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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, 1,2 Giuliana Pavone, 3 Katia Lanzafame, 3 Sebastiano Bianca, 4 Chiara Barone, 5 Cristina Gorgone, 6 Marco Fichera, 1,2 Whare Wananga o te Whare Wananga o Manzella, 7 Livia o te Whare Wananga Catania, Catania, 95123, Italy;2 Center for Experimental Oncology and Hematology, AOU Policlinico "G.Rodolico - San Marco", Catania , 95123, Itari; 3 Medical Oncology, AOU Policlinico "G. Rodolico - San Marco", Catania, 95123, Itari; 4 Medical Genetics, ARNAS Garibaldi, Catania, 95123, Italy; 5 Medicine Genetics, ASP, Syracuse, 96100, Italy; 6 Tari Pūtaiao Hauora me te Hangarau Koiora, Te Whare Wānanga o Catania, Ira Hauora, Catania, Itari, 95123; 7Oasi Research Institute-IRCCS, Troina, 94018, Itari Whakawhitiwhiti Kōrero: Stefania Stella, waea +39 095 378 1946, īmēra [email protected]; [email protected] Kaupapa: Ngā whakarerekētanga ira i roto i te BRCA1 me te BRCA2 me te mate pukupuku ū kua whakapumautia (BC), te ovary (OC) me ētahi atu e pā ana ki te mōrearea o te mate pukupuku mō te wa katoa. Ko te whakamātautau mō te ira BRCA he mea nui ki te aromatawai i te mōrearea takitahi, me te kimi tikanga ārai i roto i ngā kaikawe hauora me te whakarite maimoatanga i roto i ngā tūroro mate pukupuku. He rerekē te horapa o ngā whakarerekētanga BRCA1 me te BRCA2 puta noa i ngā rohe matawhenua, ā, ahakoa kei reira ngā raraunga mō ngā momo mate BRCA i roto i ngā whānau Sicilian, kāore i te nui ngā rangahau e aro ana ki ngā taupori i te rawhiti o Sicily. Ko te whāinga o tā mātou rangahau he tirotiro i te auau me te tohatoha o ngā whakarerekētanga ira mate BRCA i roto i tētahi rōpū o ngā tūroro BC mai i te rawhiti o Sicily me te aromatawai i tō rātou hononga ki ngā āhuatanga BC motuhake mā te whakamahi i te raupapatanga o te whakatupuranga e whai ake nei. Ko te aroaro o ngā whakarerekētanga e pā ana ki te tohu pukupuku me te taupū tipu. NGĀ HUA: I te katoa, 35 ngā tūroro (9%) he momo mate BRCA, 17 (49%) i roto i te BRCA1 me te 18 (51%) i roto i te BRCA2. He whānui ngā whakarerekētanga BRCA1 i roto i ngā tūroro BC toru-kino, engari he nui ake te noa o ngā whakarerekētanga BRCA2 i roto i ngā tūroro BC luminal. Ki te whakatauritea ki mō ngā tāngata kāore i te kawe i te ira, he nui ake te taumata pukupuku me te taupū tipu o ngā tāngata whai ira BRCA1. Ngā Whakatau: Ka whakaratohia e ā mātou kitenga he tirohanga whānui mō te mana whakarerekētanga BRCA i roto i ngā tūroro BC mai i te rawhiti o Sicily, ā, ka whakaū i te tūranga o te tātari NGS ki te tautuhi i ngā tūroro whai ira tuku iho BC. I te nuinga, he rite ēnei raraunga ki ngā taunakitanga o mua e tautoko ana i te tirotiro BRCA mō te ārai me te maimoatanga tika o te mate pukupuku i roto i ngā tāngata kawe ira whakarerekētanga.
Ko te mate pukupuku o te ū (BC) te mate pukupuku tino noa o te ao, ā, ko te mate pukupuku tino whakamate i roto i ngā wāhine.1 Kua rangahaua whānuitia ngā āhuatanga koiora e whakatau ana i te matapae me te whanonga haumanu o te BC, ā, kua whakamāramahia ētahi i roto i te wā. Inaa, he maha ngā tohu whakakapi e whakamahia ana i tēnei wā hei whakarōpū i te BC ki ngā momo ngota ngota rerekē. Ko ēnei ko te estrogen (ER) me/ranei te progesterone receptor (PgR), te human epidermal growth factor receptor 2 (HER2) amplification, te proliferation index Ki-67 me te tumor grade (G).2 Nā te huinga o ēnei taurangi i tautuhia ngā kāwai BC e whai ake nei: 1) Ko ngā pukupuku Luminal, e whakaatu ana i te whakaaturanga ER me/ranei PgR, i 75% o ngā BC. I wehea anō ēnei pukupuku ki Luminal A, i te wā i raro iho i te 20% te Ki-67, ā, he kino te HER2, me Luminal B, i te wā i rite, i runga ake rānei te Ki-67 i te 20%, ā, i te aroaro o te whakanui HER2, ahakoa te tohu whakanui; 2) Ngā pukupuku HER2+ he kino te ER me te PgR engari e whakaatu ana i te whakanui HER2. Ko tēnei rōpū e 10% o ngā pukupuku ū katoa; 3) Ko te mate pukupuku ū toru-kino (TNBC), kāore e whakaatu i te whakaaturanga ER me te PgR me te whakanui HER2, e kapi ana i te 15% o ngā mate pukupuku ū.2-4
I roto i ēnei momo BC, ko te taumata pukupuku me te taupū tipu e tohu ana i ngā tohu koiora whakawhiti-wāhanga e hono tika ana, ā, motuhake ana ki te kaha o te pukupuku me te matapae.5,6
Haunga ngā āhuatanga koiora kua whakahuatia ake nei, kua piki haere te hiranga o ngā whakarerekētanga ira tuku iho e ārahi ana ki te whanaketanga o te BC i ngā tau kua pahure ake nei.7 Tata ki te 1 i roto i te 10 ngā pukupuku ū ka tukuna iho nā ngā whakarerekētanga germline i roto i ngā ira motuhake.8 E rua ngā rangahau mate urutā nui i uru atu ki te neke atu i te 180,000 ngā wāhine kua tautuhia tata nei he rōpū ira e waru (arā, ATM, BARD1, BRCA1, BRCA2, CHK2, PALB2, RAD51C, me RAD51D) te kawenga matua mō te BC tuku iho. I roto i ēnei ira, ko te BRCA1 me te BRCA2 (e kiia nei ko BRCA1/2) i whakaatu i te hononga kaha rawa atu ki te whanaketanga o ngā pukupuku ū.9-12 Inaa, ko ngā whakarerekētanga germline BRCA1/2 ka whakanui ake i te mōrearea o te BC me ētahi atu mate pukupuku, tae atu ki te ovarian, te prostate, te pancreatic, te colorectal, me te melanoma. Mai i te 13 ki te 80 tau te pakeke, ko te auau o te BC he 72% i roto i ngā wāhine he momo pathogenic BRCA1 (PV) me te 69% i roto i ngā wāhine he BRCA2. PV.14
He mea nui, e kī ana tētahi pukapuka hou ko te mōrearea o te BC ka whakawhirinaki ki te momo PV. Inaa, ki te whakatauritea ki ngā momo mate e whakaiti ana i te mate, ko ngā momo ngaronga nui, inā koa i roto i te ira BRCA1, e hono ana ki te whakaiti i te mōrearea o te BC, inā koa i roto i ngā wāhine kaumātua.15
I honoa te aroaro o te BRCA1, te BRCA2 PV rānei ki ngā āhuatanga koiora me ngā āhuatanga haumanu rerekē.16,17 Ko ngā BC e pā ana ki te BRCA1 he kaha ki te taha haumanu, he ngoikore te wehewehe, ā, he tino tipu haere. Ko te tikanga he toru ngā kino o ēnei pukupuku, ā, he wawe te tīmatanga. Ko ngā pukupuku e puta ana i roto i ngā tūroro kua whakarerekētia te BRCA2 he maha ngā tohu rerekētanga ki te pai me ngā tohu tipu rerekē. He nui ake te kitea o ēnei pukupuku i roto i te lumen B, ā, he maha ngā wā ka puta i roto i ngā kaumātua.16-18 He mea nui, ko ngā whakarerekētanga i roto i te BRCA1 me te BRCA2 ka whakanui ake i te aro ki ngā maimoatanga motuhake, tae atu ki ngā tote konukawata me ngā rongoā kua tohua pēnei i ngā aukati poly(ADP-ribose) polymerase (PARPi).19,20
I ngā tau kua taha ake nei, nā te whakatinanatanga o te raupapatanga whakatupuranga-muri (NGS) i roto i te mahi haumanu kua taea ai e te maha o ngā tūroro BC te whai i te whakamātautau ngota mō ngā mate pukupuku, tae atu ki te BRCA1/2.21 I te wā kotahi, ko ngā whakamāramatanga i runga i ngā paearu tika e pā ana ki te hītori whānau, ngā āhuatanga taupori, me te haumanutanga hei tautuhi pai ake i ngā tāngata e tika ana kia whakamatautauria te BRCA1/2.22,23 I roto i tēnei horopaki, kei te piki haere ngā taunakitanga mō te tirotiro BRCA1/2 i roto i ngā taupori motuhake, e whakaatu ana i ngā rerekētanga puta noa i ngā rohe matawhenua.24–27 Ahakoa he pūrongo mō te rōpū BC i te taha hauauru o Sicily, he iti ake ngā raraunga e wātea ana mō te tirotiro BRCA1/2 i te taupori rawhiti o Sicily.28,29
Ka whakaahuahia e mātou i konei ngā hua o te tirotiro ira BRCA1/2 i roto i ngā tūroro BC mai i te rawhiti o Sicily, e hono ana i te aroaro o ngā whakarerekētanga ira BRCA1, BRCA2 rānei ki ngā āhuatanga matua o ēnei pukupuku.
I whakahaerehia he rangahau whakamuri i te "Center for Experimental Oncology and Hematology" i te Hōhipera Policlinico. Rodolico – San Marco i Catania. Mai i te marama o Hanuere 2017 ki te marama o Poutū-te-rangi 2021, e 455 ngā tūroro katoa he mate pukupuku ū me te mate pukupuku ovarian, melanoma, pancreatic, prostate rānei i tukuna ki tā mātou taiwhanga tātaritanga ngota mō te whakamātautau ira BRCA/2. I whakahaerehia tēnei rangahau i runga anō i te Whakapuakitanga o Helsinki, ā, i tukuna e ngā kaiuru katoa he whakaaetanga ā-tuhi i mua i te tātari ngota.
I aromatawaihia ngā āhuatanga histological me te koiora (ER, PgR, tūnga HER2, Ki-67, me te taumata) o te BC i runga i te koiora matua, i ngā tauira pokanga rānei, me te whakaaro ki ngā wāhanga pukupuku kaha anake. I runga i ēnei āhuatanga, i whakarōpūtia ngā BC penei: luminal A (ER+ me/ranei PgR+, HER2-, Ki-67<20%), luminal B (ER+ me/ranei PgR+, HER2-, Ki-67≥20%), luminal B-HER2+ (ER me/ranei PgR+, HER2+), HER2+ (ER me PgR-, HER2+) triple negative rānei (ER me PgR-, HER2-).
I mua i te aromatawai i te mana o te whakarerekētanga BRCA1 me te BRCA2, i whakahaerehia e tētahi tīma maha-mātauranga tae atu ki tētahi tohunga mate pukupuku, he tohunga ira, me tētahi tohunga hinengaro he kōrero ira pukupuku mō ia tūroro hei whakatau i te aroaro o te BRCA1 me/ranei te BRCA1. ngā tāngata rānei he nui te mōrearea o te PV i roto i te ira BRCA2. I mahia te kōwhiringa tūroro i runga anō i ngā aratohu a te Italian Society of Medical Oncology (AIOM) me ngā taunakitanga ā-rohe o Sicilian.30,31 Kei roto i ēnei paearu: (i) te hītori whānau o ngā momo mate e mōhiotia ana i roto i ngā ira ngoikore (hei tauira, BRCA1, BRCA2, TP53, PTEN); (ii) ngā tāne me te BC; (iii) te hunga me te BC me te OC; (iv) ngā wāhine me te BC <36 tau, TNBC <60 tau, te BC rua rānei <50 tau; (v) te hītori hauora whaiaro o te BC <50 tau me te iti rawa o tētahi whanaunga tuatahi: (a) BC <50 tau; (b) OC kore-mucinous me te kore-rohe o tētahi tau; (c) BC rua; (d) BC tāne; (e) mate pukupuku repeure; (f) mate pukupuku repeure; (vi) e rua, neke atu rānei Ngā hītori whaiaro o te BC neke atu i te 50 tau me te hītori whānau o te BC, OC, mate pukupuku repeure rānei mō ngā whanaunga he whanaunga tuatahi tetahi ki tetahi (tae atu ki ngā whanaunga e whanaunga tuatahi ana ia); (vii) Hītori whaiaro o te OC me te iti rawa o te kotahi whanaunga tuatahi: (a) BC <50 tau; (b) NOC; (c) BC rua; (d) BC tāne; (vii) wahine he OC serous teitei.
I tangohia he tauira toto ā-taha 20 mL mai i ia tūroro, ā, i kohia ki roto i ngā ngongo EDTA (BD Biosciences). I wehea te DNA ira mai i ngā tauira toto katoa 0.7 mL mā te whakamahi i te QIAsymphony DSP DNA Midi kit Isolation Kit (QIAGEN, Hilden, Itari) e ai ki ngā tohutohu a te kaihanga, ā, i tukuna mā roto i te Qubit® 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA). Whakaotihia te ine. Ko te whakarei ake i te whāinga me te whakarite whare pukapuka ka mahia e te Oncomine™ BRCA Research Assay Chef, kua rite ki te utaina ki roto i te Ion AmpliSeq™ Chef Reagents DL8 Kit mō te whakarite whare pukapuka aunoa e ai ki ngā tohutohu a te kaihanga. Kei roto i te kete he puna paraimere PCR maha e rua ka taea te whakamahi hei ako i ngā ira BRCA1 (NM_007300.3) me BRCA2 (NM_000059.3) katoa. I roto i te poto, 15 µL o ia tauira DNA kua whakaranua (10 ng) i tāpirihia ki ngā pereti waeherepae mō te whakarite whare pukapuka, ā, i utaina ngā tauhohenga me ngā mea pau katoa ki runga i te taputapu Ion Chef™. Kātahi ka mahia te whakarite whare pukapuka aunoa me te kohikohinga whare pukapuka tauira waeherepae ki runga i te taputapu Ion Chef™. Kātahi ka aromatawaihia te maha o ngā whare pukapuka kua whakaritea e te Qubit® 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) e ai ki ngā tohutohu a te kaihanga. Hei whakamutunga, ka whakakotahihia ngā whare pukapuka ki ngā ōwehenga equimolar i roto i ngā ngongo tauira whare pukapuka Ion Chef™ (ngā ngongo waeherepae). ā, i utaina ki te taputapu Ion Chef™. I whakahaerehia te raupapatanga mā te whakamahi i te taputapu Ion Torrent S5 (Thermo Fisher Scientific) (Thermo Fisher Scientific) mā te whakamahi i te Maramara Ion 510 (Thermo Fisher Scientific). I whakahaerehia te tātari raraunga e Amplicon Suite (SmartSeq srl) me te Pūmanawa Ion Reporter.
I whai ngā whakaingoatanga rerekē katoa i ngā aratohu o nāianei o te Human Genome Variation Consortium, e wātea ana i te ipurangi (HGVS, http://www.hgvs.org/mutnomen). I tautuhia te hiranga haumanu o ngā rerekētanga BRCA1/2 mā te whakamahi i te whakarōpūtanga o te International Consortium ENIGMA (Evidence-Based Network for Interpreting Germline Mutant Alleles, https://enigmaconsortium.org/) me te tirotiro i ngā pātengi raraunga rerekē pērā i a ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, me UMD. Kei roto i te whakarōpūtanga e rima ngā kāwai mōrearea motuhake: he pai (kāwai I), he pai pea (kāwai II), he rerekētanga kāore i te tino mārama (VUS, kāwai III), he mate pea (kāwai IV), me te mate (kāwai V). I tātarihia hoki e VarSome te pānga o ngā whakarerekētanga ki te hanganga me te mahi pūmua, he taputapu whakamōhio me te urunga atu ki te 30 pātengi raraunga.32
Hei tohu i te hiranga haumanu pea ki ia VUS, i whakamahia ngā rauropi matapae pūmua rorohiko e whai ake nei: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/) me Align-GVGD (http://agvgd.hci.utah.edu/agvgd_input.php). Ko ngā momo rerekē i whakarōpūtia hei akomanga 1 me te 2 i kiia he momo mohoao.
I whakaūhia e te raupapatanga Sanger te aroaro o ia momo mate. I roto i te poto, i hangaia he takirua o ngā paraimere motuhake mō ia momo i kitea mā te whakamahi i ngā raupapatanga tohutoro ira BRCA1 me BRCA2 (NG_005905.2, NM_007294.3 me NG_012772.3, NM_000059.3, ia). Nō reira, i mahia te PCR kua arotahihia, ā, i muri mai ko te raupapatanga Sanger.
I whakamātauria ngā tūroro i whakamātauhia he kino mō te ira BRCA1/2 mā te whakakaha ira-whakawhirinaki maha (MLPA) e ai ki ngā tohutohu a te kaihanga hei aromatawai i te aroaro o ngā whakarerekētanga ira nui (LGR). I roto i te poto, ka tangohia te āhua o ngā tauira DNA, ā, tae atu ki te 60 ngā ira-motuhake BRCA1 me BRCA2 ka whakamahia, ia ira ka kitea he raupapa DNA motuhake tata ki te 60 ngā nucleotide te roa. Ko ngā hua whakakaha ira, he huinga ahurei o ngā amplicons PCR, i tātarihia mā te electrophoresis capillary me te pūmanawa Cofalyser.Net me ngā ripanga Cofalyser motuhake-puranga e tika ana (www.mrcholland.com).
I honoa ngā taurangi haumanu mate pukupuku kua tīpakohia (te taumata histological me te taupū tipu Ki-67%) ki te aroaro o te BRCA1/2 PV, i tatauhia mā te whakamahi i te pūmanawa Prism v. 8.4 mā te whakamahi i te whakamātautau tika a Fisher me te whakaaro he hiranga te uara-p <0.05.
I waenganui i a Hānuere 2017 me Maehe 2021, e 455 ngā tūroro i tirotirohia mō ngā whakarerekētanga ira BRCA1/2. I whakahaerehia ngā whakamātautau whakarerekētanga ira i te Pokapū mō te Oncology Whakamātautau me te Hematology o te Hōhipera Policlinico. E ai ki te aratohu Sicilian (http://www.gurs.regione.sicilia.it/Indicep1.htm, N. 02-Venerdì 10 Hanuere 2020), ko te Rodolico o Catania – San Marco” katoa, 389 ngā tūroro. He mate pukupuku ū, 37 mate pukupuku ovarian, 16 mate pukupuku repeure, 8 mate pukupuku repeure me te 5 melanoma. Ko te tohatoha o ngā tūroro e ai ki te momo mate pukupuku me ngā hua tātaritanga e whakaatuhia ana i te Pikitia 1.
E whakaatu ana te Pikitia 1 i tētahi tūtohi rere e whakaatu ana i te tirohanga whānui o te rangahau. I whakamātauria ngā tūroro he pukupuku ū, he pukupuku melanoma, he pukupuku repeure, he pukupuku repeure, he pukupuku whatukuhu rānei mō ngā whakarerekētanga ira i roto i ngā ira BRCA1 me BRCA2.
Ngā Whakarāpopototanga: PV, momo mate; VUS, momo kāore i te tino mārama te hiranga; WT, raupapatanga BRCA1/2 momo-mohoao.
I arotahi motuhake mātou i ā mātou rangahau ki ngā rōpū mate pukupuku ū. Ko te pakeke toharite o ngā tūroro he 49 tau (mai i te 23 ki te 89 tau) ā, ko te nuinga he wāhine (n=376, 97% rānei).
O ēnei kaupapa, 64 (17%) he whakarerekētanga BRCA1/2, ā, he wahine katoa. Toru tekau mā rima (9%) he PV, ā, 29 (7.5%) he VUS. Tekau mā whitu (48.6%) o ngā momo mate 35 i puta i roto i te BRCA1, ā, 18 (51.4%) i roto i te BRCA2, ko te 5 VUS i puta i roto i te BRCA1 (17.2%) me te 24 (82.8%) i roto i te BRCA2 (Pikitia 1 me te 2). Kāore i kitea te LGR i roto i te tātaritanga MLPA.
Pikitia 2. Te tātari i ngā whakarerekētanga BRCA1 me BRCA2 i roto i te 389 o ngā tūroro matepukupuku ū.(A) Te tohatoha o ngā momo matepukupuku (PV) (whero), ngā momo kāore i te tino mārama te hiranga (VUS) (karaka), me te WT (kikorangi) i roto i te 389 o ngā tūroro matepukupuku ū; (B) 389 o ngā tūroro matepukupuku ū E toru tekau mā rima (9%) (he momo matepukupuku BRCA1/2 (PV). I roto i a rātou, 17 (48.6%) he kawe BRCA1 PV (whero pouri) me te 18 (51.4%) he kawe BRCA2 (whero mārama); (C) 29 (7.5%) o te 389 o ngā kaupapa i mau VUS, 5 (17.2%) ngā ira BRCA1 (karaka pouri) me te 24 (82.8%) ngā ira BRCA2 (karaka mārama).
Ngā Whakarāpopototanga: PV, momo mate; VUS, momo kāore i te tino mārama te hiranga; WT, raupapatanga BRCA1/2 momo-mohoao.
I muri mai ka tirotirohia e mātou te horapa o ngā momo ira BC i roto i ngā tūroro me te BRCA1/2 PV. Ko te tohatoha i whakaurua ki roto ko te 2 (5.7%) luminal A, 15 (42.9%) luminal B, 3 (8.6%) luminal B-HER2+, 2 (5.7%) HER2+ me te 13 (37.1%) tūroro TNBC. I roto i ngā tūroro BRCA1-pai, 5 (29.4%) he luminal B BC, 2 (11.8%) he mate HER2+, ā, 10 (58.8%) he TNBC. Ko ngā pukupuku kāore he whakarerekētanga BRCA1 he luminal A, he luminal B-HER2+ rānei (Pikitia 3). I roto i te rōpū iti BRCA2-pai, 10 (55.6%) ngā pukupuku he luminal B, 3 (16.7%) he luminal B-HER2+, 3 (16.7%) TNBC me te 2 (11.1%) he luminal A (Pikitia 3). Kāore he pukupuku HER2+. i roto i tēnei rōpū. Nō reira, he nui ngā whakarerekētanga BRCA1 i roto i ngā tūroro TNBC, engari ko ngā whakarerekētanga BRCA2 he nui ngā whakarerekētanga i roto i ngā tāngata lumen B.
Ahua 3 Te auau o ngā momo mate pukupuku ū i roto i ngā tūroro he momo mate pukupuku i roto i te BRCA1 me te BRCA2. Ngā histogram e whakaatu ana i te tohatoha o ngā PV BRCA1- (whero pouri) me te BRCA2- (whero mārama) i roto i ngā momo ngota ngota o ngā tūroro mate pukupuku ū. Ko ngā tau i tukuna i roto i ia pouaka e tohu ana i te ōrau o ngā tūroro he PV BRCA1 me te BRCA2 mō ia momo mate pukupuku ū.
Ngā Whakarāpopototanga: PV, momo mate pukupuku; HER2+, kaiwhakawhiwhi tipu epidermal tangata 2 pai; TNBC, mate pukupuku ū triple-negative.
I muri mai, i aromatawaihia e mātou te momo me te taunga ira o ngā PV BRCA1 me BRCA2. I roto i te PV BRCA1, i kitea e mātou e 7 ngā momo nucleotide kotahi (SNV), e 6 ngā mukunga, e 3 ngā tāruarua me te 1 whakaurunga. Kotahi anake te whakarerekētanga (c.5522delG) e tohu ana i tētahi kitenga hou. Ko te PV BRCA1 tino kitea i roto i ngā kaupapa e rua ko c.5035_5039delCTAAT. Ko tēnei whakarerekētanga e uru ana ki te mukunga o ngā nucleotide e rima (CTAAT) i roto i te exon 15 o te BRCA1, ka hua ake te whakakapinga o te waikawa amino leucine ki te tyrosine i te codon 1679, ā, nā te nekehanga anga whakawhiti me te codon aukati rerekē i matapaetia ka arahi ki te tapahi pūmua wawe. Ko ngā huringa katoa ka kitea i roto i te kotahi anake te take. He mea nui, ko tētahi o ngā PV i pūrongohia i noho ki te rohe whakaaetanga pae splice (c.4357+1G>T) (Ripanga 1).
Mō te BRCA2 PV, i kitea e mātou e 6 ngā mukunga, e 6 ngā SNV me te 2 ngā tāruarua. Kāore he mea hou o ngā huringa i kitea. E toru ngā whakarerekētanga i puta anō i roto i tō mātou taupori, ko te c.428dup me te c.8487+1G>A i kitea i roto i te 3 ngā kaupapa, ā, i muri mai ko te c.5851_5854delAGTT i tangohia i roto i ngā take e rua. Ko te whakarerekētanga c.428dup e pā ana ki te tukurua o te C i roto i te exon 5 o BRCA2, i matapaetia hei whakakōrero i tētahi pūmua kua tapahia, kāore e mahi. Ka puta te whakarerekētanga c.8487+1G>A i roto i te rohe intronic o te BRCA2 intron 19 (± 1,2) ā, ka pā ki te raupapatanga whakaaetanga splicing, ka hua ake he splicing kua whakarerekētia ka hua ake he pūmua rerekē, kāore rānei i te kitea. Ko te rerekētanga pathogenic c.5851_5854delAGTT e pā ana ki te mukunga 4-nucleotide mai i ngā tūranga nucleotide 5851 ki te 5854 i roto i te exon whakakōrero 10 o te ira BRCA2 ā, ka hua ake he nekehanga anga whakawhiti me te codon aukati rerekē kua matapaetia (p.S1951WfsTer). He mea nui, e ai ki ngā pūrongo o mua, i kitea ngā whakarerekētanga e rua c.631G>A me c.7008-2A>T i roto i te tūroro kotahi.34 Ko te whakarerekētanga tuatahi ko te whakakapinga o te adenosine (A) i roto i te BRCA2 exon 7 ki te guanine (G) kei roto te nucleotide ka hua ake he huringa o te valine ki te isoleucine i te codon 211, isoleucine Ko te waikawa amino he waikawa amino me ngā āhuatanga tino rite. Ka pā tēnei huringa ki te hononga mRNA noa. Kei roto i te rohe intronic te rerekētanga tuarua, ā, ka hua ake he whakakapinga takirua A ki te thymine (T) i mua i te exon 13 o te ira e whakamārama ana i te BRCA2. Ka taea e te huringa c.7008-2A>T te whakaputa i ngā tuhinga maha o ngā roa rerekē. Hei tāpiri, i roto i te rōpū o ngā BRCA2 PV, 4 o te 18 ngā huringa (22.2%) he intronic.
I muri mai ka maherehia e mātou ngā whakarerekētanga kino o te BRCA1/2 i roto i ngā rohe mahi me ngā rohe here-pūmua (Pikitia 4). I roto i te ira BRCA1, 50% o ngā PV i kitea i roto i te rohe rōpū mate pukupuku ū (BCCR), ko te 22% o ngā whakarerekētanga i kitea i roto i te rohe rōpū mate pukupuku ovarian (OCCR) (Pikitia 4A). I ​​roto i te BRCA2 PV, 35.7% o ngā rerekētanga i kitea i roto i te rohe BCCR, ā, 42.8% o ngā whakarerekētanga i kitea i roto i te OCCR (Pikitia 4B). Muri iho, i aromatawaihia e mātou te wāhi o te PV i roto i ngā rohe pūmua BRCA1 me BRCA2. Mō te pūmua BRCA1, i kitea e mātou e toru ngā PV i roto i ngā rohe koropiko me te koiri, me ngā whakarerekētanga e rua i roto i te rohe BRCT (Pikitia 4A). Mō te pūmua BRCA2, e 4 ngā PV i maherehia ki te rohe tukurua BRC, ko te 3 ngā huringa intronic me te 3 i kitea i roto i ngā rohe here-oligo/oligosaccharide (OB) me te pourewa (T) (Pikitia 4B).
Ahua 4 Te whakaaturanga kauwhata o ngā pūmua BRCA1 me BRCA2 me te taunga o ngā momo mate pukupuku. E whakaatu ana tēnei ahua i te tohatoha o ngā momo mate pukupuku BRCA1 (A) me BRCA2 (B) i roto i ngā tūroro mate pukupuku ū. Kei te whakaatuhia ngā whakarerekētanga exonic i roto i te kikorangi, ko ngā momo intronic i roto i te karaka. Ko te teitei o te pae e tohu ana i te maha o ngā take. Kua ripoatahia ngā pūmua BRCA1 me BRCA2 me ō rātou rohe mahi.(A) Kei roto i te pūmua BRCA1 he rohe koropiko (RING) me te raupapatanga taunga karihi (NLS), he rohe koiri-koiri, he rohe tautau SQ/TQ (SCD), me te rohe C-terminal BRCA1 (BRCT).(B) Kei roto i te pūmua BRCA2 e waru ngā tukurua BRC, he rohe here-DNA me te rohe helical (Helical), e toru ngā kopa here-oligonucleotide/oligosaccharide (OB), he rohe pourewa (T), me te An NLS i te taha C. Kei raro ngā wāhi e kiia nei ko te Rohe Tautau Mate Pukupuku Uma (BCCR) me te Rohe Tautau Mate Pukupuku Ovarian (OCCR).*E tohu ana i ngā whakarerekētanga e whakatau ana i te mutu ngā kōtona
I muri mai ka tirotirohia e mātou ngā āhuatanga haumanu o te BC e hono pea ana ki te aroaro o te BRCA1/2 PV. I wātea mai ngā rekoata haumanu katoa mō te 181 o ngā tūroro BRCA1/2-kino (ehara i te hunga kawe) me ngā kawe katoa (n = 35). He hononga i waenga i te tere tipu o te pukupuku me te taumata.
I tatauhia e mātou te tohatoha o te Ki-67 i runga i te tau waenga o tā mātou rōpū (25%, awhe <10-90%). Ko ngā kaupapa he Ki-67 < 25% i tautuhia he "Ki-67 iti", ko ngā tāngata he uara ≥ 25% i kiia he "Ki-67 teitei". I kitea he rerekētanga nui o te Ki-67 (p<0.01) i waenga i ngā kaikawe kore-kaikawe me ngā kaikawe BRCA1 PV (Pikitia 5A).
Ahua 5 Te hononga o te Ki-67 ki te tohatoha taumata i roto i ngā wāhine mate pukupuku ū me te BRCA1 me te BRCA2 PV, me te kore.(A) Kauwhata pouaka e whakaatu ana i ngā uara Ki-67 waenga i roto i te 181 tūroro BC kore-kawe, me ngā tūroro BRCA1 (18) BRCA2 rānei (17) PV. I kiia he hiranga tatauranga ngā uara P i raro i te 0.5.(B) Histogram e tohu ana i te wehenga o ngā tūroro mate pukupuku BC ki ngā rōpū taumata histological (G2 me G3) e ai ki te mana whakarerekētanga BRCA1 me te BRCA2 (ngā kaupapa WT, ngā kaikawe BRCA1 me te BRCA2 PV).
Waihoki, i tirotirohia e mātou mēnā he hononga te taumata pukupuku ki te aroaro o te BRCA1/2 PV. Nā te mea kāore a G1 BC i roto i tō mātou taupori, i wehea e mātou ngā tūroro kia rua ngā rōpū (G2, G3 rānei). E ai ki ngā hua Ki-67, i whakaatuhia e te tātaritanga he hononga nui i waenga i te taumata pukupuku me te whakarerekētanga BRCA1, me te nui ake o te ōwehenga o ngā pukupuku G3 i roto i ngā kaikawe BRCA1 ki te whakataurite ki ngā mea kāore e kaikawe (p<0.005) (Pikitia 5B).
Nā ngā whanaketanga o te hangarau raupapatanga ira kua taea ai ngā whanaketanga onge i roto i te whakamātautau ira BRCA1/2, me ngā pānga nui ki ngā tūroro he hītori whānau o te mate pukupuku. Tae noa ki tēnei wā, tata ki te 20,000 ngā momo BRCA1/2 kua tautuhia, kua whakarōpūtia hoki e ai ki te American Society of Medical Genetics 35 me te pūnaha ENIGMA.35,36 E mōhiotia whānuitia ana ko te whānuitanga o ngā whakarerekētanga BRCA1/2 he rerekē puta noa i ngā rohe matawhenua.37 I roto i Itari, ko te tere o ngā PV BRCA1/2 i waenga i te 8% ki te 37%, e whakaatu ana i te rerekētanga whānui i roto i te whenua.38,39 Me te taupori tata ki te 5 miriona, ko Sicily te tuarima o ngā rohe nui rawa atu i Itari e pā ana ki te maha o ngā kainoho. Ahakoa kei reira ngā raraunga mō te tohatoha o te BRCA1/2 i te taha hauauru o Sicily, kāore he taunakitanga whānui i te taha rawhiti o te moutere.
Ko tā mātou rangahau tētahi o ngā pūrongo tuatahi mō te auau o te BRCA1/2 PV i roto i ngā tūroro BC i te rawhiti o Sicily.28 I arotahi tā mātou tātaritanga ki te BC, nā te mea koinei te mate tino noa i roto i tā mātou rōpū.
I te whakamātautau i ngā tūroro BC 389, 9% i mau i ngā BRCA1/2 PV, i tohatohahia ōrite i waenga i te BRCA1 me te BRCA2. He rite tonu ēnei hua ki ngā mea i pūrongohia i mua i roto i te taupori Itari.28 He mea whakamīharo, 3% (13/389) o tā mātou rōpū he tāne. He teitei ake tēnei reiti i te mea i tumanakohia mō te mate pukupuku ū tāne (1% o ngā BC katoa),40 e whakaata ana i tā mātou kōwhiringa o ngā taupori i runga i te mōrearea o te whakarerekētanga BRCA1/2. Heoi, kāore tētahi o ēnei tāne i whakawhanake i te BRCA1/2 PV, nō reira he kaitono rātou mō ētahi atu tātaritanga ngota hei whakakore i te aroaro o ngā whakarerekētanga iti ake te noa pērā i te PALB2, RAD51C me te D, me ētahi atu. I kitea ngā momo rerekē kāore i te tino mārama te hiranga i roto i te 7% o ngā kaupapa i kitea ai te BRCA2 VUS. Ahakoa tēnei hua he rite tonu ki ngā taunakitanga o mua.28,41,42
I tā mātou tātaritanga i te tohatoha o ngā momo ira BC i roto i ngā wāhine ira whakarerekē BRCA1/2, i whakaū mātou i ngā hononga e mōhiotia ana i waenga i te TNBC me te BRCA1 PV (58.8%) me waenga i te luminal B BC me te BRCA2 PV (55.6%).16,43 He rite tonu ngā pukupuku luminal A me te HER2+ i roto i ngā kaikawe BRCA1 me te BRCA2 PV ki ngā raraunga tuhinga o nāianei.16,43
Kātahi ka arotahi mātou ki te momo me te wāhi o te BRCA1/2 PV. I roto i tā mātou rōpū, ko te BRCA1 PV tino noa ko te c.5035_5039delCTAAT. Ahakoa i kī a Incorvaia me ētahi atu... kāore i whakaahua i tēnei momo rerekētanga i roto i tā rātou rōpū Sicilian, kua pūrongohia e ētahi atu kaituhi hei BRCA1 PV germline.34 He maha ngā BRCA1 PV i kitea i roto i tā mātou rōpū – hei tauira c.181T>G, c.514del, c.3253dupA me c.5266dupC – kua kitea i Sicily.28 O ēnei, e rua ngā whakarerekētanga taketake BRCA1 (c.181T>G me c.5266dupC) e kitea whānuitia ana i roto i ngā Hūrai Ashkenazi o te Rawhiti me te Waenganui o Ūropi (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian me Tiamana), 44,45 ā, i te United States me Argentina, i tautuhia tata nei hei "momo germline recurrent" i roto i ngā tūroro Itari me BC me OC. I tautuhia i mua te momo 34c.514del i roto i te 8 ngā tūroro mate pukupuku ū mai i te raki o Sicily i Palermo me Messina. He mea whakamere, tae noa ki a Incorvaia et al. i kitea te momo c.3253dupA i roto i ētahi whānau i Catania.28 Ko ngā PV BRCA2 tino kitea ko c.428dup, c.5851_5854delAGTT me te momo intronic c.8487+1G>A, kua pūrongohia ake nei 28 i roto i tētahi tūroro i Palermo me te c.428dup, c.5851_5854delAGTT PV i kitea i roto i ngā whare i te raki-mā-uru o Sicily, te nuinga i roto i ngā rohe o Trapani me Palermo, engari ko c.5851_5854delAGTT PV i kitea i roto i ngā whare i te raki-mā-uru o Sicily. Ko te momo 8487+1G>A he mea noa ake i roto i ngā kaupapa mai i Messina, Palermo, me Caltanissetta.28 Rebbeck et al. i whakaahuahia i mua te whakarerekētanga c.5851_5854delAGTT i Colombia.37 Kua kitea tētahi atu BRCA2 PV, c.631+1G>A, i roto i ngā tūroro BC me OC mai i Sicily (Agrigento, Siracusa me Ragusa).28 He mea nui, i kite mātou i te noho tahi o ngā momo BRCA2 e rua (BRCA2 c.631G>A me c.7008-2A>T) i roto i te tūroro kotahi, i whakaarohia e mātou he wehewehe i roto i te aratau cis, e ai ki te pūrongo o mua.34,46 He maha tonu te kitenga o ēnei whakarerekētanga BRCA2 i te rohe o Itari, ā, kua kitea he whakauru i ngā codon aukati wawe, ka pā ki te hononga RNA karere, ā, ka kore e angitu te pūmua BRCA2.47,48
I maherehia hoki e mātou ngā PV BRCA1 me BRCA2 i roto i ngā rohe OCCR me BCCR pea o ngā rohe pūmua me ngā ira. I whakaahuahia ēnei rohe e Rebbeck et al. hei wāhi mōrearea mō te whakawhanake i te mate pukupuku ovarian me te mate pukupuku ū.49 Heoi, kei te tautohetia tonu ngā taunakitanga e pā ana ki te hononga i waenga i te wāhi o ngā momo germline me te mōrearea o te mate pukupuku ū, ovarian rānei.28,50-52 I roto i tō mātou taupori, ko ngā PV BRCA1 te nuinga kei roto i te rohe BCCR, ko ngā PV BRCA2 ia kei roto i te rohe OCCR. Heoi, kāore i kitea e mātou he hononga i waenga i ngā rohe OCCR me BCCR pea me ngā āhuatanga BC. Tērā pea nā te iti o te maha o ngā tūroro me ngā whakarerekētanga BRCA1/2. Mai i te tirohanga rohe pūmua, ka tohatohahia ngā PV BRCA1 puta noa i te pūmua katoa, ā, ko ngā whakarerekētanga BRCA2 ka kitea i roto i te rohe tukurua BRC.
Hei whakamutunga, i honoa e mātou ngā āhuatanga haumanu o BC ki te BRCA1/2 PV. Nā te iti o ngā tūroro i whakaurua mai, i kitea noa e mātou he hononga nui i waenga i te Ki-67 me te taumata pukupuku. Ahakoa he tautohetohe tonu te aromatawai me te whakamaoritanga o te Ki-67, he tino pono ko ngā reiti tipu teitei e pā ana ki te pikinga o te mōrearea o te hokinga mai o te mate me te hekenga o te oranga. Tae noa ki tēnei wā, ko te rohe mo te wehewehe i waenga i te "teitei" me te "iti" Ki-67 he 20%. Heoi, kāore tēnei paepae e pā ki tā mātou taupori tūroro whakarerekētanga BRCA1/2, he 25 te uara Ki-67 toharite. Ka taea te whakamārama i tēnei ia o ngā reiti Ki-67 teitei e te horapa i roto i ā mātou rōpū luminal B me TNBC, he iti noa iho ngā pukupuku luminal A i reira. Heoi, ko ētahi taunakitanga e kī ana ko te rohe Ki-67 teitei ake (25–30%) ka pai ake te wehewehe i ngā tūroro i runga i tā rātou matapae.53,54 Mai i ngā hua o tā mātou tātaritanga, ehara i te mea miharo te hononga nui. Ka puta i waenga i te Ki-67 teitei me ngā tohu me te aroaro o BRCA1 PV. Ina hoki, he rite tonu ngā pukupuku e pā ana ki te BRCA1 ki te TNBC, ā, he kaha ake ngā āhuatanga e whakaatuhia ana.16,17
Hei whakamutunga, ka whakaratohia e tēnei rangahau he pūrongo mō te tūnga whakarerekētanga o te BRCA1/2 i roto i tētahi rōpū BC mai i te rawhiti o Sicily. I te nuinga, he rite ā mātou kitenga ki ngā taunakitanga o mua, e pā ana ki te horapa o ngā whakarerekētanga me ngā āhuatanga haumanu mate i roto i te BC. He mea tika kia nui ake ngā rangahau i roto i ngā taupori nui ake o ngā tūroro BC whakarerekētanga BRCA1/2, pērā i te whakamahi i te tātaritanga whakarerekētanga whānui maha-ira, hei aromatawai i te aroaro o ngā PV he rerekē, he iti ake te auau i te BRCA1/2. Mā tēnei ka taea te tautuhi me te whakahaere tika i te maha o ngā tāngata e piki haere ana te mōrearea ki te mate pukupuku nā ngā whakarerekētanga ira.
I whakaū mātou i hainatia e ngā tūroro te whakaaetanga whai whakaaro kia tukuna ā-ingoatia ā rātou tauira pukupuku mō ngā kaupapa rangahau. I hainatia e ngā tūroro katoa te whakaaetanga whai whakaaro ā-tuhi e ai ki te Whakapuakitanga o Helsinki. E ai ki te kaupapa here a AOU Policlinico "G.Rodolico - S.Marco", i whakawāteatia tēnei rangahau i te arotake matatika nā te mea i mahia te tātaritanga BRCA1/2 e ai ki ngā mahi haumanu, ā, i tukuna e ngā tūroro katoa te whakaaetanga whai whakaaro ā-tuhi. Ka whakaae hoki ngā tūroro ki te whakamahinga o ā rātou raraunga mō ngā kaupapa rangahau.
Ka mihi nui mātou ki a Ahorangi Paolo Vigneri mō tana āwhina i te tiaki i ngā tūroro mate pukupuku ū e ai ki te tono a te Komiti Matatika.
E ripoata ana a Federica Martorana i ngā honoraria mai i Istituto Gentili, Eli Lilly, Novartis, Pfizer. E kī ana ngā kaituhi kē atu kāore he taupatupatu pānga ki tēnei mahi.
1. Sung H, Ferlay J, Siegel RL, et al. Ngā Tatauranga Mate Pukupuku Ao 2020: E whakatau tata ana a GLOBOCAN i te auau me te matenga o te 36 mate pukupuku i roto i te 185 whenua huri noa i te ao. CA Cancer J Clin.2021;71(3):209-249.doi: 10.3322/caac.21660