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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 Siliviya 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, 6, 7 Livia Manzella1 Ubutaliyani; Ikigo 2 cy’ubushakashatsi bwa Oncology na Hematology, AOU Policlinico “G.Rodolico - San Marco”, Catania, 95123, Ubutaliyani; 3 Oncology yubuvuzi, AOU Policlinico “G. Rodolico - San Marco”, Catania, 95123, Ubutaliyani; 4 Ubuvuzi bwubuvuzi, ARNAS Garibaldi, Catania, 95123, Ubutaliyani; 5 Ubuvuzi bwubuvuzi, ASP, Syracuse, 96100, Ubutaliyani; 6 Ishami ry’Ubumenyi bw’Ubuvuzi n’Ikoranabuhanga, Kaminuza ya Catania, Ibyerekeye Genetiki mu Buvuzi, Catania, Ubutaliyani, 95123; 7Oasi Research Institute-IRCCS, Troina, 94018, Ubutaliyani Itumanaho: Stefania Stella, tel +39 095 378 1946, imeri [email protected]; [email protected] Intego: Impinduka mu miterere y’uturemangingo muri BRCA1 na BRCA2 kandi hashyizweho kanseri y’ibere (BC), ovary (OC) n’izindi zifitanye isano n’ibyago byo kurwara kanseri mu buzima bwose. Gupima gene ya BRCA ni ingenzi mu gusuzuma ibyago by’umuntu ku giti cye, ndetse no gushaka uburyo bwo kwirinda mu bantu bazima banduye no kuvura abarwayi ba kanseri. Impinduka za BRCA1 na BRCA2 ziratandukanye cyane mu turere tw’isi, kandi nubwo hari amakuru ku bwoko bwa BRCA butera indwara mu miryango ya Sicily, ubushakashatsi bwibanda cyane ku baturage bo mu burasirazuba bwa Sicily ntiburaboneka. Intego y’ubushakashatsi bwacu kwari ugusuzuma ikwirakwira n’ikwirakwira ry’impinduka mu miterere y’uturemangingo twa BRCA mu itsinda ry’abarwayi ba BC bakomoka mu burasirazuba bwa Sicily no gusuzuma isano bafitanye n’imiterere yihariye ya BC hakoreshejwe uburyo bwo gukurikirana ubukana bw’ibisekuru bishya. Kuba hariho impinduka zijyanye n’urwego rw’ibibyimba n’igipimo cyo kwiyongera. IBISUBIZO: Muri rusange, abarwayi 35 (9%) bari bafite ubwoko bwa BRCA butera indwara, 17 (49%) muri BRCA1 na 18 (51%) muri BRCA2. Impinduka za BRCA1 zikunze kugaragara mu barwayi ba BC batatu, mu gihe impinduka za BRCA2 zikunze kugaragara mu barwayi ba BC ba luminal. Ugereranije Ku bantu batari abanduye, abarwayi bafite ubwoko bwa BRCA1 bari bafite igipimo cyo hejuru cyane cy’ibibyimba n’igipimo cyo kwiyongera kw’ibibyimba. Umwanzuro: Ibyo twabonye bitanga ishusho rusange y’imiterere ya BRCA mu barwayi ba BC bakomoka mu burasirazuba bwa Sicily kandi byemeza uruhare rw’isesengura rya NGS mu kumenya abarwayi ba BC bakomoka mu murage. Muri rusange, aya makuru ahuye n’ibimenyetso byabanje bishyigikira isuzuma rya BRCA mu rwego rwo gukumira no kuvura kanseri ku bantu banduye.
Kanseri y'ibere (BC) ni yo kanseri ikunze kugaragara cyane ku isi kandi ikaba ari yo yica abagore cyane.1 Ibintu by'ibinyabuzima bigaragaza ko BC ihagaze ndetse n'imyitwarire y'ubuvuzi byakozweho ubushakashatsi bwinshi kandi bigasobanurwa buhoro buhoro uko igihe cyagiye gihita. Mu by'ukuri, ibimenyetso byinshi by'inyongera ubu bikoreshwa mu gushyira BC mu byiciro bitandukanye bya molekile. Ni estrogen (ER) na/cyangwa receptor ya progesterone (PgR), receptor ya 2 (HER2) yo gukura kw'umubiri w'umuntu, ikigereranyo cyo kwiyongera kwa Ki-67 n'urwego rwa tumor (G).2 Uruvange rw'ibi bintu rwagaragaje ibyiciro bikurikira bya BC: 1) Ibibyimba bya Luminal, bigaragaza ER na/cyangwa PgR, byagize 75% bya BC. Ibi bibyimba byagabanyijwemo Luminal A, ubwo Ki-67 yari munsi ya 20% na HER2 negative, na Luminal B, ubwo Ki-67 yari ingana cyangwa irenga 20% kandi iyo hari HER2 yongerewe, hatitawe ku gipimo cyo kwiyongera; 2) Ibibyimba bya HER2+ bifite ER na PgR ariko bigaragaza HER2 amplification. Iri tsinda rigizwe na 10% by'ibibyimba byose by'ibere; 3) Kanseri y'ibere ifite triple-negative (TNBC), idafite ER na PgR amplification ndetse na HER2 amplification, igizwe na 15% bya kanseri y'ibere. 2-4
Muri izi ngero za BC, igipimo cy’ikibyimba n’igipimo cy’ubwiyongere bw’ikibyimba bigaragaza ibimenyetso bihuza neza kandi byigenga n’ubukana bw’ikibyimba n’uko kimeze.5,6
Uretse ibintu byavuzwe haruguru, uruhare rw'impinduka mu miterere y'uturemangingo zikomoka ku ngirabuzimafatizo zituma BC ikura rwarushijeho kuba ingenzi mu myaka mike ishize.7 Hafi 1 kuri 10 ibibyimba by'ibere birandurwa bitewe n'impinduka mu miterere y'uturemangingo mu turemangingo twihariye.8 Ubushakashatsi bubiri bunini bw'indwara z'ibyorezo bwakorewe ku bagore barenga 180.000 buherutse kugaragaza itsinda ry'uturemangingo umunani (ni ukuvuga ATM, BARD1, BRCA1, BRCA2, CHK2, PALB2, RAD51C, na RAD51D) ahanini bitera BC y'uruhererekane. Muri izi ngirabuzimafatizo, BRCA1 na BRCA2 (izwi nka BRCA1/2) byagaragaje isano ikomeye n'impinduka mu miterere y'uturemangingo tw'ibere.9-12 Mu by'ukuri, impinduka mu miterere y'uturemangingo BRCA1/2 zongera cyane ibyago byo kurwara BC ndetse n'izindi kanseri, harimo udusabo tw'intanga, prostate, pancreas, colorectal, na melanoma. Kuva ku myaka 13 kugeza kuri 80, umubare w'abagore barwara BC ni 72% mu bagore bafite ubwoko bwa BRCA1 pathogenic variant (PV) na 69% mu bagore bafite BRCA2 PV.14
Igitangaje ni uko igitabo giherutse gutangaza ko ibyago bya BC biterwa n'ubwoko bwa PV. Mu by'ukuri, ugereranije n'ubwoko butera indwara, ubwoko bugaragara cyane, cyane cyane muri gene ya BRCA1, bufitanye isano no kugabanuka k'ibyago bya BC, cyane cyane ku bagore bakuze.15
Kuba hariho BRCA1 cyangwa BRCA2 PV byafitanye isano n'imiterere itandukanye y'ibinyabuzima n'iy'indwara.16,17 BC zifitanye isano na BRCA1 zikunze kuba zikomeye mu buvuzi, zitaratandukanye neza, kandi zikwirakwira cyane. Izi kanseri akenshi ziba zifite imiterere itatu kandi zitangira ubwana. Ibibyimba biba ku barwayi ba BRCA2 bahindutse akenshi bigaragaza amanota ari hagati kugeza ku atandukanye neza hamwe n'ibipimo bitandukanye byo kwiyongera. Ibi byibyimba bikunze kugaragara muri lumen B kandi akenshi biba ku bantu bakuru.16-18 By'umwihariko, impinduka muri BRCA1 na BRCA2 zongerera ubushobozi bwo kuvura indwara runaka, harimo umunyu wa platine n'imiti igamije imiti nka poly (ADP-ribose) polymerase inhibitors (PARPi).19,20
Mu myaka mike ishize, ishyirwa mu bikorwa rya gahunda yo gukurikirana indwara z’abanduye indwara zifata abantu benshi (NGS) mu buvuzi ryafashije umubare munini w’abarwayi ba BC gupimwa indwara zifata abantu benshi, harimo na BRCA1/2.21. Ibisobanuro bishingiye ku bipimo nyabyo birebana n’amateka y’umuryango, imiterere y’abaturage, n’imiterere y’indwara kugira ngo hamenyekane neza abantu bakwiye gupimwa BRCA1/2.22,23 Muri uru rwego, ibimenyetso birimo kwiyongera ku isuzuma rya BRCA1/2 mu baturage runaka, bigaragaza itandukaniro mu turere dutandukanye.24–27 Nubwo hari raporo ku itsinda rya BC mu burengerazuba bwa Sicily, amakuru make araboneka ku isuzuma rya BRCA1/2 mu baturage ba Sicily yo mu burasirazuba.28,29
Aha turasobanura ibyavuye mu isuzuma rya germline BRCA1/2 ku barwayi ba BC bakomoka mu burasirazuba bwa Sicily, bikanahuza kuba hari impinduka za BRCA1 cyangwa BRCA2 n'ibimenyetso by'ingenzi by'indwara z'ibi bibyimba.
Inyigo yo gusuzuma ibyavuye mu bushakashatsi yakozwe mu kigo "Center for Experimental Oncology and Hematology" mu bitaro bya Policlinico.Rodolico – San Marco muri Catania. Kuva muri Mutarama 2017 kugeza muri Werurwe 2021, abarwayi 455 barwaye kanseri y'ibere n'intanga ngore, melanoma, pancreas cyangwa prostate bose boherejwe muri laboratwari yacu yo gusuzuma molekile kugira ngo bapimwe BRCA/2. Ubu bushakashatsi bwakozwe hakurikijwe Itangazo rya Helsinki, kandi abitabiriye bose batanze icyemezo cyanditse mbere yo gusesengura molekile.
Imiterere y’imiterere y’umubiri n’iy’ibinyabuzima (ER, PgR, HER2 status, Ki-67, n’urwego) bya BC byapimwe hakoreshejwe ibizamini by’ibanze bya biopsy cyangwa ingero zo kubaga, hashingiwe gusa ku bice by’ikibyimba gikomeye. Hashingiwe kuri ibi bimenyetso, BC zashyizwe mu byiciro bikurikira: luminal A (ER+ na/cyangwa PgR+, HER2-, Ki-67<20%), luminal B (ER+ na/cyangwa PgR+, HER2-, Ki-67≥20%), luminal B-HER2+ (ER na/cyangwa PgR+, HER2+), HER2+ (ER na PgR-, HER2+) cyangwa triple negative (ER na PgR-, HER2-).
Mbere yo gusuzuma uko BRCA1 na BRCA2 zihagaze, itsinda ry’abantu benshi barimo umuganga w’indwara za kanseri, inzobere mu by’imiterere y’uturemangingo, n’umuganga w’imitekerereze ya muntu bakoze inama ku bijyanye n’imiterere y’uturemangingo kuri buri murwayi kugira ngo bamenye niba BRCA1 cyangwa BRCA1 ariho cyangwa abantu bafite ibyago byinshi byo kurwara PV muri gene ya BRCA2. Gutoranya umurwayi byakozwe hakurikijwe amabwiriza y’Umuryango w’Abataliyani w’Ubuvuzi bwa Oncology (AIOM) n’inama zo muri Sicilian.30,31 Ibi bipimo birimo: (i) amateka y’umuryango w’ubwoko buzwi bw’indwara mu turemangingo tw’ubuhumekero (urugero: BRCA1, BRCA2, TP53, PTEN); (ii) abagabo bafite BC; (iii) abafite BC na OC; (iv) abagore bafite BC
Ingero z'amaraso ya 20 mL zafashwe kuri buri murwayi maze zishyirwa mu miyoboro ya EDTA (BD Biosciences). ADN ya genomic yakuwe mu ngero z'amaraso yose ya 0.7 mL hakoreshejwe QIAsymphony DSP DNA Midi Kit Isolation Kit (QIAGEN, Hilden, Ubutaliyani) hakurikijwe amabwiriza y'uwakoze, hanyuma inyuzwa muri Qubit® 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA). Kora isuzuma. Gutunganya intego no gutegura isomero bikorwa na Oncomine™ BRCA Research Assay Chef, yiteguye gushyirwa muri Ion AmpliSeq™ Chef Reagents DL8 Kit kugira ngo isomero ritegurwe hifashishijwe amabwiriza y'uwakoze. Iyi kit igizwe n'ibice bibiri bya PCR primer bishobora gukoreshwa mu kwiga genes zose za BRCA1 (NM_007300.3) na BRCA2 (NM_000059.3). Muri make, 15 µL ya buri sample ADN yakuwemo (10 ng) yongewe ku byapa bya barcoded kugira ngo isomero ritegurwe kandi reagents zose n'ibikoresho byose byashyizwe ku gikoresho cya Ion Chef™. Gutegura isomero hifashishijwe automated na barcoded isomero ritegurwe hifashishijwe igikoresho cya Ion Chef™. Umubare w'amasomero yateguwe wapimwe na Qubit® 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) hakurikijwe amabwiriza y'uwakoze. Amaherezo, amasomero ahuzwa mu bipimo bingana mu duce tw'ingero z'isomero rya Ion Chef™. (imiyoboro ifite barcode) kandi ishyirwa ku gikoresho cya Ion Chef™. Gukurikirana byakozwe hakoreshejwe igikoresho cya Ion Torrent S5 (Thermo Fisher Scientific) (Thermo Fisher Scientific) hakoreshejwe Ion 510 Chip (Thermo Fisher Scientific). Isesengura ry'amakuru ryakozwe na Amplicon Suite (SmartSeq srl) na Ion Reporter Software.
Inyito zose z’ubwoko butandukanye zakurikije amabwiriza ariho ubu ya Human Genome Variation Consortium, iboneka kuri interineti (HGVS, http://www.hgvs.org/mutnomen). Akamaro k’ubuvuzi bw’ubwoko bwa BRCA1/2 kagenwe hakoreshejwe icyiciro cya International Consortium ENIGMA (Evidence-Based Network for Interpreting Germline Mutant Alleles, https://enigmaconsortium.org/) no kugisha inama ku bubiko butandukanye nka ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, na UMD. Icyiciro kirimo ibyiciro bitanu bitandukanye by’ibyago: bidakomeye (icyiciro cya I), bidakomeye (icyiciro cya II), bidakomeye (VUS, icyiciro cya III), bishobora gutera indwara (icyiciro cya IV), na bidakomeye (icyiciro cya V).VarSome yanasesenguye ingaruka z’impinduka ku miterere ya poroteyine n’imikorere yayo, igikoresho gitanga amakuru gifite uburyo bwo kugera ku bubiko 30.32
Kugira ngo hamenyekane akamaro gashoboka k’ubuvuzi kuri buri VUS, hakoreshejwe uburyo bukurikira bwo guhanura poroteyine: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/) na Align-GVGD (http://agvgd.hci.utah.edu/agvgd_input.php). Impinduka zashyizwe mu cyiciro cya 1 na 2 zafatwaga nk'ubwoko bw'inyamaswa.
Gukurikirana Sanger byemeje ko buri bwoko bw’indwara buhari. Muri make, hakozwe primers ebyiri zihariye kuri buri bwoko bwabonetse hakoreshejwe uburyo bwo gusuzuma gene bwa BRCA1 na BRCA2 (NG_005905.2, NM_007294.3 na NG_012772.3, NM_000059.3, uko bikurikirana). Bityo, PCR yakozwe hifashishijwe uburyo bwo gusuzuma Sanger.
Abarwayi bapimwe badafite gene ya BRCA1/2 bapimwe hakoreshejwe uburyo bwa multiplex ligation-dependent probe amplification (MLPA) hakurikijwe amabwiriza y’uwakoze kugira ngo basuzume niba hari uburyo bunini bwo guhuza genome (LGR). Muri make, ingero za ADN zirahinduka maze hakoreshwa ibyuma bigera kuri 60 bya BRCA1 na BRCA2 byihariye, buri kimwe kikabona uruhererekane rwa ADN runaka rufite uburebure bwa nucleotides zigera kuri 60. Ibikoresho byo kongera ingufu za probe, bigizwe n’itsinda ryihariye rya PCR amplicons, byasesenguwe hakoreshejwe capillary electrophoresis na porogaramu ya Cofalyser.Net hamwe n’imbonerahamwe za Cofalyser zikwiye (www.mrcholland.com).
Ibipimo byatoranijwe by’ubuvuzi (urwego rw’impinduka mu miterere y’umubiri n’igipimo cyo kwiyongera kwa Ki-67%) byafitanye isano no kuba hari BRCA1/2 PV, byabazwe hakoreshejwe porogaramu ya Prism v. 8.4 hakoreshejwe ikizamini nyacyo cya Fisher gifata agaciro ka p <0.05 ko ari ingenzi.
Hagati ya Mutarama 2017 na Werurwe 2021, abarwayi 455 basuzumwe indwara ya BRCA1/2 germline. Isuzuma ry’impinduka ryakorewe mu Kigo cy’Ibitaro bya Policlinico gishinzwe Oncology and Hematology. Dukurikije amabwiriza ya Sicilian (http://www.gurs.regione.sicilia.it/Indicep1.htm, N. 02-Venerdì 10 Gennaio 2020), Rodolico wa Catania – San Marco muri rusange, abarwayi 389 Hari kanseri y’ibere, kanseri y’intanga 37, kanseri ya pancreas 16, kanseri ya prostate 8 na melanoma 5. Ikwirakwizwa ry’abarwayi hakurikijwe ubwoko bwa kanseri n’ibyavuye mu isesengura bigaragara ku Ishusho ya 1.
Ishusho ya 1 igaragaza imbonerahamwe yerekana incamake y'ubushakashatsi. Abarwayi bafite ibibyimba by'ibere, melanoma, pancreas, prostate, cyangwa ovarian bapimwe impinduka mu ngirabuzimafatizo za BRCA1 na BRCA2.
Incamake: PV, ubwoko bwa pathogen; VUS, ubwoko butazwi neza; WT, urukurikirane rwa BRCA1/2 rwo mu bwoko bwa wild-type.
Twibanda ku bushakashatsi bwacu ku matsinda y’abantu barwaye kanseri y’ibere. Abarwayi bari bafite imyaka 49 (hagati ya 23-89) kandi biganjemo abagore (n=376, cyangwa 97%).
Muri aba bantu, 64 (17%) bari bafite impinduka za BRCA1/2 kandi bose bari abagore. Mirongo itatu na batanu (9%) bari bafite PV naho 29 (7.5%) bari bafite VUS. Cumi na barindwi (48.6%) muri 35 ubwoko bw'indwara bwagaragaye muri BRCA1 na 18 (51.4%) muri BRCA2, mu gihe 5 VUS yagaragaye muri BRCA1 (17.2%) na 24 (82.8%) muri BRCA2 (Ishusho ya 1 na 2). LGR ntabwo yari ihari mu isesengura rya MLPA.
Ishusho ya 2. Isesengura ry’impinduka za BRCA1 na BRCA2 mu barwayi 389 ba kanseri y’ibere. (A) Ikwirakwizwa ry’ubwoko bw’indwara (PV) (umutuku), ubwoko butazwi neza (VUS) (umuhondo), na WT (ubururu) mu barwayi 389 ba kanseri y’ibere; (B) abarwayi 389 ba kanseri y’ibere Mirongo itatu na batanu (9%) bari bafite ubwoko bw’indwara za BRCA1/2 (PV). Muri bo, 17 (48.6%) bari abanduye BRCA1 PV (umutuku wijimye) na 18 (51.4%) bari abanduye BRCA2 (umutuku wijimye); (C) 29 (7.5%) mu bantu 389 bari bafite VUS, 5 (17.2%) BRCA1 (umuhondo wijimye) na 24 (82.8%) BRCA2 (umuhondo wijimye).
Incamake: PV, ubwoko bwa pathogen; VUS, ubwoko butazwi neza; WT, urukurikirane rwa BRCA1/2 rwo mu bwoko bwa wild-type.
Hanyuma twakoze ubushakashatsi ku kuntu ubwoko bwa BC molekile bukwirakwira mu barwayi bafite BRCA1/2 PV. Ikwirakwizwa ryakozwe ryarimo 2 (5.7%) luminal A, 15 (42.9%) luminal B, 3 (8.6%) luminal B-HER2+, 2 (5.7%) HER2+ na 13 (37.1%) abarwayi ba TNBC. Mu barwayi ba BRCA1 bafite ubwandu, 5 (29.4%) bari bafite luminal B BC, 2 (11.8%) bari bafite indwara ya HER2+, naho 10 (58.8%) bari bafite TNBC. Ibibyimba bitarimo impinduka za BRCA1 byari luminal A cyangwa luminal B-HER2+ (Ishusho ya 3). Mu itsinda rito rya BRCA2-positive, ibibyimba 10 (55.6%) byari luminal B, 3 (16.7%) byari luminal B-HER2+, 3 (16.7%) byari TNBC na 2 (11.1%) byari luminal A (Ishusho ya 3). Oya. Ibibyimba bya HER2+ byari biri muri iri tsinda. Bityo, impinduka za BRCA1 zigaragara cyane ku barwayi ba TNBC, mu gihe impinduka za BRCA2 zigaragara cyane ku bantu bafite lumen B.
Ishusho ya 3 Ubwiyongere bw'ubwoko bwa kanseri y'ibere mu barwayi bafite ubwoko bwa kanseri y'ibere butera indwara muri BRCA1 na BRCA2. Histograms igaragaza uko BRCA1- (umutuku wijimye) na BRCA2- (umutuku woroshye) bikwirakwira mu bwoko bwa molekile z'abarwayi ba kanseri y'ibere. Imibare yagaragajwe muri buri gasanduku igaragaza ijanisha ry'abarwayi bafite BRCA1 na BRCA2 PV kuri buri bwoko bwa kanseri y'ibere.
Incamake: PV, ubwoko bw'indwara; HER2+, receptor 2 nziza ku ruhu rw'umuntu; TNBC, kanseri y'ibere ifite ingaruka eshatu.
Nyuma y’ibyo, twasuzumye ubwoko n’aho BRCA1 na BRCA2 PVs ziherereye. Muri BRCA1 PV, twabonye ubwoko 7 bwa nucleotide imwe (SNVs), gusiba 6, gukuba 3 no gushyiramo 1. Impinduka imwe gusa (c.5522delG) ni yo igaragara mu buvumbuzi bushya. PV ya BRCA1 ikunze kugaragara mu bantu bombi ni c.5035_5039delCTAAT. Iri hinduka rikubiyemo gusiba nucleotides eshanu (CTAAT) muri BRCA1 exon 15, bigatuma aside amino leucine isimburwa na tyrosine kuri codon 1679, kandi bitewe no guhindura frameshift hamwe na codon yavuzwe ko yahagaze bituma poroteyine icika imburagihe. Izindi mpinduka zose ziboneka mu rubanza rumwe gusa. Ikigaragara ni uko imwe muri PVs zavuzwe yari iherereye mu gace k’aho splice ihurira (c.4357+1G>T) (Imbonerahamwe ya 1).
Ku bijyanye na BRCA2 PV, twabonye gusiba 6, SNV 6 na duplications 2. Nta na kimwe mu mpinduka zabonetse ari gishya. Impinduka eshatu zagarutse mu baturage bacu, c.428dup na c.8487+1G>A byagaragaye mu bantu 3, hagakurikiraho c.5851_5854delAGTT byabonetse mu manza ebyiri. Impinduka za c.428dup zirimo gusubiramo C muri exon 5 ya BRCA2, byahanuwe ko izashyiraho poroteyine yagabanijwe, idakora. Impinduka za c.8487+1G>A ziba mu gace ka BRCA2 intron 19 (± 1,2) kandi zigira ingaruka ku ruhererekane rw'impinduka, bigatuma gusibangana guhindagurika bigatera poroteyine idasanzwe cyangwa idahari. Impinduka za c.5851_5854delAGTT ziterwa no gusiba kwa nucleotide 4 kuva ku myanya ya nucleotide 5851 kugeza 5854 muri exon 10 ya Gene ya BRCA2 kandi igatanga impinduka mu buryo bwa frameshift hamwe na codon yavuzwe mbere (p.S1951WfsTer). Nkuko byatangajwe mbere, impinduka zombi c.631G>A na c.7008-2A>T zabonetse ku murwayi umwe.34 Impinduka ya mbere irimo gusimbuza adenosine (A) muri BRCA2 exon 7 na guanine (G) irimo nucleotide bigatuma valine ihinduka isoleucine kuri codon 211, isoleucine Aside amino ni aside amino ifite imiterere isa cyane. Iyi mpinduka igira ingaruka ku guhuza kwa mRNA bisanzwe. Ubwoko bwa kabiri buherereye mu gace ka intronic kandi butuma A ebyiri zisimburwa na thymine (T) mbere ya exon 13 ya gene ikora BRCA2. Impinduka ya c.7008-2A>T ishobora gutanga inyandiko nyinshi z'uburebure butandukanye. Byongeye kandi, mu itsinda rya BRCA2 PV, impinduka 4 kuri 18 (22.2%) zari intronic.
Hanyuma twakoze isuzuma ry’impinduka za BRCA1/2 mu bice by’imikorere n’uturere duhuza poroteyine (Ishusho ya 4). Muri gene ya BRCA1, 50% bya PV byari mu gace k’itsinda rya kanseri y’ibere (BCCR), mu gihe 22% bya imihindagurikire byari mu gace k’itsinda rya kanseri y’intanga ngore (OCCR) (Ishusho ya 4A). Muri PV ya BRCA2, 35.7% by’ubwoko butandukanye byari mu gace ka BCCR naho 42.8% by’imihindagurikire byari muri OCCR (Ishusho ya 4B). Hanyuma, twasuzumye aho PV iri mu bice bya poroteyine ya BRCA1 na BRCA2. Kuri poroteyine ya BRCA1, twabonye PV eshatu mu bice by’itsinda rya loop na coiled coil, hamwe n’impinduka ebyiri mu bice bya BRCT (Ishusho ya 4A). Kuri poroteyine ya BRCA2, PV 4 zashyizwe mu bice by’itsinda rya BRC, mu gihe impinduka 3 za intronic na 3 zabonetse mu bice bya oligo/oligosaccharide-binding (OB) na tower (T) (Ishusho ya 4B).
Ishusho ya 4 Ishusho ya poroteyine ya BRCA1 na BRCA2 hamwe n'aho ubwoko butandukanye bw'indwara buherereye. Iyi shusho igaragaza uko ubwoko butandukanye bw'indwara bwa BRCA1 (A) na BRCA2 (B) buhagaze mu barwayi ba kanseri y'ibere buhagaze. Impinduka za exonic zigaragazwa mu ibara ry'ubururu, mu gihe ubwoko butandukanye bw'intronic bugaragazwa mu ibara ry'umuhondo. Uburebure bw'umurongo bugaragaza umubare w'abanduye. Poroteyine za BRCA1 na BRCA2 n'imiterere yazo biravugwa. (A) Poroteyine ya BRCA1 irimo domaine ya loop (RING) n'uruhererekane rw'aho ubwoko bw'umubiri buherereye (NLS), domaine ya coiled-coil, domaine ya SQ/TQ cluster (SCD), na domaine ya BRCA1 C-terminal (BRCT). (B) Poroteyine ya BRCA2 irimo BRC repeats umunani, domaine ya ADN ifite domaine ya helical (Helical), folds eshatu za oligonucleotide/oligosaccharide-binding (OB), domaine ya tower (T), na An NLS ku ruhande rwa C. Uduce twitwa Breast Cancer Cluster Region (BCCR) na Ovarian Cancer Cluster Region (OCCR) tugaragazwa kuri hasi.* Igaragaza impinduka zigena kodoni zihagarara.
Hanyuma twakoze ubushakashatsi ku bintu bya BC clinicopathological bishobora kuba bifitanye isano no kuba hari BRCA1/2 PV. Inyandiko zuzuye z’ubuvuzi zarabonetse ku barwayi 181 ba BRCA1/2 (abatari abanduye) n’abanduye bose (n = 35). Hari isano iri hagati y’igipimo cyo kwiyongera kwa kanseri n’icyiciro cyayo.
Twabaruye ikwirakwizwa rya Ki-67 dukurikije impuzandengo y'itsinda ryacu (25%, urwego ruri <10-90%). Abantu bafite Ki-67 <25% basobanuwe nka "Ki-67 yo hasi", mu gihe abantu bafite agaciro ka ≥ 25% bafatwaga nk' "Ki-67 yo hejuru". Itandukaniro rikomeye rya Ki-67 (p<0.01) ryabonetse hagati y'abatari abatwara ibintu n'abatwara ibintu bya BRCA1 PV (Ishusho ya 5A).
Ishusho ya 5 Isano ya Ki-67 n'ikwirakwizwa ry'amanota mu bagore ba kanseri y'ibere bafite na badafite BRCA1 na BRCA2 PV. (A) Agasanduku kerekana agaciro ka Ki-67 mu barwayi 181 ba BC batari abanduye ugereranyije na BRCA1 (18) cyangwa BRCA2 (17) ba PV. Agaciro ka P kari munsi ya 0.5 kafashwe nk'akamaro mu mibare. (B) Histogram yerekana ishyirwa ry'abarwayi ba kanseri ya BC mu matsinda y'amanota y'ubumenyi (G2 na G3) hakurikijwe imiterere ya BRCA1 na BRCA2 (abantu bafite WT, abafata BRCA1 na BRCA2 PV).
Mu buryo nk'ubwo, twasuzumye niba igipimo cy'ikibyimba gifitanye isano no kuba hari BRCA1/2 PV. Kubera ko G1 BC itari ihari mu baturage bacu, twagabanyije abarwayi mu matsinda abiri (G2 cyangwa G3). Dukurikije ibyavuye muri Ki-67, isesengura ryagaragaje isano iri hagati y'igipimo cy'ikibyimba n'impinduka za BRCA1, aho igipimo kinini cy'ibibyimba bya G3 mu banduye BRCA1 ugereranije n'abatabyirwaye (p<0.005) (Ishusho ya 5B).
Iterambere mu ikoranabuhanga ryo gukurikirana ADN ryatumye habaho iterambere ridasanzwe mu gupima BRCA1/2, bikagira ingaruka zikomeye ku barwayi bafite amateka ya kanseri mu muryango wabo. Kugeza ubu, ubwoko bwa BRCA1/2 bugera ku 20.000 bwarabonetse kandi bushyirwa mu byiciro hakurikijwe Umuryango w’Abanyamerika w’Ubuvuzi bw’Indwara 35 na sisitemu ya ENIGMA.35,36 Birazwi neza ko imiterere y’impinduka za BRCA1/2 itandukana cyane mu turere tw’isi.37 Mu Butaliyani, igipimo cya BRCA1/2 PV cyari hagati ya 8% na 37%, kigaragaza itandukaniro rikomeye hagati mu gihugu.38,39 Kubera ko ituwe n’abaturage bagera kuri miliyoni 5, Sicily ni akarere ka gatanu mu Butaliyani mu mubare w’abaturage. Nubwo hari amakuru ku ikwirakwizwa rya BRCA1/2 mu burengerazuba bwa Sicily, nta bimenyetso byinshi biraboneka mu gice cy’iburasirazuba bw’ikirwa.
Ubushakashatsi bwacu ni bumwe muri raporo za mbere ku ikwirakwira rya BRCA1/2 PV mu barwayi ba BC mu burasirazuba bwa Sicile.28 Twibanze ku isesengura ryacu kuri BC, kuko iyi ari yo ndwara ikunze kugaragara mu itsinda ryacu.
Ubwo bapimaga abarwayi 389 ba mbere ya Yesu, 9% bari bafite BRCA1/2 PV, zikwirakwizwa ku buryo bungana hagati ya BRCA1 na BRCA2. Ibi bisubizo birahuye n'ibyari byatangajwe mbere mu baturage b'Abataliyani.28 Igishimishije ni uko 3% (13/389) b'itsinda ryacu bari abagabo. Iki gipimo kiri hejuru ugereranyije n'igitekerezo cyatanzwe kuri kanseri y'ibere y'abagabo (1% by'aba mbere bose),40 bigaragaza ubwoko bwacu bushingiye ku byago byo guhinduka kwa BRCA1/2. Ariko, nta n'umwe muri aba bagabo wagize BRCA1/2 PV, bityo bari abakandida bo gusesengura inyigo y'uturemangingo kugira ngo bagaragaze ko hari impinduka zidakunze kubaho nka PALB2, RAD51C na D, n'ibindi. Impinduka zitazwi neza zabonetse muri 7% by'abantu BRCA2 VUS yagaragayemo. Ndetse n'iki gisubizo gihuye n'ibimenyetso byari bihari mbere.28,41,42
Ubwo twasesenguraga uko ubwoko bwa molekile za BC bukwirakwira mu bagore bahinduye imiterere ya BRCA1/2, twemeje isano izwi hagati ya TNBC na BRCA1 PV (58.8%) no hagati ya luminal B BC na BRCA2 PV (55.6%).16,43 Ibibyimba bya luminal A na HER2+ mu batwara BRCA1 na BRCA2 PV birahuye n'amakuru asanzweho.16,43
Hanyuma twibanda ku bwoko n'aho BRCA1/2 PV iherereye. Mu itsinda ryacu, BRCA1 PV ikunze gukoreshwa cyane yari c.5035_5039delCTAAT. Nubwo Incorvaia et al. Ntaho basobanuye ubu bwoko bw’impinduka mu itsinda ryabo rya Sicilia, abandi banditsi babivuze nk’umuti wa BRCA1 PV.34 Hari ubwoko bwinshi bwa BRCA1 PV bwabonetse mu itsinda ryacu – urugero: c.181T>G, c.514del, c.3253dupA na c.5266dupC – bwagaragaye muri Sicily.28 Muri ubwo bwoko, hari ubwoko bubiri bwa BRCA1 bwashinze impinduka (c.181T>G na c.5266dupC) bukunze kuboneka mu Bayahudi ba Ashkenazi bo mu Burayi bw’Iburasirazuba no Hagati (Polonye, Tchèque), Siloveniya, Otirishiya, Hongiriya, Belarusiya n’Ubudage), 44,45 kandi, muri Leta Zunze Ubumwe za Amerika na Arijantine, buherutse gusobanurwa nk “ubwoko bw’impinduka busubira” mu barwayi b’Abataliyani barwaye BC na OC. Ubwoko bwa 34c.514del bwari bwarabonetse mbere mu barwayi 8 ba kanseri y’ibere bo mu majyaruguru ya Sicily muri Palermo na Messina. Igishimishije ni uko ndetse na Incorvaia n’abandi. basanze ubwoko bwa c.3253dupA mu miryango imwe n'imwe muri Catania.28 Ubwoko bwa BRCA2 PV bugaragara cyane ni c.428dup, c.5851_5854delAGTT na intronic variant c.8487+1G>A, byavuzwe mu buryo burambuye 28 ku murwayi wo muri Palermo ufite c.428dup, c.5851_5854delAGTT PV yagaragaye mu ngo zo mu majyaruguru y'uburengerazuba bwa Sicily, cyane cyane mu turere twa Trapani na Palermo, mu gihe c.5851_5854delAGTT PV yagaragaye mu ngo zo mu majyaruguru y'uburengerazuba bwa Sicily. Ubwoko bwa 8487+1G>A bwakunze kugaragara mu bantu bo muri Messina, Palermo, na Caltanissetta.28 Rebbeck et al. mbere byasobanuwe ku mpinduka ya c.5851_5854delAGTT muri Kolombiya.37 Indi PV ya BRCA2, c.631+1G>A, yabonetse mu barwayi ba BC na OC bo muri Sicily (Agrigento, Siracusa na Ragusa).28 By’umwihariko, twabonye ko ubwoko bubiri bwa BRCA2 (BRCA2 c.631G>A na c.7008-2A>T) bubayeho mu murwayi umwe, twatekereje ko yatandukanijwe mu buryo bwa cis, nk’uko byatangajwe mbere.34,46 Izi mpinduka za BRCA2 zikunze kugaragara mu karere k’Ubutaliyani kandi byagaragaye ko zinjiza codons zihagarara mbere y’igihe, zigira ingaruka ku guhuza kwa RNA y’intumwa bigatuma poroteyine ya BRCA2 inanirwa.47,48
Twanashyize ku rutonde BRCA1 na BRCA2 PV mu duce twa OCCR na BCCR tw’imiterere ya poroteyine na genes. Utu duce twasobanuwe na Rebbeck n'abandi nk'ahantu hashobora gutera kanseri y'intanga ngore n'iy'ibere.49 Ariko, ibimenyetso bijyanye n'isano riri hagati y'aho ubwoko bw'imiti buherereye n'ibyago byo kurwara kanseri y'ibere cyangwa iy'intanga ngore biracyavugwaho rumwe.28,50-52 Mu baturage bacu, BRCA1 PV zari ziherereye cyane mu gace ka BCCR, mu gihe BRCA2 PV zari ziherereye cyane mu gace ka OCCR. Ariko, ntitwashoboye kubona isano iri hagati y'uturere twa OCCR n'uturere twa BCCR n'ibimenyetso bya BC. Ibi bishobora guterwa n'umubare muto w'abarwayi bafite impinduka za BRCA1/2. Ukurikije imiterere ya poroteyine, BRCA1 PV zikwirakwizwa muri poroteyine yose, kandi impinduka za BRCA2 ziboneka cyane mu gace ka BRC gasubiramo.
Amaherezo, twahuje ibimenyetso bya BC clinicopathological na BRCA1/2 PV. Bitewe n'umubare muto w'abarwayi barimo, twabonye gusa isano ikomeye hagati ya Ki-67 n'igipimo cya kanseri. Nubwo isuzuma n'isesengura rya Ki-67 bikomeje gutera impaka, nta gushidikanya ko igipimo cyo kwiyongera cyane gifitanye isano no kwiyongera kw'ibyago byo kugaruka kw'indwara no kugabanuka k'ubuzima. Kugeza ubu, ishingiro ryo gutandukanya Ki-67 "hejuru" na "hasi" ni 20%. Ariko, iki gipimo ntigikurikizwa ku barwayi bacu ba BRCA1/2 mutation, bafite igipimo cya Ki-67 cya 25%. Iki gipimo cyo hejuru cya Ki-67 gishobora gusobanurwa n'ubwiyongere bw'itsinda ryacu rya luminal B na TNBC, aho hari ibibyimba bike bya luminal A. Ariko, hari ibimenyetso bisa nkaho bigaragaza ko igabanuka rya Ki-67 (25-30%) rishobora gutuma abarwayi bashyirwa mu byiciro birushijeho bitewe n'uko babyiteze.53,54 Dukurikije ibyavuye mu isesengura ryacu, isano ikomeye ntabwo itangaje. Bibaho hagati ya Ki-67 iri hejuru n'amanota no kuba hari BRCA1. Mu by’ukuri, ibibyimba bifitanye isano na BRCA1 ni ibisanzwe kuri TNBC kandi bigaragaza ibimenyetso bikomeye.16,17
Mu gusoza, ubu bushakashatsi butanga raporo ku miterere ya BRCA1/2 mu itsinda rya BC rikomoka mu burasirazuba bwa Sicile. Muri rusange, ibyo twabonye bihuye n'ibimenyetso byari bisanzweho, haba mu bijyanye n'ubwiyongere bw'impinduka mu miterere ndetse n'imiterere y'indwara muri BC. Ubushakashatsi bwinshi ku baturage benshi ba BRCA1/2-mutant BC, nko gukoresha isesengura rya multigenome expanded mutational analysis, ni ngombwa kugira ngo hamenyekane niba hari PV zitandukanye kandi zidakunze kugaragara nka BRCA1/2. Ibi bizatuma hamenyekana kandi hagafatwa ingamba zikwiye ku mubare w'abantu bafite ibyago byinshi byo kurwara kanseri bitewe n'impinduka mu miterere y'uturemangingo.
Twemeje ko abarwayi basinye icyemezo cyo gutanga ingero zabo z'ibibyimba mu ibanga ku mpamvu z'ubushakashatsi. Abarwayi bose basinye icyemezo cyanditse nk'uko biteganywa n'Itangazo rya Helsinki. Dukurikije politiki ya AOU Policlinico "G.Rodolico - S.Marco", ubu bushakashatsi bwakuweho isuzuma ry'amahame mbwirizamuco kuko isesengura rya BRCA1/2 ryakozwe hakurikijwe ubuvuzi kandi abarwayi bose batanze icyemezo cyanditse. Abarwayi nabo bemera ikoreshwa ry'amakuru yabo mu bikorwa by'ubushakashatsi.
Turashimira Porofeseri Paolo Vigneri ku bufasha bwe mu kwita ku barwayi ba kanseri y'ibere nk'uko byasabwe na Komite Ishinzwe Imyitwarire.
Federica Martorana avuga ko hari amateka y’icyubahiro yatanzwe na Istituto Gentili, Eli Lilly, Novartis, Pfizer. Abandi banditsi batangaza ko nta makimbirane y’inyungu muri iki gitabo.
1. Sung H, Ferlay J, Siegel RL, n'abandi. Imibare ya kanseri ku isi 2020: GLOBOCAN ipima umubare w'abarwaye kanseri 36 n'impfu zabo mu bihugu 185 ku isi. CA Cancer J Clin.2021;71(3):209-249.doi: 10.3322/caac.21660
Igihe cyo kohereza ubutumwa: 15 Mata 2022
