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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 ye-Experimental Clinic, 1 IYunivesithi yaseCaritania, 1 iDyunivesithi yaseCaperimental1, i-Maperitanial Clinic, i-16 yeYunivesithi yaseCaperimental, i-Maperitanial Clinic. , Catania, 95123, Italy;2 Centre for Experimental Oncology and Hematology, AOU Policlinico "G.Rodolico - San Marco", Catania, 95123, Italy;3 I-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 ezinxulumene nobungozi bokuphila komhlaza.Uvavanyo lwe-BRCA gene lungundoqo ekuhloleni umngcipheko womntu ngamnye, kunye nokufumana iindlela zokukhusela kubathwali abaphilileyo kunye nokulungelelanisa unyango kwizigulane zomhlaza. Iintlobo ze-BRCA ze-pathogenic kwiintsapho zaseSicily, izifundo ezijolise ngokukodwa kubantu basempuma yeSicily ziyasilela.Injongo yophononongo lwethu yayikukuphanda iziganeko kunye nokuhanjiswa kwe-BRCA pathogenic germline alterations kwiqela lezigulane ze-BC ezivela empuma yeSicily kunye nokuvavanya ukudibanisa kwabo kunye neempawu ezithile ze-BC usebenzisa isizukulwana esilandelayo sokulandelelana kwe-tumor yokulandelelana kwe-tumor, i-3. Izigulane ze-5 (9%) zine-BRCA ye-pathogenic variant, i-17 (49%) kwi-BRCA1 kunye ne-18 (51%) kwi-BRCA2.BRCA1 iinguqu zixhaphake kwi-triple-negative BC izigulane, kanti ukuguqulwa kwe-BRCA2 kuxhaphake kakhulu kwizigulane ze-luminal BC. Ubume be-BRCA benguqu 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 ziye zafundwa ngokubanzi kwaye zicaciswa ngokuyinxenye ngokuhamba kwexesha.Enyanisweni, abamakishi abaninzi be-surrogate okwangoku basetyenziselwa ukwahlula i-BC kwii-subtypes ezahlukeneyo ze-molecular.Ziyi-estrogen (ER) kunye/okanye i-progesterone yokukhula kwabantu, i-progesterone yabantu isalathisi se-ration 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 engalunganga, kunye ne-Luminal B, xa i-0% ilingana ne-proparation ye-27 okanye i-pro-2 ye-HER2, xa ubukho be-Ki-67 bulingana no-200% okanye i-pro-2. isalathisi;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 tumors ifunyenwe njengefa ngenxa yokuguqulwa kwe-germline kwiigenes ezithile.8 Izifundo ezimbini ze-epidemiological ezibandakanya ngaphezu kwe-180,000 yabasetyhini baye bachonga i-genes ye-TM2, i-1CH , i-1, i-BCA, i-1, i-B. I-K2, i-PALB2, i-RAD51C, kunye ne-RAD51D) eyona nto ijongene ne-hereditary BC.Phakathi kwezi genes, i-BRCA1 kunye ne-BRCA2 (emva koku kuthiwa yi-BRCA1 / 2) ibonise ukulungelelaniswa okunamandla kunye nokuphuhliswa kwezicubu zesifuba. I-ectal, 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-tumor ye-se ixhaphake kakhulu kwi-lumen B kwaye ngokuqhelekileyo ivela 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
Kule minyaka imbalwa idlulileyo, ukuphunyezwa kolandelelwano lwesizukulwana esilandelayo (NGS) ekusebenzeni kwezonyango kwenze ukuba inani elonyukayo lezigulane ze-BC zenze uvavanyo lwe-molecular susceptibility syndromes, kubandakanywa ne-BRCA1 / 2.21 Ngaxeshanye, iinkcazo ezisekelwe kwiimpawu ezichanekileyo malunga nembali yentsapho , i-demographic, kunye neempawu ze-clinicopathological ukuchonga ngcono abantu ngabanye23c kuvavanyo lwe-BRCA1 / BR22 kuvavanyo lwe-BRCA1 / 22. Ukuhlolwa kwe-BRCA1 / 2 kubantu abathile, 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 - eSan 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 BRCA2 ye-Healthology. lsinki, kunye nabo bonke abathathi-nxaxheba banikeze 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 zokuhlinzwa, ngokuqwalasela kuphela amacandelo e-tumor aggressive.Ngokusekelwe kwezi mpawu, i-BCs yahlelwa ngolu hlobo lulandelayo: i-luminal A (ER+ kunye/okanye i-PGR+, HER2-, i-HER2-, i-HER2-, i-HER2-, i-HER2-, i-HER2-, i-HER2-, i-HER2-, i-ER2, i-R2, i-6, i-K-6, i-7 -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 ukufumanisa 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 eyahlukayo ilandele izikhokelo zangoku ze-Human Genome Variation Consortium, ekhoyo kwi-intanethi (HGVS, http://www.hgvs.org/mutnomen) .Ukubaluleka kweklinikhi ye-BRCA1/2 eyahlukileyo yachazwa ngokusebenzisa ulwahlulo lwe-International Consortium ENIGMA (Ubungqina obusekelwe kwiNethiwekhi ye-Mutanteniing Alemconsor , i-https: // i-database ye-Mutanteniing Alglelesline/ ezifana ne-ARUP, i-BRCAEXCHANGE, i-ClinVar, i-IARC_LOVD, kunye ne-UMD.Uluhlu lubandakanya iindidi ezinobungozi ezintlanu ezihlukeneyo: i-benign (udidi I), mhlawumbi i-benign (udidi II), ukwahluka kokubaluleka okungaqinisekanga (VUS, udidi III), kunokwenzeka ukuba i-pathogenic (udidi lwe-IV), kunye ne-pathogenic (i-protein ye-protein) kunye ne-pathogenic (i-protein ye-protein) kunye ne-pathogenic (i-protein ye-protein) kunye ne-pathogenic (i-protein ye-protein) kunye ne-pathogenic (i-protein ye-protein) ukufikelela kuma-database angama-30.32
Ukwabela ukubaluleka okunokubakho kweklinikhi kwi-VUS nganye, oku kulandelayo kusetyenziswe i-algorithms yeprotheyini yokuqikelela iprotheyini: I-MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/G) kunye ne-Align. d_input.php).Iintlobo ngeentlobo ezihlelwa njengeklasi 1 kunye ne-2 zazithathwa njengohlobo 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. ukuncwina.
Izigulana eziye zavavanya zingenayo i-BRCA1/2 gene zavavanywa yi-multiplex ligation-dependent probe amplification (MLPA) ngokwemiyalelo yomenzi yokuhlola ubukho be-genomic rearrangements (LGR) ngokufutshane, iisampulu ze-DNA zidenatured kwaye ukuya kuthi ga kwi-60 BRCA1 kunye ne-BRCA2 kusetyenziswa i-DNA ecacileyo Ii-nucleotides ngobude.Probe iimveliso zokukhulisa, ezibandakanya isethi ekhethekileyo ye-PCR amplicon, 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 noMatshi 2021, izigulane ze-455 zihlolwe ukuguqulwa kwentsholongwane ye-BRCA1 / 2. Uvavanyo lokuguquka lwenziwa kwiZiko leSibhedlele se-Policlinico kwi-Experimental Oncology kunye ne-Hematology. Ngokuhambelana nesikhokelo saseSicilian (http://www.gurs.regione.sicilia.sicilia.it/Itim2i-Indiceip. Ngo-2020), iRodolico yaseCatania-San Marco” iyonke, izigulana ezingama-389 bekukho umhlaza wamabele, umhlaza we-ovarian angama-37, umhlaza wepancreatic uli-16, umhlaza wedlala lesi-8 kunye ne-5 melanoma.Ukuhanjiswa kwezigulane ngokohlobo lomhlaza kunye neziphumo zokuhlalutya 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%) ine-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-BRCA 42%) kwaye yenzeke kwi-51.4% ye-BRCA18 (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 siye saphanda 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 ze-9, i-5. , I-2 (11.8%) yayinesifo se-HER2 +, kwaye i-10 (58.8%) yayine-TNBC.Ii-Tumors ngaphandle kokuguqulwa kwe-BRCA1 yayiyi-luminal A okanye i-luminal B-HER2 + (umzobo 3) .Kwiqela elincinane le-BRCA2, i-10 (55.6%) i-tumors yayiyi-luminal B, i-3 (i-16) ye-BBC (i-16%) kunye ne-16 HER2%) yayiyi-luminal B, i-3 (16) . .1%) yayiyi-luminal A (Figure 3) .Akukho HER2 + tumors ekhoyo kweli qela.Ngoko, ukuguqulwa kwe-BRCA1 kuxhaphake kwizigulane ze-TNBC, kanti ukuguqulwa kwe-BRCA2 kuninzi kwi-lumen B yabantu.
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 wesifuba.
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 kwe-553V kokubini kwi-503V eyona nto ifunyenwe BRCA50. 9delCTAAT.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 yokuguqulela kunye nekhodon yokumisa eqikelelweyo ekhokelela kwi-protein yangaphambi kwexesha efunyenweyo enye iprotheyini efunyenwe kwi-PtaV enye inguqu efunyenwe kwi-PtaV enye ifunyenwe kwi-PtaV enye. indawo yesivumelwano sendawo ye-splice (c.4357+1G>T) (Itheyibhile 1).
Ngokuphathelele i-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-extrendation ye-c. I-5 ye-BRCA2, iqikelelwe ukuba ifake i-protein ene-truncated, engasebenziyo.I-c.8487 + 1G>Ukuguqulwa kwenzeka kwingingqi ye-intronic ye-BRCA2 intron 19 (± 1,2) kwaye ichaphazela ukulandelelana kwe-splicing ye-splicing, okubangelwa ukuguqulwa kwe-splicing eguquguqukayo ebangela ukuba i-absent54 i-protein ye-absent515. ukuya kwi-4-nucleotide yokucinywa kwi-nucleotide izikhundla ze-5851 ukuya kwi-5854 kwi-coding exon 10 ye-gene ye-BRCA2 kwaye iphumela kwi-frameshift yokuguqulela kunye ne-codon yokumisa enye eqikelelweyo (p.S1951WfsTer) . Ngokucacileyo, njengoko kuchazwe ngaphambili, zombini iinguqu> i-0 i-c.831G ifunyenwe i-C. Utshintsho lokuqala lubandakanya 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-isoleucine i-Amino acid i-amino acid eneepropati ezifanayo kakhulu.Olu tshintsho luchaphazela i-mRNA eqhelekileyo kwi-splicing ye-mRNA.Iziphumo ze-mRNA eziqhelekileyo kwi-double substitution i-double exstitution kwi-double exstitution i-avant ant institution in a prion-T. I-13 ye-gene encoding BRCA2.I-c.7008-2A>T utshintsho lunokuvelisa imibhalo emininzi yobude obuhlukeneyo.Ngaphezu koko, kwiqela le-BRCA2 PVs, i-4 kwi-18 utshintsho (22.2%) yayiyi-intronic.
Emva koko siye senza imephu ye-BRCA1 / 2 yokuguqulwa kwenguqu enobungozi kwimimandla esebenzayo 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) kwingingqi ye-BRCA52, i-PCR ibekwe kwi-PCR. kunye ne-42.8% yeenguqu eziguquguqukayo zibekwe kwi-OCCR (umzobo 4B) . Emva koko, siye savavanya 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-domain ye-BRCT (Umfanekiso, i-protein ye-42 ye-BRCA) iphinda ibuyele kwi-4A. I-intronic kunye neenguqu ze-3 ze-exonic zifunyenwe 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 webele.Ukuguqulwa kwe-Exonic kuboniswe ngeblue, ngelixa iinguqu ze-intronic ziboniswa kwi-orange.Ubude bebha bumele inani lamatyala.I-BRCA21 iprotheni esebenzayo kunye ne-BRCA21 yesizinda esisebenzayo. 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) Iprotheyini ye-BRCA2 iqulethe i-BRCA ephindaphinda ezisibhozo, i-DNA-binding domain ene-helical domain (Helical), i-domain ye-oligonding/i-toharide ye-oligonucleotide, i-toharide ye-oligonuccle kunye ne-toharide emithathu I-NLS kwicala le-C. Iingingqi ezibizwa ngokuba yi-Breast Cancer Cluster Region (BCCR) kunye ne-Ovarian Cancer Cluster Region (OCCR) ziboniswe ezantsi.*Imele iinguqulelo ezibonisa ii-codons 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 ukuhanjiswa kwe-Ki-67 ngokusekelwe kwi-median ye-cohort yethu (25%, uluhlu <10-90%).Izifundo ezine-Ki-67 <25% zichazwe njenge "low Ki-67", ngelixa abantu abanexabiso ≥ 25% babhekwa "kwi-Ki-67 ephezulu" .Umehluko obalulekileyo (i-CAp-carrier) ifunyenwe i-1P-607 ifunyenwe kunye ne-CAp-607. abathwali (Fig. 5A).
Umzobo we-5 Unxulumano lwe-Ki-67 kunye nokuhanjiswa kwebakala kubasetyhini abanomhlaza webele kunye nangaphandle kwe-BRCA1 kunye ne-BRCA2 PVs. izigulane ezinomhlaza 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 le-tumor lihambelana nobukho be-BRCA1 / 2 PV. Ekubeni i-G1 BC yayingekho kubantu bethu, sahlula izigulane zibe ngamaqela amabini (G2 okanye i-G3) .Ngokungqinelana neziphumo ze-Ki-67, uhlalutyo lubonise ulungelelwaniso olubalulekileyo lwezibalo phakathi kwebanga le-tumor kunye ne-BRCA1 ukuguqulwa, kunye ne-proportion ephezulu ye-05 ye-G3 ye-tumorcarriers (i-01 ye-BRCA) i-tumorcarrier-0. ) (Umfanekiso 5B).
Ukuqhubela phambili kwi-DNA yokulandelelanisa iteknoloji kwenze ukuba kubekho ukuqhubela phambili okungazange kubonwe ngaphambili kwi-BRCA1 / 2 yovavanyo lwemfuzo, kunye nefuthe elibalulekileyo kwizigulane ezinembali yentsapho yomhlaza.Ukuza kuthi ga ngoku, malunga ne-20.000 BRCA1 / 2 ezahlukeneyo ziye zachongwa kwaye zahlelwa ngokwe-American Society ye-Medical Genetics 35 kunye ne-ENIGMA inkqubo eyaziwayo ngokubanzi kwi-BRCA136 iyaziwa ngokubanzi kwi-BRCA1 / 35. imimandla yemizobo.37 Ngaphakathi kwe-Italiya, izinga le-BRCA1/2 PVs lisuka kwi-8% ukuya kwi-37%, libonisa ukuguquguquka okubanzi kwelizwe.38,39 Nabemi abaphantse babe zizigidi ezi-5, iSicily yindawo yesihlanu ngobukhulu eItali ngokwenani labemi.
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 uvavanywa izigulana ezingama-389, iipesenti ezi-9 eziphethe i-Brca1 / 2 PVs, ezisasazwa ngokulinganayo phakathi kwe-BOSTATARTALS (i-1%) ye-BOSTER) ye-BOORTALS. I-BRCA1 / 2 PV, ngenxa yoko babefudumeza uhlalutyo lwe-molecro ukuba bakwazi ukuhlengahlengisa iipesenti ezingama-7 ,.
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 le ntlukwano kwiqela labo laseSicilian, abanye ababhali baye babika njengentsholongwane ye-BRCA1 PV.34 Ii-PV ezininzi ze-BRCA1 zifunyenwe kwiqela lethu - umz. I-G kunye ne-c.5266dupC) ifumaneka ngokuqhelekileyo kumaYuda ase-Ashkenazi aseMpuma kunye neYurophu Ephakathi (ePoland, eCzech), iSlovenian, i-Austrian, isiHungary, iBelarusian kunye neJamani ), i-44,45 kwaye, e-United States nase-Argentina, isandul 'ukuchazwa ngokuthi "i-germline eguquguqukayo" kwizigulane zase-Italiyane ezine-BC kunye ne-OCdel 34 izigulane zomhlaza ezichongiweyo ngaphambili kwi-cancer ye-BC34 ngaphambili. e Palermo kunye Messina.Okubangela umdla, nkqu 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 kwiinkcukacha ezithe kratya 28 kwisigulane ePalermo kunye ne-c.528 yendlu ye-C. kumntla-ntshona weSicily, ngokukodwa kwimimandla yaseTrapani nasePalermo, kanti i-c.5851_5854delAGTT PV yabonwa kumakhaya asemntla-ntshona weSicily.I-8487 + 1G>Ukwahluka kwakuxhaphake kakhulu kwizifundo ezivela kuMessina, ePalermo, naseCaltanissetta.28 Rebbeck et al.ichazwe ngaphambili i-c.5851_5854delAGTT inguqu e-Colombia.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-31GT ye-31GT efanayo kunye ne-31GT ye-c. , esicinga ukuba sahlulwe kwimodi ye-cis, njengoko kuchazwe ngaphambili njengaleyo.34,46 Ezi nguqu ze-BRCA2 eziguquguqukayo ngokwenene zibonwa rhoqo kummandla wase-Italiya kwaye zifunyenwe ukuba zingenise i-codons yokuyeka ngaphambi kwexesha, echaphazela isithunywa se-RNA splicing kwaye ibangela ukuba iprotheni ye-BRCA2 ingaphumeleli.47,48
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. Imimandla ye-BCCR kunye neempawu ze-BC.Oku kunokuthi kubangelwa inani elilinganiselweyo lezigulane ezine-BRCA1 / 2 zokuguqulwa.Kusuka kwiprotheyini ye-protein ye-protein, 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 izinga eliphezulu lokunyuka lihambelana nomngcipheko okhulayo wokunciphisa isifo kunye nokunciphisa "ukubuya kwesifo" I-Ki-67 yi-20%.Nangona kunjalo, lo mqobo awusebenzi kwi-BRCA1/2 yethu yezigulane eziguquguqukayo, enexabiso eliphakathi le-Ki-67 lama-25%.Lo mkhwa kumazinga aphezulu e-Ki-67 unokuchazwa ngokuxhaphaka kwe-luminal B kunye ne-TNBC cohorts, apho ezimbalwa ze-luminal A tumors zikhona.Nangona kunjalo, ukuba i-30 ibonakaliso ephezulu inokuthi i-2% ibonise ukuba i-cutoff iphakamisa i-2% ukuya kwi-prognosis yabo.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 enxulumene ne-tumor ifana ne-TNBC kwaye ibonisa iimpawu ezinobundlobongela.16,17
Ukuqukumbela, olu pho nonongo lubonelela ngengxelo malunga nemeko yokuguquka kwe-BRCA1 / 2 kwiqela le-BC ukusuka empuma yeSicily. Ngokubanzi, iziphumo zethu zihambelana nobungqina obukhoyo, zombini ngokubhekiselele kwinguqu yenguqu kunye neempawu zekliniki kwi-BC.Izifundo ezingaphezulu kwinani elikhulu labantu be-BRCA1 / 2-mutant-mutant BC, uhlalutyo oluguquguqukayo lwe-PV oluguquguqukayo lwezigulane ze-BC eziguquguqukayo, ezifana nohlalutyo oluguquguqukayo lwe-PV, olufana nolwandiso lwe-P. zihluke kwaye zingaphantsi rhoqo kune-BRCA1 / 2. Oku kuya kuvumela ukuchongwa kunye nokulawulwa ngokufanelekileyo kwenani elikhulayo lezifundo ezisengozini yokwanda komhlaza ngenxa yokuguqulwa kofuzo.
Siye saqinisekisa ukuba izigulane zisayine imvume enolwazi lokukhulula iisampulu zabo zethumba ngokungaziwa ngenjongo yophando.Zonke izigulana zisayine imvume ebhaliweyo enolwazi ngokweSibhengezo saseHelsinki.Ngokomgaqo-nkqubo we-AOU Policlinico "G.Rodolico - S.Marco", olu phononongo lukhululwe ekuphononongweni kokuziphatha ngenxa yokuba i-BRCA1/2 uhlalutyo lwenziwa ngokuhambelana nenjongo yophando lwezonyango kunye nedatha yophando lwenziwa ngokweemvumelwano zophando olubhaliweyo lwePatie. .
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