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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 Experimental Clinic, 6 Marco Fichera 2 Clinical Clinic, 16 ea Clinical Clinic, 16 ea Caperimental University , Catania, 95123, Italy;Setsi sa 2 sa Tlhahlobo ea Oncology le 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 Lefapha la Biomedical le Biotechnology Sciences, Univesithi ea Catania, Medical Genetics, Catania, Italy, 95123;7Oasi Research Institute-IRCS, Troina, 94018, Italy Lipuisano: Stefania Stella, tel +39 095 378 1946, imeile [imeile e sirelelitsoeng];[imeile e sirelelitsoeng] Sepheo: Liphetoho tsa likokoana-hloko ho BRCA1 le BRCA2 le ho theha kankere ea matsoele (BC), ovary (OC) le tse ling tse amanang le kotsi ea bophelo bohle ba kankere.Ho hlahloba lefutso la BRCA ke senotlolo sa ho hlahloba kotsi ea motho ka mong, hammoho le ho fumana mekhoa ea thibelo ho bajari ba bophelo bo botle le ho lokisa mekhoa ea phekolo ho bakuli ba kankere. BRCA pathogenic variants malapeng a Sicily, liphuputso tse tobaneng le baahi ba Sicily bochabela li haella. Bakuli ba 5 (9%) ba ne ba e-na le phapang ea BRCA pathogenic, 17 (49%) ho BRCA1 le 18 (51%) ho BRCA2.BRCA1 liphetoho li atile ho bakuli ba BC ba makhetlo a mararo, athe liphetoho tsa BRCA2 li tloaelehile haholo ho bakuli ba luminal BC. Boemo ba phetoho ea BRCA ho bakuli ba BC ba tsoang bochabela ba Sicily le ho tiisa karolo ea tlhahlobo ea NGS ho khetholla bakuli ba nang le lefutso la BC. Ka kakaretso, lintlha tsena li lumellana le bopaki bo fetileng bo tšehetsang tlhahlobo ea BRCA bakeng sa thibelo e nepahetseng le phekolo ea kankere ho bajari ba phetoho.
Kankere ea matsoele (BC) ke lefu le atileng ka ho fetesisa lefats'eng ka bophara le mofets'e o bolaeang ka ho fetesisa ho basali.1 Likarolo tsa likokoana-hloko tse khethollang BC prognosis le boits'oaro ba kliniki li 'nile tsa ithutoa ka mokhoa o pharaletseng le ho hlakisoa ka mokhoa o itseng ha nako e ntse e feta.Ha e le hantle, matšoao a' maloa a surrogate a sebelisoa hona joale ho arola BC ka mefuta e sa tšoaneng ea limolek'hule.Ke estrogen (ER) le/kapa progesterone growth receptor, epiprogesterone ea batho ration index Ki-67 le tumor grade (G) .2 Motsoako oa mefuta ena e fapaneng e ile ea khetholla lihlopha tse latelang tsa BC: 1) Lihlahala tsa Luminal, tse bontšang ER le / kapa PgR polelo, li ne li e-na le karolo ea 75% ea BCs. Lihlahala tsena li ile tsa aroloa ka ho eketsehileng ka Luminal A, ha Ki-67 e ne e le ka tlase ho 20% le HER2 e mpe, le Luminal B, e lekanang le 0% ea ho ba teng kapa ho 6plification ea HER2 ho sa tsotellehe hore na ho ba teng ha Ki-6 ka holimo ho HER kapa 27% ea ho ba teng ha Ki-6-life. index;2) HER2 + lihlahala tse ER le PgR tse mpe empa li bontša HER2 amplification. Sehlopha sena se etsa karolo ea 10% ea lihlahala tsohle tsa matsoele;3) Kankere ea matsoele ea Triple-negative (TNBC), e sa bontšeng ER le PgR polelo le HER2 amplification, e etsa karolo ea 15% ea kankere ea matsoele.2-4
Har'a tsena BC subtypes, tumor grade le proliferation index li emela li-biomarker tsa cross-sectional tse amanang ka ho toba le ka boikemelo tse amanang le hlahala aggressiveness le prognosis.5,6
Ho phaella ho likarolo tse boletsoeng ka holimo tsa likokoana-hloko, karolo ea phetoho ea liphatsa tsa lefutso e lebisang ho nts'etsopele ea BC e fetohile ea bohlokoa haholo lilemong tse 'maloa tse fetileng.7 Hoo e ka bang 1 ho 10 lihlahala tsa matsoele li futsitsoe ka lebaka la liphetoho tsa likokoana-hloko liphatsa tsa lefutso tse khethehileng. K2, PALB2, RAD51C, le RAD51D) haholo-holo e ikarabellang bakeng sa lefutso la BC. Har'a liphatsa tsa lefutso, BRCA1 le BRCA2 (tseo ho thoeng ke BRCA1 / 2) li bontšitse kamano e matla ka ho fetisisa le nts'etsopele ea lihlahala tsa matsoele. Ectal, le melanoma. Ho tloha lilemong tse 13 ho isa ho tse 80, palo e akaretsang ea BC ke 72% ho basali ba nang le BRCA1 pathogenic variant (PV) le 69% ho basali ba nang le BRCA2 PV.14.
Ka ho hlakileng, khatiso ea morao-rao e fana ka maikutlo a hore kotsi ea BC e itšetlehile ka mofuta oa PV. Ha e le hantle, ha e bapisoa le mefuta e fapaneng ea truncating ea pathogenic, mefuta e sa tšoaneng ea glaring missense, haholo-holo gene ea BRCA1, e amahanngoa le kotsi e fokotsehileng ea BC, haholo-holo ho basali ba hōlileng.15
Ho ba teng ha BRCA1 kapa BRCA2 PV ho ne ho amahanngoa le likarolo tse fapaneng tsa likokoana-hloko le tsa kliniki.16,17 BRCA1-e amanang le BCs e atisa ho ba mabifi, ho khetholloa ka mokhoa o fokolang, le ho ata haholo.Lihlahala tsena hangata li mpe ka makhetlo a mararo 'me li na le lilemo tse nyenyane tsa ho qala. li-tumor tsa se li atile haholo ho lumen B 'me hangata li etsahala ho batho ba baholo ba hōlileng.16-18 Ka ho hlakileng, liphetoho tsa BRCA1 le BRCA2 li eketsa kutloisiso ho phekolo e khethehileng, ho akarelletsa le letsoai la platinum le lithethefatsi tse lebisitsoeng tse kang poly(ADP-ribose) polymerase inhibitors (PARPi) .19,20
Lilemong tse 'maloa tse fetileng, ts'ebetsong ea tatellano ea moloko o latelang (NGS) ts'ebetsong ea bongaka e nolofalelitse palo e ntseng e eketseha ea bakuli ba BC ho etsa liteko tsa limolek'hule bakeng sa li-syndromes tsa kankere, ho akarelletsa le BRCA1 / 2.21 Ka nako e ts'oanang, litlhaloso tse itšetlehileng ka mekhoa e nepahetseng mabapi le histori ea lelapa, palo ea batho, le litšobotsi tsa kliniki ho tseba hantle batho ba tšoanelehang23c2322 ho hlahloba boemo bona. Ho hlahlojoa ha BRCA1 / 2 ho batho ba itseng, ho totobatsa phapang ho pholletsa le libaka tsa libaka.24-27 Le hoja ho na le litlaleho tsa sehlopha sa BC karolong e ka bophirimela ea Sicily, lintlha tse fokolang li fumaneha ho hlahloba BRCA1 / 2 ho baahi ba bochabela ba Sicily.28,29
Mona re hlalosa liphetho tsa tlhahlobo ea germline BRCA1/2 ho bakuli ba BC ba tsoang bochabela ho Sicily, ho tsoela pele ho hokahanya boteng ba liphetoho tsa BRCA1 kapa BRCA2 le likarolo tsa mantlha tsa kliniki ea lihlahala tsena.
Phuputso ea morao-rao e ile ea etsoa "Setsi sa Teko ea Oncology le Hematology" Sepetlele sa Policlinico.Rodolico - San Marco in Catania.Ho tloha ka January 2017 ho fihlela March 2021, kakaretso ea bakuli ba 455 ba nang le kankere ea matsoele le ea mahe a bomme, melanoma, pancreatic kapa tšoelesa ea senya ba ile ba fetisetsoa ho rona bakeng sa tlhahlobo ea limolek'hule tsa BRCA2 ea Heclaration. lsinki, le barupeluoa bohle ba fane ka tumello e ngotsoeng e nang le tsebo pele ho tlhahlobo ea limolek'hule.
Litšobotsi tsa histological le biological (ER, PgR, HER2 boemo, Ki-67, le grade) ea BC li ile tsa hlahlojoa ka lisampole tsa mantlha tsa biopsy kapa ho buuoa, ho nahanoa feela ka likaroloana tse mabifi tsa hlahala.Ho latela litšobotsi tsena, BCs e ne e arotsoe ka tsela e latelang: luminal A (ER+ le/kapa PgR+, HER2-, (ER20) , HER20, P-R-6, HER2-, HER20, P-R-6, Kiminal, B. -67≥20%), luminal B-HER2+ (ER le/kapa PgR+, HER2+), HER2+ (ER le PgR-, HER2+) kapa tse tharo tse mpe (ER le PgR-, HER2-).
Pele ho hlahloba boemo ba phetoho ea BRCA1 le BRCA2, sehlopha sa mekhatlo e mengata e kenyelletsang ngaka ea oncologist, setsebi sa lefutso, le setsebi sa kelello se ile sa etsa tlhahlobo ea liphatsa tsa lefutso bakeng sa mokuli e mong le e mong ho fumana boteng ba BRCA1 le/kapa BRCA1.kapa batho ba nang le kotsi e kholo ea PV ka liphatsa tsa lefutso tsa BRCA2. Khetho ea mokuli e ile ea etsoa ho ea ka tataiso ea Mokhatlo oa Italy oa Medical Oncology (AIOM) le likhothaletso tsa sebaka sa Sicilian.30,31 Mekhoa ena e kenyelletsa: (i) histori ea malapa ea mefuta e tsebahalang ea pathogenic ka liphatsa tsa lefutso (mohlala, BRCA1, BRCA2, TP53, PTEN);(ii) banna ba nang le BC;(iii) ba nang le BC le OC;(iv) basali ba nang le BC <36 lilemo, TNBC <60 lilemo, kapa linaha tse peli BC <50 lilemo;(v) nalane ea bophelo ea motho ea BC lilemo tse 50 le nalane ea lelapa ea BC, OC, kapa mofets'e oa pancreatic bakeng sa beng ka bona bao e leng beng ka bona ba pele (ho kenyeletsoa beng ka eena bao e leng beng ka bona ba pele);(vii) Histori ea botho ea OC le bonyane mong ka eena oa tekanyo ea pele: (a) BC <50 lilemo;(b) NOC;(c) linaha tse peli BC;(d) monna BC;(vii) mosali ea nang le serous OC ea boemo bo holimo.
Ho ile ha fumanoa sampole ea mali ea 20 mL ho tsoa ho mokuli e mong le e mong 'me ea bokelloa ka har'a li-tubes tsa EDTA (BD Biosciences).Genomic DNA e ile ea aroloa ho lisampole tsa mali tse 0.7 mL ho sebelisoa QIAsymphony DSP DNA Midi Kit Isolation Kit (QIAGEN, Hilden, Italy) ho latela litaelo tsa moetsi 'me ea feta 3. , MA, USA) Etsa quantification.Ntlafatso ea sepheo le boitokiso ba laeborari li etsoa ke Oncomine™ BRCA Research Assay Chef, e se e loketse ho kenngoa ka har'a Ion AmpliSeq™ Chef Reagents DL8 Kit bakeng sa ho itokisa laeboraring ho latela litaelo tsa moetsi. Thepa e na le matamo a mabeli a multiplex PCR a ka sebelisoang ho ithuta kaofela BRCA7 (3M0030) BRCA7 (3M0030). ) cientific, Waltham, MA, USA) ho latela ditaelo tsa moetsi Saense).Tlhahlobo ea data e entsoe ke Amplicon Suite (SmartSeq srl) le Ion Reporter Software.
Mefuta eohle e fapaneng ea mabitso e ile ea latela tataiso ea morao-rao ea Human Genome Variation Consortium, e fumanehang Inthaneteng (HGVS, http://www.hgvs.org/mutnomen).Bohlokoa ba kliniki ba mefuta e fapaneng ea BRCA1/2 bo ile ba hlalosoa ho sebelisoa lihlopha tsa International Consortium ENIGMA (Evidence-Based Network for Interpreting Alemconsline) https://interpreting.com joalo ka ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, le UMD. Sehlopha se kenyelletsa mekhahlelo e mehlano e fapaneng ea kotsi: benign (sehlopha sa I), mohlomong se nang le bokooa (sehlopha sa II), se fapaneng sa bohlokoa bo sa tsitsang (VUS, sehlopha sa III), mohlomong pathogenic (sehlopha sa IV), le pathogenic (category ea protheine ea V, le ts'ebetso e fapaneng ea protheine ea V). phihlello ya mabolokelo a 30.32
Ho abela VUS e 'ngoe le e 'ngoe bohlokoa bo ka bang teng, ho ile ha sebelisoa mekhoa e latelang ea khomphutha ea protheine: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/G) le Align. d_input.php).Mefuta e fapaneng e khetholloang e le sehlopha sa 1 le sa 2 li ne li nkoa e le tsa mofuta o hlaha.
Tatelano ea Sanger e netefalitse ho ba teng ha mofuta o mong le o mong oa pathogenic. Ka bokhutšoane, para ea li-primers tse khethehileng li etselitsoe mofuta o mong le o mong o lemohileng ka ho sebelisa BRCA1 le BRCA2 liphatsa tsa lefutso tsa tatellano ea liphatsa tsa lefutso (NG_005905.2, NM_007294.3 le NG_012772.3, NM5. hleng.
Bakuli ba ileng ba fumana hore ha ba na tšoaetso bakeng sa lefutso la BRCA1/2 ba ile ba lekoa ke multiplex ligation-dependent probe amplification (MLPA) ho latela litaelo tsa moetsi ho hlahloba boteng ba li-genomic rearrangements (LGR) tse kholo. li-nucleotide ka bolelele.Lihlahisoa tsa ho hōlisa li-probe, tse nang le sehlopha se ikhethang sa li-amplicon tsa PCR, li ile tsa hlahlobjoa ka capillary electrophoresis le ke software ea Cofalyser.Net hammoho le litafole tse nepahetseng tsa batch-specific Cofalyser (www.mrcholland.com).
Liphetoho tse khethiloeng tsa clinicopathological (histological grade le Ki-67% proliferation index) li ne li amahanngoa le ho ba teng ha BRCA1 / 2 PV, ho baloa ho sebelisoa software ea Prism v. 8.4 ho sebelisa tlhahlobo e nepahetseng ea Fisher ho nka hore p-value <0.05 e bohlokoa.
Pakeng tsa Pherekhong 2017 le Hlakubele 2021, bakuli ba 455 ba ile ba hlahlojoa bakeng sa liphetoho tsa likokoana-hloko tsa BRCA1/2. Teko ea phetoho e ile ea etsoa Setsing sa Sepetlele sa Policlinico bakeng sa Teko ea Oncology le Hematology. 2020), Rodolico ea Catania - San Marco” ka kakaretso, bakuli ba 389 Ho ne ho e-na le mofetše oa matsoele, mofetše oa mahe a 37, mofetše oa pancreatic o 16, mofetše oa tšoelesa ea senya le 5 melanoma.Kabo ea bakuli ho latela mofuta oa mofets'e le liphetho tsa tlhahlobo li bonts'itsoe ho Setšoantšo sa 1.
Setšoantšo sa 1 se bontša chate e phallang e bontšang kakaretso ea thuto.Bakuli ba nang le matsoele, melanoma, pancreatic, prostate, kapa lihlahala tsa mahe a bomme ba ile ba lekoa bakeng sa liphetoho tsa liphatsa tsa lefutso tsa BRCA1 le BRCA2.
Likhutšoaane: li-PV, phapang ea pathogenic;VUS, phapang ea bohlokoa bo sa tsitsang;WT, mofuta o hlaha oa BRCA1/2 tatelano.
Re tsepamisitse maikutlo lithutong tsa rona ho lihlopha tsa kankere ea matsoele.Bakuli ba ne ba e-na le lilemo tse mahareng tsa lilemo tse 49 (tse fapaneng 23-89) 'me e ne e le basali haholo (n = 376, kapa 97%).
Har'a lihlooho tsena, 64 (17%) e bile le liphetoho tsa BRCA1 / 2 'me kaofela e ne e le basali.Mashome a mararo a metso e mehlano (9%) a ne a e-na le PV le 29 (7.5%) e nang le VUS. Leshome le metso e supileng (48.6%) ea mefuta e 35 ea pathogenic e etsahetse ho BRCA1 le 18 (51.4%) ho BRCA2, ha 51.4%) ho BRCA2, ha 51.4 BRCA2%) le . (Lipalo 1 le 2) LGR e ne e le sieo tlhahlobisong ea MLPA.
Setšoantšo sa 2. Tlhahlobo ea liphetoho tsa BRCA1 le BRCA2 ho bakuli ba kankere ea matsoele ba 389. (A) Kabo ea mefuta e fapaneng ea pathogenic (PV) (e khubelu), mefuta e sa tšoaneng ea bohlokoa bo sa tsitsang (VUS) (orange), le WT (blue) ho bakuli ba kankere ea matsoele ba 389;(B) Bakuli ba 389 ba kankere ea matsoele ba mashome a mararo a metso e mehlano (9%) ba ne ba e-na le mefuta e fapaneng ea BRCA1 / 2 pathogenic (PVs) . Har'a bona, 17 (48.6%) e ne e le bajari ba BRCA1 PV (bofubelu bo lefifi) 'me 18 (51.4%) e ne e le bajari ba BRCA2 (bofubelu bo khanyang);(C) 29 (7.5%) ea lithuto tsa 389 li nkile VUS, 5 (17.2%) BRCA1 liphatsa tsa lefutso (lamunu e lefifi) le 24 (82.8%) liphatsa tsa lefutso tsa BRCA2 (leseli la lamunu).
Likhutšoaane: li-PV, phapang ea pathogenic;VUS, phapang ea bohlokoa bo sa tsitsang;WT, mofuta o hlaha oa BRCA1/2 tatelano.
Ka mor'a moo re ile ra batlisisa ho ata ha li-molecular subtypes tsa BC ho bakuli ba BRCA1/2 PV. Kabo e kenyelletsa 2 (5.7%) luminal A, 15 (42.9%) luminal B, 3 (8.6%) luminal B-HER2+, 2 (5.7%) HER2+ le 13 (37.1%) har'a bakuli ba 2 (37.1%) ba luminal TNBC. , 2 (11.8%) e ne e e-na le lefu la HER2 +, 'me 10 (58.8%) e ne e e-na le TNBC. Lihlahala tse se nang liphetoho tsa BRCA1 li ne li le luminal A kapa luminal B-HER2 + (Figure 3) .Sehlopheng sa BRCA2-positive, 10 (55.6%) lihlahala e ne e le luminal B, 3 (16) 16 BC (16) BBC le 16 HER2%) le BTN (16 BC) 16 . .1%) e ne e le luminal A (Setšoantšo sa 3) .Ha ho lihlahala tsa HER2 + tse neng li le teng sehlopheng sena. Ka hona, liphetoho tsa BRCA1 li atile ho bakuli ba TNBC, athe liphetoho tsa BRCA2 ke tsona tse ka sehloohong ho batho ba lumen B.
Setšoantšo sa 3 Ho ata ha li-subtypes tsa kankere ea matsoele ho bakuli ba nang le mefuta e sa tšoaneng ea pathogenic ho BRCA1 le BRCA2.Histograms e bontšang ho ajoa ha BRCA1- (bofubelu bo lefifi) le BRCA2- (bofubelu bo khanyang) PVs har'a lihlopha tsa limolek'hule tsa bakuli ba kankere ea matsoele.
Likhutšoaane: li-PV, phapang ea pathogenic;HER2 +, epidermal growth factor receptor 2 e ntle;TNBC, mofetše oa matsoele o nang le makhetlo a mararo.
Ka mor'a moo, re ile ra hlahloba mofuta le liphatsa tsa lefutso tsa sebaka sa BRCA1 le BRCA2 PVs. Ho BRCA1 PV, re hlokometse mefuta e 7 e le 'ngoe ea nucleotide (SNVs), ho tlosoa ha 6, ho pheta-pheta ha 3 le ho kenngoa ha 1. Phetoho e le 'ngoe feela (c.5522delG) e emela ntho e ncha e fumanoeng 5530 ka bobeli e fumanoeng BRCA10 ka bobeli BRCA10 lihlooho tse peli tsa P530. 9delCTAAT.Phetoho ena e kenyelletsa ho hlakoloa ha li-nucleotide tse hlano (CTAAT) ho BRCA1 exon 15, e leng se etsang hore ho behoe leucine ea amino acid ka tyrosine ho codon 1679, 'me ka lebaka la foreimi ea phetolelo e nang le mokhoa o boletsoeng esale pele oa ho emisa codon ho lebisa ho protheine ea pele ho nako e le 'ngoe feela e fumanoeng ka lebaka la liphetoho tse ling tsa PtaV. sebaka sa tumellano sa sebaka sa splice (c.4357+1G>T) (Letlapa la 1).
Mabapi le BRCA2 PV, re hlokometse ho hlakoloa ha 6, li-SNV tse 6 le li-duplications tse 2. Ha ho liphetoho tse fumanoeng e le libuka.Liphetoho tse tharo li ile tsa boela tsa hlaha ho baahi ba rona, c.428dup le c.8487 + 1G>A hlokometsoe lihloohong tse 3, tse lateloang ke c.5851_5854Tlhaloso ea ho pheta-pheta ha c. 5 ea BRCA2, e boletsoeng esale pele hore e tla kenyelletsa protheine e fokolang, e sa sebetseng. The c.8487 + 1G>Phetoho e etsahala sebakeng sa intronic sa BRCA2 intron 19 (± 1,2) 'me e ama tatellano ea tumellano ea splicing, e fellang ka ho fetoha ha splicing ho bakoang ke absent5451 protheine ea absent58del protheine ea absent581. ho tlosoa ha 4-nucleotide ho tloha libakeng tsa nucleotide 5851 ho 5854 ka coding exon 10 ea BRCA2 gene 'me e fella ka foreimi ea phetolelo e nang le mokhoa o boletsoeng esale pele oa ho emisa codon (p.S1951WfsTer). Ka ho hlakileng, joalokaha ho tlalehiloe pele, liphetoho tse peli tsa c.837G li ne li tšoana> 0 C. Phetoho ea pele e kenyelletsa phetoho ea adenosine (A) ho BRCA2 exon 7 e nang le guanine (G) e nang le nucleotide e bakang phetoho ea valine ho isoleucine ho codon 211, isoleucine Amino acid ke amino acid e nang le thepa e tšoanang haholo.Phetoho ena e ama e tloaelehileng ea mRNA splicing. 13 ea liphatsa tsa lefutso encoding BRCA2. The c.7008-2A>T phetoho e ka hlahisa litlaleho tse ngata tsa bolelele bo fapaneng.Ho feta moo, sehlopheng sa BRCA2 PVs, 4 ho tsoa ho 18 liphetoho (22.2%) e ne e le intronic.
Ka mor'a moo re ile ra etsa 'mapa oa liphetoho tse senyang tsa BRCA1 / 2 libakeng tse sebetsang le libaka tse tlamang liprotheine (setšoan.4) .Mofuteng oa BRCA1, 50% ea li-PVs li ne li le sebakeng sa lihlopha tsa kankere ea matsoele (BCCR), ha 22% ea liphetoho li ne li le sebakeng sa lihlopha tsa kankere ea mahe a bomme (OCCR) (Fig. BRCA52 ea BCRV sebakeng sa BRCA57 BCR). 'me 42.8% ea liphetoho li ne li le teng ho OCCR (Fig. 4B) .Ka mor'a moo, re ile ra hlahloba sebaka sa PV ka har'a libaka tsa protheine tsa BRCA1 le BRCA2. Bakeng sa protheine ea BRCA1, re fumane li-PV tse tharo sebakeng sa loop le li-coil coil, le liphetoho tse peli sebakeng sa BRCT (Sebakeng sa 4A, 4A re pheta-pheta protheine ea BRCA). liphetoho tsa intronic le tsa 3 tsa exonic li ile tsa fumanoa libakeng tsa oligo / oligosaccharide-binding (OB) le tora (T) (Setšoantšo sa 4B).
Figure 4 Schematic representation of BRCA1 le BRCA2 proteins and localization of pathogenic variants.Palo ena e bontša kabo ea BRCA1 (A) le BRCA2 (B) pathogenic variants ho bakuli ba kankere ea matsoele.Liphetoho tsa Exonic li bontšoa ka boputsoa, ​​athe intronic variants li bontšoa ka lamunu.Bophahamo ba bar bo emela palo ea linyeoe.The BRCA21 protheine e na le protheine ea BRCA21 e tlalehiloeng. sebaka sa loop (RING) le tatellano ea sebaka sa nyutlelie (NLS), sebaka sa coil-coil, sebaka sa SQ/TQ cluster (SCD), le BRCA1 C-terminal domain (BRCT) .(B) Protheine ea BRCA2 e na le tse robeli tse pheta-phetang tsa BRC, sebaka se tlamang DNA se nang le helical domain (Helical), litharollo tse tharo tsa oligo-oligo-touch (TQ), oligonucleotide, le TQ, oligonucleotide. NLS ka lehlakoreng la C. Libaka tse bitsoang Breast Cancer Cluster Region (BCCR) le Ovarian Cancer Cluster Region (OCCR) li bontšitsoe ka tlaase.*E emela liphetoho tse etsang qeto ea ho emisa li-codon.
Ka mor'a moo re ile ra batlisisa likarolo tsa BC clinicopathological tse ka 'nang tsa amahanngoa le boteng ba BRCA1 / 2 PV. Litlaleho tse feletseng tsa kliniki li ne li fumaneha bakeng sa bakuli ba 181 BRCA1 / 2-negative (bao e seng bajari) le bohle ba tsamaisang (n = 35) .Ho ne ho e-na le kamano pakeng tsa sekhahla sa ho ata ha hlahala le kereiti.
Re ile ra bala kabo ea Ki-67 ho latela karolelano ea sehlopha sa rona (25%, range <10-90%). Lihlooho tse nang le Ki-67 <25% li ne li hlalosoa e le "Ki-67" e tlaase, ha batho ba nang le litekanyetso ≥ 25% ba ne ba nkoa e le "Ki-67" e phahameng. Phapang ea bohlokoa (CAp-67) e sa fumaneheng (CAp-60) e fumanoeng e sa tloaeleha (CAp-67). bajari (setšoantšo sa 5A).
Setšoantšo sa 5 Khokahano ea Ki-67 e nang le kabo ea maemo ho basali ba mofetše oa matsoele ba nang le BRCA1 le BRCA2 PVs (A) Boxplot e bonts'ang boleng ba Ki-67 ba mahareng ho bakuli ba 181 bao e seng bajari ba BC khahlano le BRCA1 (18) kapa BRCA2 (17) PV ea bakuli ba bohlokoa. bakuli ba mofets'e ka lihlopha tsa sehlopha sa histological (G2 le G3) ho latela boemo ba phetoho ea BRCA1 le BRCA2 (lihlooho tsa WT, BRCA1 le BRCA2 PVs bajari).
Ka mokhoa o ts'oanang, re ile ra hlahloba hore na boemo ba tumor bo amana le boteng ba BRCA1 / 2 PV. Kaha G1 BC e ne e le sieo ho baahi ba rona, re arola bakuli ka lihlopha tse peli (G2 kapa G3) . Tumellanong le liphetho tsa Ki-67, tlhahlobo e ile ea senola kamano ea bohlokoa ka lipalo pakeng tsa sehlopha sa tumor le phetoho ea BRCA1, e nang le karolo e phahameng ea carriers01 ho G3 ea nonneng ea BRCA 01 ho feta G3. ) (Setšoantšo sa 5B).
Tsoelo-pele ea theknoloji ea tatellano ea DNA e nolofalelitse tsoelo-pele e neng e e-s'o ka e e-ba teng litekong tsa liphatsa tsa lefutso tsa BRCA1/2, ka liphello tsa bohlokoa ho bakuli ba nang le histori ea malapa ea kankere. libaka tsa litšoantšo.37 Ka hare ho Italy, sekhahla sa BRCA1/2 PVs se ne se tloha ho 8% ho isa ho 37%, se bontšang phapang e pharaletseng ka hare ho naha.38,39 Ka baahi ba ka bang limilione tse 5, Sicily ke sebaka sa bohlano se seholo ka ho fetisisa Italy ho latela palo ea baahi.
Boithuto ba rona ke e 'ngoe ea litlaleho tsa pele mabapi le liketsahalo tsa BRCA1 / 2 PV ho bakuli ba BC ba karolong e ka bochabela ea Sicily.28 Re tsepamisitse tlhahlobo ea rona ho BC, kaha ena ke lefu le atileng haholo ho sehlopha sa rona.
Ha ho hlahlojoa bakuli ba 389 BC, 9% e ne e nkile BRCA1 / 2 PVs, e arolelitsoeng ka mokhoa o lekanang pakeng tsa BRCA1 le BRCA2. Liphetho tsena li lumellana le tse tlalehiloeng pele ho baahi ba Italy.28 Hoa thahasellisa hore 3% (13/389) ea sehlopha sa rona e ne e le banna.Sekhahla sena se phahame ho feta kamoo ho neng ho lebeletsoe kateng bakeng sa kankere ea matsoele ea banna (1% ea 4 BR) khetho ea rona e thehiloeng ho kankere ea matsoele ea banna BC (1% 4 BR) Leha ho le joalo, ha ho le ea mong oa banna bana ea ileng a hlahisa BRCA1 / 2 PV, kahoo e ne e le bakhethoa bakeng sa tlhahlobo e eketsehileng ea limolek'hule ho thibela boteng ba liphetoho tse sa tloaelehang tse kang PALB2, RAD51C le D, har'a tse ling. Mefuta e sa tšoaneng ea bohlokoa bo sa tsitsang e ile ea fumanoa ho 7% ea lithuto tseo BRCA2 VUS e neng e bonahala ho tsona.
Ha re ne re sekaseka kabo ea li-molecular subtypes tsa BC ho basali ba fetohileng ba BRCA1/2, re netefalitse litloaelano tse tsejoang pakeng tsa TNBC le BRCA1 PV (58.8%) le pakeng tsa luminal B BC le BRCA2 PV (55.6%).16,43 Lihlahala tsa luminal A le HER2+ ho BRCA1 le BRCA1 le li-carriers tsa BRCA2 tse teng, lingoliloeng tse teng tsa BRCA2 ke boitsebiso ba BRCA2.
Joale re tsepamisa maikutlo ho mofuta le sebaka sa BRCA1/2 PV. Sehlopheng sa rona, BRCA1 PV e tloaelehileng haholo e ne e le c.5035_5039delCTAAT.Le hoja Incorvaia et al.ha baa ka ba hlalosa phapang ena sehlopheng sa bona sa Sicilian, bangoli ba bang ba e tlalehile e le kokoana-hloko BRCA1 PV.34 Li-PV tse 'maloa tsa BRCA1 li fumanoe sehlopheng sa rona - mohlala c.181T>G, c.514del, c.3253dupA le c.5266dupC - tse fumanoeng 1BRCA1 tse peli ho tse 18 tsa Six. G le c.5266dupC) li atisa ho fumanoa ho Bajuda ba Ashkenazi ba Europe Bochabela le Bohareng (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian le Sejeremane ), 44,45 le, United States le Argentina, e sa tsoa hlalosoa e le "ho fapana ha likokoana-hloko" ho bakuli ba Setaliana ba nang le BC le OC3cant pele ho bakuli ba kankere ea matsoele ba neng ba tsejoa ka leboea ho OC3 OC51. ho Palermo le Messina.Ho khahlisang, esita le Incorvaia et al.e fumane mofuta oa c.3253dupA malapeng a mang a Catania.28 Li-PV tse emetseng ka ho fetisisa tsa BRCA2 ke c.428dup, c.5851_5854delAGTT le intronic variant c.8487+1G>A, tse tlalehiloeng ka ho qaqileng haholoanyane 28 ho mokuli Palermo le C.52V8 lelapa la c.52V8 C. karolong e ka leboea-bophirimela ea Sicily, haholo-holo libakeng tsa Trapani le Palermo, athe c.5851_5854delAGTT PV e ile ea hlokomeloa malapeng a leboea-bophirimela ho Sicily. The 8487+1G>A variant was more common subjects from Messina, Palermo, and Caltanissetta.28 Rebbeck et al.pele e hlalositse phetoho ea c.5851_5854delAGTT naheng ea Colombia.37 E 'ngoe ea BRCA2 PV, c.631 + 1G>A, e fumanoe ho bakuli ba BC le OC ba tsoang Sicily (Agrigento, Siracusa le Ragusa) .28 Ka ho hlakileng, re hlokometse ho ba teng ha tse peli tsa BRCA2 c.6 le 8 c.2720 bakuli ba tšoanang (BRCA2> 8 C. , eo re neng re nahana hore e arotsoe ka mokhoa oa cis, joalokaha ho tlalehiloe pele joalo.34,46 Liphetoho tsena tsa BRCA2 uble li hlile li hlokomeloa khafetsa sebakeng sa Italy 'me li fumanoe li hlahisa li-codons tsa ho emisa pele ho nako, tse amang messenger RNA splicing le ho etsa hore protheine ea BRCA2 e hlōlehe.47,48
Re boetse ra etsa 'mapa oa BRCA1 le BRCA2 PVs libakeng tsa OCCR le BCCR tsa libaka tsa protheine le liphatsa tsa lefutso. Libaka tsena li hlalositsoe ke Rebbeck et al.e le libaka tse kotsi bakeng sa ho hlahisa kankere ea mae a bomme le ea matsoele, ka ho latellana.49 Leha ho le joalo, bopaki bo mabapi le kamano pakeng tsa sebaka sa mefuta e fapaneng ea likokoana-hloko le kotsi ea kankere ea matsoele kapa ea mahe a bomme e ntse e le likhang. Libaka tsa BCCR le likarolo tsa BC. Sena se ka 'na sa bakoa ke palo e lekanyelitsoeng ea bakuli ba nang le liphetoho tsa BRCA1 / 2. Ho ea ka pono ea protheine domain, BRCA1 PVs e ajoa hammoho le protheine eohle, 'me liphetoho tsa BRCA2 li fumanoa ka mokhoa o khethehileng sebakeng sa ho pheta-pheta BRC.
Qetellong, re ile ra amahanya likarolo tsa BC clinicopathological le BRCA1 / 2 PV. Ka lebaka la palo e lekanyelitsoeng ea bakuli ba kenyelelitsoeng, re fumane feela kamano e kholo pakeng tsa Ki-67 le tumor grade. Le hoja tlhahlobo le tlhaloso ea Ki-67 e ntse e e-na le likhang tse itseng, ke 'nete hore litekanyetso tse phahameng tsa ho ata li amahanngoa le kotsi e ntseng e eketseha ea "ho fokotsa ho khutla" le ho fokotseha ha lefu " Ki-67 ke 20%.Leha ho le joalo, moeli ona ha o sebetse ho bakuli ba rona ba BRCA1/2 ba feto-fetohang, ba nang le boleng ba Ki-67 bo bohareng ba 25%.Tloaelo ena ka litekanyetso tse phahameng tsa Ki-67 e ka hlalosoa ke ho ata ha lihlopha tsa rona tsa luminal B le TNBC, tseo ho tsona ho ne ho e-na le lihlahala tse seng kae tsa luminal A. ho ea ho prognosis ea bona.53,54 Ho tsoa liphethong tsa tlhahlobo ea rona, kamano ea bohlokoa ha e makatse.E etsahala pakeng tsa Ki-67 e phahameng le limaraka le ho ba teng ha BRCA1 PV. Ha e le hantle, lihlahala tse amanang le BRCA1 li tloaelehile ho TNBC 'me li bontša likarolo tse ling tse mabifi.16,17
Qetellong, phuputso ena e fana ka tlaleho ea boemo ba phetoho ea BRCA1 / 2 sehlopheng sa BC ho tloha bochabela ho Sicily. li fapane ebile li fokotseha khafetsa ho feta BRCA1 / 2. Sena se tla lumella ho tsebahatsa le tsamaiso e nepahetseng ea palo e ntseng e eketseha ea batho ba kotsing ea kankere ka lebaka la liphetoho tsa liphatsa tsa lefutso.
Re netefalitse hore bakuli ba saenetse tumello e nang le tsebo ea ho lokolla lisampole tsa bona tsa hlahala ntle le lebitso bakeng sa merero ea lipatlisiso.Bakuli bohle ba saenetse tumello e ngotsoeng e nang le tsebo ho latela Declaration of Helsinki.Ho ea ka leano la AOU Policlinico "G.Rodolico - S.Marco", thuto ena e ile ea lokolloa tlhahlobisong ea boitšoaro hobane BRCA1/2 tlhahlobo ea BRCA1/2 e ile ea etsoa ho ea ka tumello ea tšebeliso ea meriana ea bongaka le tumello ea ho sebelisoa ha bakuli. .
Re leboha Prof. Paolo Vigneri ka thuso ea hae ea tlhokomelo ea bakuli ba mofetše oa matsoele joalokaha Komiti ea Boitšoaro e kōpile.
Federica Martorana o tlaleha honoraria ho tsoa ho Istituto Gentili, Eli Lilly, Novartis, Pfizer.Bangoli ba bang ba phatlalatsa hore ha ho likhohlano tsa thahasello mosebetsing ona.
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