawulekayo (i-1p-carriers) ifunyenwe kunye ne-607 engabonakaliyo (i-1p-carriers) ifunyenwe. BRCA1 PV abathwali (Fig. 5A).
Umzobo we-5 Unxulumano lwe-Ki-67 kunye nokuhanjiswa kwebakala kubasetyhini abanomhlaza webele kunye nangaphandle kwe-BRCA1 kunye ne-BRCA2 PVs. Ukwabelwa kwezigulane zomhlaza ze-BC zibe ngamaqela ebakala le-histological (G2 kunye ne-G3) ngokwe-BRCA1 kunye ne-BRCA2 isimo sokuguquka (izifundo ze-WT, i-BRCA1 kunye ne-BRCA2 PVs abathwali).
Ngokufanayo, siye savavanya ukuba ibakala lethumba lihambelana nobukho be-BRCA1/2 PV. Ekubeni i-G1 BC yayingekho kubemi bethu, sahlula izigulane zibe ngamaqela amabini (G2 okanye i-G3). (p<0.005) (Umfanekiso 5B).
Ukuqhubela phambili kwi-DNA yokulandelelanisa iteknoloji yenze ukuba ukuqhubela phambili okungazange kubonwe ngaphambili kwi-BRCA1 / 2 yovavanyo lwemfuza, kunye nefuthe elibalulekileyo kwizigulane ezinembali yentsapho yomhlaza.Ukuza kuthi ga ngoku, malunga ne-20.000 ye-BRCA1 / 2 ezahlukeneyo ziye zachongwa kwaye zahlelwa ngokwe-American Society ye-Medical Genetics 35 kunye ne-ENIGMA yaziwa ngokuba yi-BRCA15,236 i-mutational. ngokubanzi kuyo yonke imimandla yejografi.37 Ngaphakathi kwe-Itali, izinga le-BRCA1/2 PVs lalisuka kwi-8% ukuya kwi-37%, libonisa ukuguquguquka okubanzi kwelizwe.38,39 Nabemi abaphantse babe zizigidi ezi-5, iSicily yindawo yesihlanu ngobukhulu eItali ngokwenani labemi. isiqithi.
Uphononongo lwethu lungenye yeengxelo zokuqala malunga nesiganeko se-BRCA1 / 2 PV kwizigulane ze-BC kwimpuma yeSicily.28 Sigxininise uhlalutyo lwethu kwi-BC, njengoko oku kukude kakhulu kwesifo esiqhelekileyo kwiqela lethu.
Xa uvavanya izigulane ze-389 BC, i-9% iphethe i-BRCA1 / 2 PVs, isasazwa ngokulinganayo phakathi kwe-BRCA1 kunye ne-BRCA2. Ezi ziphumo zihambelana nezo zichazwe ngaphambili kuluntu lwase-Italiya.28 Okuthakazelisayo kukuba, i-3% (13/389) yeqela lethu yayingamadoda.Eli zinga liphezulu kunokuba lilindeleke kwi-BCA1 kunye ne-BRCA2.Ezi ziphumo zihambelana nezo zichazwe ngaphambili kubemi base-Italiya.28 Kuyathakazelisa ukuba, i-3% (13/389) yeqela lethu yayingamadoda.Eli zinga liphezulu kunokuba lilindeleke kwi-BCA1 kunye ne-BRCA2.Ezi ziphumo zihambelana nezo zichazwe ngaphambili kubemi base-Italiya.28 Kuyathakazelisa ukuba, i-3% (13/389) yeqela lethu yayingamadoda.Eli zinga liphezulu kunokuba lilindeleke kwi-BCA1 kunye ne-BRCA2. Umngcipheko wokuguquka kwe-BRCA1 / 2. Nangona kunjalo, akukho namnye kula madoda aphuhlise i-BRCA1 / 2 i-PV, ngoko ke babengabaviwa bohlalutyo olongezelelweyo lwe-molecular ukuze bagweme ubukho beenguqu ezingaqhelekanga ezifana ne-PALB2, i-RAD51C kunye ne-D, phakathi kwabanye. ubungqina.28,41,42
Xa sihlalutya ukuhanjiswa kwe-BC i-molecular subtypes kwi-BRCA1 / 2 yabasetyhini abaguqukayo, siqinisekisile imibutho eyaziwayo phakathi kwe-TNBC kunye ne-BRCA1 PV (58.8%) kunye phakathi kwe-luminal B BC kunye ne-BRCA2 PV (55.6%).
Emva koko sigxininisa uhlobo kunye nendawo ye-BRCA1 / 2 PV. Kwiqela lethu, i-BRCA1 PV eqhelekileyo yayiyi-c.5035_5039delCTAAT. Nangona i-Incorvaia et al. abazange bachaze lo mahluko kwiqela labo laseSicilian, abanye ababhali baye baxela njengentsholongwane ye-BRCA1 PV.34 Ii-PV ezininzi ze-BRCA1 zifunyenwe kwiqela lethu - umz. (c.181T> G kunye ne-c.5266dupC) zifumaneka ngokuqhelekileyo kumaYuda ase-Ashkenazi aseMpuma naseMbindi Yurophu (iPoland, iCzech), iSlovenian, i-Austrian, isiHungary, iBelarusian kunye nesiJamani), i-44,45 kwaye, e-United States nase-Argentina, ichazwe kutshanje ngokuthi "i-germline eguquguqukayo" i-variant ye-germline ye-BCdel 4 ngaphambili kunye ne-4 izigulane zase-Occ. kwi-8 izigulane zomhlaza webele ukusuka emantla eSicily ePalermo naseMessina.Okuthakazelisayo, nokuba i-Incorvaia et al. ifumene ukwahluka kwe-c.3253dupA kwezinye iintsapho eCatania.28 Abona bantu bamele i-BRCA2 PVs yi-c.428dup, c.5851_5854delAGTT kunye nokwahluka kwe-intronic c.8487+1G>A, eziye zaxelwa ngokubanzi kwi-28 kwisigulane kwi-Palermo 5 52AG5 c. yabonwa kumakhaya asemntla-ntshona weSicily, ngokukodwa kwimimandla yaseTrapani nasePalermo, ngelixa i-c.5851_5854delAGTT PV yabonwa kumakhaya asenyakatho-ntshona yeSicily.I-8487 + 1G>Ukwahluka kwakuxhaphake kakhulu kwizifundo ezivela kwi-Messina, Palermo, naseCaltanissetta.28 al Rebbeck et al. ichazwe ngaphambili i-c.5851_5854delAGTT ukuguqulwa eColombia.37 Enye i-BRCA2 PV, c.631 + 1G>A, ifunyenwe kwi-BC kunye nezigulane ze-OC ezivela eSicily (Agrigento, Siracusa kunye neRagusa) .28 Ngokucacileyo, siye sabona ukuhlalisana kwee-BRCA2 ezimbini ezahlukeneyo kunye ne-31G2>A ezahlukeneyo ze-BRCA2 (BRCA2>A) c.7008-2A> T) kwisigulane esifanayo, esicinga ukuba sahlulwe kwimodi ye-cis, njengoko kuchazwe ngaphambili njengaleyo.34,46 Ezi nguqu ze-BRCA2 eziguquguqukayo ngokwenene zibonwa rhoqo kwingingqi yase-Italiya kwaye zifunyenwe ukuba zingenise i-codons yokuyeka ngaphambi kwexesha, echaphazela isithunywa se-RNA i-splicing kwaye ibangela ukuba i-BRCA2 , iprotheni ye-BRCA2 ,8 ingaphumeleli.
Siphinde senza imephu ye-BRCA1 kunye ne-BRCA2 ye-PVs kwi-OCCR ebekayo kunye nemimandla ye-BCCR yemimandla yeprotheni kunye nofuzo.Le mimandla yachazwa nguRebbeck et al. njengeendawo ezinobungozi ekuphuhliseni i-ovarian kunye nomhlaza wesifuba, ngokulandelanayo.49 Nangona kunjalo, ubungqina malunga nobudlelwane phakathi kwendawo ye-germline variants kunye nesifuba okanye umngcipheko womhlaza we-ovarian uhlala uphikisana. i-puative OCCR kunye ne-BCCR imimandla kunye ne-BC features.Oku kunokuthi kube ngenxa yenani elilinganiselwe lezigulane ezine-BRCA1 / 2 utshintsho.Ngokwembono ye-protein domain, i-BRCA1 PVs isasazwa kunye neprotheni yonke, kwaye ukuguqulwa kwe-BRCA2 kufumaneka ngokukhethekileyo kwi-domain ye-BRCA yokuphinda.
Ekugqibeleni, silungelelanise iimpawu ze-BC clinicopathological kunye ne-BRCA1 / 2 PV.Ngenxa yenani elilinganiselwe lezigulane ezibandakanyiweyo, sifumene kuphela ukulungelelaniswa okubalulekileyo phakathi kwe-Ki-67 kunye ne-tumor grade.Nangona uvavanyo kunye nokutolika kwe-Ki-67 kuhlala kungqubuzana, kuqinisekile ukuba amazinga aphezulu okwandisa ahambelana nomngcipheko okhulayo wokunciphisa ukubuya kwesifo kunye nokunciphisa ukubuya kwesifo. "iphezulu" kunye "ephantsi" i-Ki-67 yi-20%.Nangona kunjalo, lo mqobo awusebenzi kwi-BRCA1/2 yethu yezigulane eziguquguqukayo, ezinexabiso eliphakathi kwe-Ki-67 ye-25%.Lo mkhwa kumazinga aphezulu e-Ki-67 unokuchazwa ngokuxhaphaka kwi-luminal yethu ye-luminal B kunye ne-TNBC cohorts, apho ezimbalwa ze-luminal zicebisa ukuba i-6 ibonise ubungqina obuphezulu be-Ki-6. (25-30%) inokuba ngcono izigulane ngokwe-prognosis yazo.53,54 Ukususela kwiziphumo zohlalutyo lwethu, ukulungelelaniswa okubalulekileyo akumangalisi.Kuvela phakathi kwe-Ki-67 ephezulu kunye namabakala kunye nobukho be-BRCA1 PV. Enyanisweni, i-BRCA1-ehlobene ne-tumor ifana ne-TNBC kwaye ibonisa iimpawu ezinobundlobongela.16,16,16,17.
Ukuqukumbela, olu pho nonongo lubonelela ngengxelo malunga nemeko yokuguqulwa kwe-BRCA1 / 2 kwi-BC cohort ukusuka empuma yeSicily. Ngokubanzi, iziphumo zethu zihambelana nobungqina obukhoyo, zombini ngokubhekiselele kwi-mutation prevalence kunye ne-clinicopathological features kwi-BC.Izifundo ezingaphezulu kwinani elikhulu labantu be-BRCA1 / 2-mutant-mutant BC, uhlalutyo oluguquguqukayo olufana nolwandisiweyo lwezigulane ze-BC eziguquguqukayo. yee-PV ezicacileyo kwaye zingaphantsi rhoqo kune-BRCA1 / 2. Oku kuya kuvumela ukuchongwa kunye nokulawulwa ngokufanelekileyo kwenani elikhulayo lezifundo ezinobungozi obuninzi bomhlaza ngenxa yokuguqulwa kofuzo.
Siye saqinisekisa ukuba izigulane zisayine imvume enolwazi lokukhulula iisampuli zabo ze-tumor ngokungaziwa ngenjongo yophando.Zonke izigulana zisayine imvume ebhaliweyo enolwazi ngokweSibhengezo saseHelsinki.Ngokomgaqo-nkqubo we-AOU Policlinico "G.Rodolico - S.Marco", olu phononongo luxolelwe ekuphononongweni kokuziphatha ngenxa yokuba uhlalutyo lwe-BRCA1 / 2 lwenziwa ngokuhambelana nemvume yokusetyenziswa kwekliniki kunye nemvumelwano yokusetyenziswa kwekliniki. idatha yeenjongo zophando.
Siyabulela uProf. Paolo Vigneri ngoncedo lwakhe ekunyamekeleni izigulane zomhlaza webele njengoko kuceliwe yiKomiti yeeNqobo zokuziphatha.
UFederica Martorana uxela i-honoraria evela ku-Istituto Gentili, u-Eli Lilly, uNovartis, uPfizer.Abanye ababhali bavakalisa ukuba akukho zingquzulwano zomdla kulo msebenzi.
1. Sung H, Ferlay J, Siegel RL, et al. I-Global Cancer Statistics 2020: I-GLOBOCAN iqikelela ukuba iziganeko kunye nokufa kwe-36 ye-cancer kumazwe angama-185 emhlabeni jikelele. CA Cancer J Clin.2021; 71 (3): 209-249.3ca3: 209.
Ixesha lokuposa: Apr-15-2022
