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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 Lefapha la Meriana 7, Maperinze Clinic1 Univesithi ea Catania, 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.Teko bakeng sa 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. Leha ho na le lintlha tse mabapi le mefuta e fapaneng ea likokoana-hloko tsa BRCA malapeng a Sicily, lithuto tse tobaneng le baahi ba Sicily e ka bochabela li haella. index.RESULTS: Ka kakaretso, bakuli ba 35 (9%) ba ne ba e-na le BRCA pathogenic variant, 17 (49%) ho BRCA1 le 18 (51%) ho BRCA2.BRCA1 liphetoho li atile haholo ho bakuli ba triple-negative BC, athe BRCA2 liphetoho li tloaelehile haholo ho luminal BC bakuli. proliferative index.Qetellong: Liphuputso tsa rona li fana ka kakaretso ea boemo ba phetoho ea BRCA ho bakuli ba BC ba tsoang bochabela ho 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 ea.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 receptor (Pgder2 receptor) ea motho amplification, proliferation index Ki-67 le tumor grade (G) .2 Motsoako oa mefuta ena ea mefuta-futa e ile ea khetholla lihlopha tse latelang tsa BC: 1) Lihlahala tsa Luminal, tse bontšang ER le / kapa PgR polelo, li ne li le 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 ne e le mpe ha 60% e le teng, le ho ba teng ha Luminal 6 le 62% le B-62. HER2 amplification, ho sa tsotellehe index proliferation; 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 ea lihlahala tsa matsoele li futsitsoe ka lebaka la liphetoho tsa likokoana-hloko liphatseng tse itseng. BRCA2, CHK2, 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.9-12 Ha e le hantle, likokoana-hloko tse ling tsa BRCA1 li eketsa haholo bophelo ba BRCA1. ho kenyelletsa le mae a bomme, tšoelesa ea senya, pancreatic, colorectal, le melanoma. Ho tloha lilemong tsa 13 ho isa ho lilemo tse 80, liketsahalo tsa 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-indices tsa proliferative.Lihlahala tsena li atile haholo ho lumen B 'me hangata li etsahala ho batho ba baholo.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 thehiloeng ho litekanyetso tse nepahetseng mabapi le histori ea lelapa, palo ea batho, le litšobotsi tsa kliniki ho tseba hantle batho ba tšoanelehang CA1 / BR22 tekong ena. ho bokella 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 "Center for Experimental Oncology and Hematology" Sepetlele sa Policlinico.Rodolico - San Marco in Catania.Ho tloha ka January 2017 ho ea ho March 2021, kakaretso ea bakuli ba 455 ba nang le kankere ea matsoele le ea mae a bomme, melanoma, pancreatic kapa tšoelesa ea senya ba ile ba fetisetsoa ho rona bakeng sa tlhahlobo ea limolek'hule tsa BRCA2. Phatlalatso ea Helsinki, le barupeluoa bohle ba fane ka tumello e ngotsoeng e nang le tsebo pele ho tlhahlobo ea limolek'hule.
Litšobotsi tsa histological le bioloji (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 li ne li arotsoe ka tsela e latelang: luminal A (ER+ le/kapa PgR+, HER2-, BER20) le luminal
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 tloha ho 0.7 mL ea disampole tsa mali kaofela ho sebelisoa QIAsymphony DSP DNA Midi Kit Isolation Kit (QIAGEN, Hilden, Italy) ho latela litaelo tsa moetsi 'me ea feta 3rometer Fishing.0 Scientific, Waltham, 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 itlhophisetsa laebrari ho latela litaelo tsa moetsi. Thepa e na le matamo a mabeli a multiplex PCR a ka sebelisoang ho ithuta kaofela BRCA7 le 30020. (NM_000059.3) liphatsa tsa lefutso. Ka bokhuts'oanyane, 15 µL ea sampole e 'ngoe le e 'ngoe e hlapolotsoeng ea DNA (10 ng) e kentsoe lipoleiting tse nang le barcode bakeng sa ho lokisoa laeboraring, 'me lisebelisuoa tsohle le lisebelisoa li ile tsa kengoa sesebelisoa sa Ion Chef™. Qubit® 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) ho ea ka litaelo tsa moetsi.Qetellong, lilaebrari li kopantsoe ka li-equimolar ratios ho Ion Chef™ library sample tubes (barcoded tubes) 'me li kentsoe holim'a sesebelisoa sa Ion Chef™.Sequencing e ile ea etsoa ka mokhoa oa ho sebelisa Fisher Scient (Thermo Fisher Scientific) ka ho sebelisa Ion 510 Chip (Thermo Fisher Scientific). 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 Almconsline.org) ho buisana le li-database tse fapaneng tse kang ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, le UMD. Sehlopha se kenyelletsa mekhahlelo e mehlano ea likotsi tse fapaneng: 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 (category IV), le phello ea ho fetoha ha VUS (mohlopha oa IV), le anazeth pathogenic (mohlopha oa IV) le anazeth pathogenic. sebopeho sa protheine le tšebetso, sesebelisoa se rutang se nang le phihlello ho 30 databases.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-G (http://agvgd.hci.utah.edu/agvgd_input.php). Mefuta e fapa-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 bokhutšoanyane, para ea li-primers tse khethehileng li etselitsoe mofuta o mong le o mong o lemohuoeng ka ho sebelisa BRCA1 le BRCA2 genere reference sequencences (NG_005905.2, NM_007294.3 le NG_012772.3, NM9.000 e latetsoe targeted). ka tatellano ea Sanger.
Bakuli ba ileng ba fumana hore ha ba na tšoaetso bakeng sa lefutso la BRCA1/2 ba ile ba lekoa ka multiplex ligation-dependent probe amplification (MLPA) ho latela litaelo tsa moetsi tsa ho hlahloba boteng ba li-genomic rearrangements (LGR) tse kholo. tatellano e ka bang bolelele ba li-nucleotide tse 60. Lihlahisoa tsa amplification tsa Probe, tse nang le sete e ikhethang ea li-amplicon tsa PCR, li ile tsa hlahlojoa ke 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 germline BRCA1/2. Teko ea phetoho e ile ea etsoa Setsing sa Sepetlele sa Policlinico bakeng sa liteko tsa Oncology le Hematology. Gennaio 2020), the Rodolico of 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 e 8 le melanoma e 5. Kabo ea bakuli ho latela mofuta oa mofetše le liphetho tsa tlhahlobo e 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 ne e e-na 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 fapaneng ea 35 pathogenic e etsahetse BRCA1 le 18 (51.4%) ho BRCA2, ha 51.4% BRCA2, ha . ho BRCA2 (Litšoantšo tsa 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 limolek'hule tsa BC ho bakuli ba nang le 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 9 BRCA, 5% ba nang le 9 BRCA. luminal B BC, 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). (16.7%) TNBC le 2 (11.1%) 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 ea li-nucleotide tse sa tšoaneng (SNVs), ho tlosoa ha 6, ho pheta-pheta ha 3 le ho kenya 1. Phetoho e le 'ngoe feela (c.5522delG) e emela ntho e ncha e fumanoeng BRCA1V ka bobeli e fumanoeng ho PRC1V. c.5035_5039delCTAAT.Phetoho ena e kenyelletsa ho hlakolwa ha li-nucleotide tse hlano (CTAAT) ho BRCA1 exon 15, e leng se etsang hore ho behoe sebaka sa amino acid leucine ka tyrosine ho codon 1679, mme ka lebaka la foreimi ea phetolelo e nang le mokhoa o boletsoeng esale pele oa ho emisa codon, liphetoho tse ling tsa protheine e le 'ngoe feela. case.Habohlokoa, e 'ngoe ea li-PV tse tlalehiloeng e ne e le sebakeng 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 tse ileng tsa boela tsa hlaha ho baahi ba rona, c.428dup le c.8487 + 1G>A hlokometsoe lihloohong tse 3, tse lateloang ke c.5851_5854alter228.TT C ho exon 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 fetoloa ha protheine kapa ho fetoha ha protheine. c.5851_5854delAGTT phapang ea pathogenic e bakoa ke ho tlosoa ha 4-nucleotide ho tloha libakeng tsa nucleotide 5851 ho ea 5854 ho coding exon 10 ea gene ea BRCA2 'me e fella ka foremeshift ea phetolelo ka mokhoa o boletsoeng esale pele oa ho emisa codon (p.S1951W ka bobeli e tlalehiloeng). c.631G> A le c.7008-2A>T li ile tsa fumanoa ho mokuli a le mong.34 Phetoho ea pele e kenyelletsa ho nkeloa sebaka ha adenosine (A) ho BRCA2 exon 7 e nang le guanine (G) e nang le nucleotide e bakang phetoho ea valine ho isoleucine ka codon 211, amino acid e ts'oanang e ama amino acid e ts'oanang le amino acid. splicing.Mofuta oa bobeli o fumaneha sebakeng sa intronic 'me o fella ka hore ho be le sebaka sa A ho thymine (T) habeli pele ho exon 13 ea gene 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, 8 liphetoho li ne li tsoa 2% ea intro1.
Ka mor'a moo re ile ra etsa 'mapa oa liphetoho tse senyang tsa BRCA1 / 2 libakeng tse sebetsang le libakeng tse tlamang liprotheine (setšoantšo sa 4) .Mofuteng oa BRCA1, 50% ea li-PV 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, V. sebaka sa BCCR le 42.8% ea liphetoho li ne li le 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 ile ra fumana li-PV tse tharo sebakeng sa loop le coil coil, le liphetoho tse peli sebakeng sa BRCT4 mapped, bakeng sa protheine ea BRCAV2. ho ea sebakeng se pheta-phetoang sa BRC, ha liphetoho tsa 3 tsa intronic le 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 blue, ha intronic variants li bontšoa ka lamunu.Bophahamo ba bar bo emela palo ea linyeoe.The domain BRCA21 e tlalehiloeng ke protheine. BRCA1 protheine e na le loop domain (RING) le nuclear localization sequence (NLS), domain coiled-coil, a SQ/TQ cluster domain (SCD), le BRCA1 C-terminal domain (BRCT) .(B) BRCA2 protein e na le tse robeli tse pheta-phetoang tsa BRC, sebaka se tlamang DNA se nang le helical domain oligobinding) oligobinding three oligobinding (Heligobinding) three oligobinding (Heligobinding) menahano, sebaka sa tora (T), le An 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 ho ajoa ha 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 (1p-carrier) e fumanoeng 1p-60. Bajari ba BRCA1 PV (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 le ntle le eona. kabelo ea bakuli ba mofetše oa BC 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 mojari oa hlahala ea G3 ha a bapisoa le G3 (p<0.005) (Setšoantšo sa 5B).
Tsoelo-pele ea theknoloji ea tatellano ea DNA e nolofalelitse tsoelo-pele e e-s'o ka e e-ba teng litekong tsa liphatsa tsa lefutso tsa BRCA1/2, tse nang le liphello tsa bohlokoa ho bakuli ba nang le histori ea malapa ea kankere. ho pharaletseng ho pholletsa le libaka tsa geographic.37 Ka hare ho Italy, sekhahla sa BRCA1/2 PVs se ne se tloha ho 8% ho ea ho 37%, ho bontša 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 mabapi le palo ea baahi. sehlekehleke.
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 ho lekana 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 40 ea baahi bohle ba BC) Kotsi ea phetoho ea BRCA1 / 2. Leha ho le joalo, ha ho le ea mong oa banna bana ea ileng a hlahisa BRCA1 / 2 PV, kahoo e ne e le baemeli ba 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 e neng e le teng ka lebaka la VUS e neng e le teng. bopaki.28,41,42
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 ba ka ba hlalosa phapang ena sehlopheng sa bona sa Sicilian, bangoli ba bang ba e tlalehile e le germline 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 tse peli tsa 2BRCA1 tsa Sici1. (c.181T> 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 "phapang e tloaelehileng ea likokoana-hloko" BCdel 4 bakuli ba pele ba neng ba tsejoa ka BC31. ho bakuli ba 8 ba kankere ea matsoele ba tsoang karolong e ka leboea ea Sicily e Palermo le Messina. Hoa thahasellisa hore esita le Incorvaia et al. e fumane mofuta oa c.3253dupA malapeng a mang a Catania.28 Li-PV tsa BRCA2 tse emetseng ka ho fetisisa ke c.428dup, c.5851_5854delAGTT le intronic variant c.8487+1G>A, tse tlalehiloeng ka ho qaqileng haholoanyane 28 ho mokuli ea Palermo le c.528A c.52AG5 C. e ne e hlokomeloa malapeng a karolong e ka leboea-bophirimela ea Sicily, haholo-holo libakeng tsa Trapani le Palermo, athe c.5851_5854delAGTT PV e ne e hlokomeloa malapeng a leboea-bophirimela ho Sicily. The 8487+1G>Aphapang e ne e tloaelehile haholo litabeng tse tsoang Messina, Palermo, le Caltanissetta.28 al 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 mefuta e 'meli ea BRCA2 c.6 (BRCA2>A 31G>A) c.7008-2A>T) ho mokuli a le mong, eo re neng re nahana hore e arotsoe ka mokhoa oa cis, joalokaha ho tlalehiloe pele joalo.34,46 Liphetoho tsena tsa BRCA2 uble ka sebele li hlokomeloa khafetsa sebakeng sa Italy 'me li fumanoe li hlahisa li-codons tsa ho emisa pele ho nako, tse amang lenģosa la RNA ho kopanya le ho etsa hore protheine ea BRCA2,8 e hlōlehe.
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 putative OCCR le 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 hokahanya likarolo tsa BC clinicopathological le BRCA1 / 2 PV. Ka lebaka la palo e lekanyelitsoeng ea bakuli e kenyelelitsoeng, re fumane feela kamano e kholo pakeng tsa Ki-67 le tumor grade. "phahameng" le "tlase" 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 ba bohareng ba 25%.Tloaelo ena ka litekanyetso tse phahameng tsa Ki-67 e ka hlalosoa ka ho ata ha lihlopha tsa rona tsa luminal B le TNBC, tseo tse seng kae tsa luminal A tse bontšang hore ho na le bopaki bo bongata ba A-7. (25-30%) e ka 'na ea ntlafatsa bakuli ho ea ka tsoelo-pele 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.16,16,17.
Qetellong, phuputso ena e fana ka tlaleho ea boemo ba phetoho ea BRCA1 / 2 sehlopheng sa BC ho tloha bochabela ho Sicily. ea li-PV tse ikhethang le tse fokolang 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 lefutso.
Re netefalitse hore bakuli ba saenetse tumello e nang le tsebo ea ho lokolla lisampole tsa bona tsa hlahala ba sa tsejoe molemong oa 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 tlhahlobo ea BRCA1/2 ea BRCA1/2 e ile ea boela ea fana ka tumello ea ho sebelisa meriana ea bongaka le tumello ea ho sebelisa meriana. data molemong oa lipatlisiso.
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.
1. Sung H, Ferlay J, Siegel RL, et al.Global Cancer Statistics 2020: GLOBOCAN e hakanya liketsahalo le ho shoa ha batho ba 36 ba kankere linaheng tse 185 ho pota lefatše. CA Cancer J Clin.2021;71(3):209-249.303.20ac3: 209.
Nako ea poso: Apr-15-2022
