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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 Sashen Magunguna na Jami'ar Liviazella da 1, Clinical Medicine a, Catania, 95123, Italiya;2 Cibiyar Gwajin Oncology da Hematology, AOU Policlinico "G.Rodolico - San Marco", Catania, 95123, Italiya;3 Likita Oncology, AOU Policlinico “G.Rodolico – San Marco”, Catania, 95123, Italiya;4 Medical Genetics, ARNAS Garibaldi, Catania, 95123, Italiya;5 Medicine Genetics, ASP, Syracuse, 96100, Italiya;6 Sashen Kimiyyar Halittu da Kimiyyar Halittu, Jami'ar Catania, Genetics Medical, Catania, Italiya, 95123;7Oasi Research Institute-IRCCS, Troina, 94018, Italiya Sadarwa: Stefania Stella, tel +39 095 378 1946, imel [email protected];[email protected] Manufar: Germline maye gurbi a cikin BRCA1 da BRCA2 da kafa nono ciwon daji (BC), ovary (OC) da kuma sauran hade da wani rai hadarin ciwon daji.Gwaji ga BRCA gene ne key to tantance mutum hadarin, kazalika da gano hanyoyin rigakafi a cikin masu dako lafiya da tela jiyya a cikin ciwon daji marasa lafiya.The prevalence na CABR data kasance a fadin CABR CABR data kasance a ko'ina cikin CABR CABR data a cikin marasa lafiya. Bambance-bambancen pathogenic a cikin iyalan Sicily, binciken da aka yi niyya na musamman na yawan jama'a a gabashin Sicily sun rasa. Manufar bincikenmu shine don bincika abubuwan da suka faru da kuma rarrabawar BRCA pathogenic germline gyare-gyare a cikin ƙungiyar marasa lafiya na BC daga gabashin Sicily da kuma tantance ƙungiyar su tare da ƙayyadaddun halayen BC ta hanyar amfani da tsarin tsarawa na gaba. (9%) yana da bambance-bambancen ƙwayoyin cuta na BRCA, 17 (49%) a cikin BRCA1 da 18 (51%) a cikin BRCA2.BRCA1 gyare-gyare suna da yawa a cikin marasa lafiya na BC sau uku, yayin da maye gurbin BRCA2 ya fi kowa a cikin marasa lafiya na BC. wani bayyani na matsayin maye gurbi na BRCA a cikin marasa lafiya na BC daga gabashin Sicily kuma sun tabbatar da muhimmancin nazarin NGS wajen gano marasa lafiya tare da BC na gado. Gabaɗaya, waɗannan bayanan sun yi daidai da shaidar da ta gabata ta goyan bayan gwajin BRCA don ingantaccen rigakafi da maganin ciwon daji a cikin masu ɗaukar maye gurbin.
Ciwon daji na nono (BC) shine mafi yawan malignancy a duk duniya kuma mafi yawan ciwon daji a cikin mata.1 Siffofin nazarin halittu da ke ƙayyade BC prognosis da halayyar asibiti an yi nazari sosai kuma an bayyana su a cikin lokaci. ration index Ki-67 da ƙari grade (G) .2 Haɗuwa da waɗannan masu canji sun gano nau'o'in BC masu zuwa: 1) Ciwon daji na Luminal, yana nuna ER da / ko PgR magana, sun hada da 75% na BCs. Wadannan ciwace-ciwacen ƙwayoyi sun kara rarraba zuwa Luminal A, lokacin da Ki-67 ya kasance ƙasa da 20% da HER2 mara kyau, ko kuma a sama da HER2, da kuma Luminal B2 a cikin 0% daidai, da kuma Luminal B2. ba tare da la'akari da ƙididdigar yaduwa ba;2) HER2 + ciwace-ciwacen daji waɗanda ke da ER da PgR marasa kyau amma suna nuna haɓakawar HER2. Wannan rukunin yana da kashi 10% na duk ciwon nono;3) Ciwon daji na nono sau uku (TNBC), wanda baya nuna ER da PgR magana da haɓaka HER2, yana da kusan 15% na ciwon nono.2-4
Daga cikin waɗannan nau'ikan nau'ikan nau'ikan BC, ƙimar ƙari da ƙididdigar haɓakawa suna wakiltar ma'aunin giciye-sashe waɗanda ke da alaƙa kai tsaye da kansu tare da tashin hankali da tsinkaye.5,6
Baya ga abubuwan da aka ambata a baya na kwayoyin halitta, rawar da aka gaji da aka gaji da suka gaji da 'yan ƙwayoyin cuta guda takwas (watau a cikin kumatun halittunan da suka gabata (IE, ATM, Brca1, Brca2, Chk2, P Alb2, Rad51C, da Rad51D) Da yake da alhakin hadarin BC.amgon wadannan halittu, Gerinafst da Brca1 / 2) ya nuna karfi sosai tare da sauran mawuyacin hali - ciki har da ovignacies, pcostate, percariat, prostate, pcostate , colorectal, da melanoma.rakana shekaru 13 zuwa 80 da haihuwa, cumilyics dace da BRCa1 pv.14 a cikin mata brca2 pv.14
Musamman ma, wani wallafe-wallafen kwanan nan ya nuna cewa hadarin BC ya dogara da nau'in PV. A gaskiya ma, idan aka kwatanta da bambance-bambancen ƙwayoyin cuta na ƙwayoyin cuta, bambance-bambancen rashin kuskure, musamman a cikin kwayoyin BRCA1, suna da alaƙa da rage haɗarin BC, musamman a cikin tsofaffi mata.15
Kasancewar BRCA1 ko BRCA2 PV yana da alaƙa da nau'o'in ilimin halitta da na asibiti. es.Wadannan ciwace-ciwacen sun fi yawa a cikin lumen B kuma yawanci suna faruwa a cikin tsofaffi.16-18 Musamman, maye gurbi a cikin BRCA1 da BRCA2 suna ƙara yawan jiyya ga takamaiman jiyya, ciki har da salts platinum da magungunan da aka yi niyya irin su poly (ADP-ribose) inhibitors polymerase (PARPi).19,20
A cikin 'yan shekarun da suka gabata, aiwatar da tsarin tsarawa na gaba (NGS) a cikin aikin asibiti ya ba da damar karuwar adadin marasa lafiya na BC don yin gwajin kwayoyin halitta don ciwon ciwon daji na ciwon daji, ciki har da BRCA1 / 2.21 A halin yanzu, ma'anar da aka dogara da ma'auni daidai game da tarihin iyali, alƙaluma, da halayen asibiti don mafi kyawun gano mutanen da suka cancanci gwaji a cikin CABR23. / 2 nunawa a cikin takamaiman yawan jama'a, yana nuna bambance-bambance a cikin yankuna na yanki.24-27 Ko da yake akwai rahotanni game da ƙungiyar BC a yammacin Sicily, ƙananan bayanai suna samuwa akan BRCA1/2 nunawa a gabashin Sicily.28,29
Mun bayyana a nan sakamakon germline BRCA1/2 nunawa a cikin marasa lafiya na BC daga gabashin Sicily, suna kara daidaita kasancewar BRCA1 ko BRCA2 maye gurbi tare da manyan sifofin asibiti na waɗannan ciwace-ciwacen.
An gudanar da wani nazari na baya-bayan nan a "Cibiyar gwajin Oncology da Hematology" a Asibitin Policlinico.Rodolico - San Marco a Catania.Daga Janairu 2017 zuwa Maris 2021, jimlar 455 marasa lafiya tare da nono da ovarian, melanoma, pancreatic ko prostate ciwon daji da aka gudanar a cikin binciken mu na CA2. rabon Helsinki, kuma duk mahalarta sun ba da izini a rubuce kafin nazarin kwayoyin halitta.
Halayen tarihin tarihi da ilimin halitta (ER, PgR, matsayi na HER2, Ki-67, da daraja) na BC an kimanta su a kan ainihin biopsy ko samfurori na tiyata, la'akari da abubuwan da ke tattare da ƙwayar ƙwayar cuta kawai. Bisa ga waɗannan halaye, an rarraba BCs kamar haka: luminal A (ER + da / ko PgR +, HER2-, Ki-67/20), HER2-, Ki-67/20, HER, luminal, 67, da 67-B. 7≥20%), luminal B-HER2+ (ER da/ko PgR +, HER2+), HER2+ (ER da PgR-, HER2+) ko sau uku korau (ER da PgR-, HER2-).
Kafin kimantawa BRCA1 da kungiyar B Brca1 da Brca2, da mambtenclining m da yawa ciki har da Oncoric Production don kowane mai haƙuri ya yanke gaban Brca1 da / ko Brca1.ko mutane tare da babban hadarin PV a cikin Siffology Gene na Italiya a cikin hadayar cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtukan cututtuka(ii) maza tare da BC;(iii) wadanda ke da BC da OC;(iv) matan da BC <36 shekaru, TNBC <60 shekaru, ko biyu BC <50 shekaru;(v) tarihin likita na sirri na BC <50 shekaru kuma aƙalla dangi na farko-digiri: (a) BC
An samo samfurin jini na 20 mL daga kowane mai haƙuri kuma an tattara shi a cikin tubes na EDTA (BD Biosciences) .An keɓe DNA na Genomic daga 0.7 mL dukan samfuran jini ta amfani da QIAsymphony DSP DNA Midi kit Isolation Kit (QIAGEN, Hilden, Italiya) bisa ga umarnin masana'anta kuma ya wuce ta Qubitmo 3 . ) Yi ƙididdigewa.Abubuwan wadatar da niyya da shirye-shiryen ɗakin karatu ana yin su ta hanyar Oncomine™ BRCA Research Assay Chef, shirye da za a loda su cikin Ion AmpliSeq™ Chef Reagents DL8 Kit don shirye-shiryen ɗakin karatu mai sarrafa kansa bisa ga umarnin masana'anta. Kit ɗin ya ƙunshi wuraren waha mai mahimmanci guda biyu na PCR waɗanda za a iya amfani da su don nazarin duk BRCA1 (NM_037) da 500000000000000000000000000000000000000000000000000000000000. A taƙaice, 15 µL na kowane samfurin DNA ɗin da aka diluted (10 ng) an ƙara shi a cikin faranti don shirya ɗakin karatu kuma an ɗora duk reagents da abubuwan amfani akan kayan aikin Ion Chef. , Amurka) bisa ga umarnin masana'anta. A ƙarshe, ana haɗa ɗakunan karatu daidai gwargwado a cikin bututun samfurin ɗakin karatu na Ion Chef™ (tubu ɗin barcoded) kuma an ɗora su a kan kayan aikin Ion Chef™. Suite (SmartSeq srl) da Ion Reporter Software.
Duk bambance-bambancen nomenclature sun bi ƙa'idodin yanzu na Ƙungiyar Bambancin Halittar Halittar Dan Adam, da ake samu akan layi (HGVS, http://www.hgvs.org/mutnomen) .Mahimmancin asibiti na BRCA1/2 bambance-bambancen an bayyana ta amfani da rarrabuwa na International Consortium ENIGMA (Shaida-Based Network for Interpreting Muorgma) https: // Irin su ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, da UMD. Rarraba ya haɗa da nau'ikan haɗari daban-daban guda biyar: benign (category I), mai yiwuwa benign (category II), bambance-bambancen rashin tabbas (VUS, nau'in III), mai yiwuwa pathogenic (category IV), da kuma pathogenic (category IV), da kuma pathogenic (category Vars wani tasiri na aiki akan kayan aikin mummuna). 0 bayanai.32
Don ba da mahimmancin mahimmanci na asibiti ga kowane VUS, an yi amfani da algorithms na hasashen furotin masu zuwa: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/) da Align-GVag.puta .php) .Bambance-bambancen da aka lasafta a matsayin aji na 1 da na 2 an dauki nau'in daji.
Sanger sequencing ya tabbatar da kasancewar kowane bambance-bambancen cututtuka. A taƙaice, an tsara nau'i-nau'i na musamman don kowane bambance-bambancen da aka gano ta hanyar amfani da BRCA1 da BRCA2 gene reference jerin (NG_005905.2, NM_007294.3 da NG_012772.3, NM_0300re PC). quencing.
Marasa lafiya waɗanda suka gwada mummunan ga BRCA1/2 gene an gwada su ta hanyar haɓaka bincike mai dogaro da yawa (MLPA) bisa ga umarnin masana'anta don tantance kasancewar manyan sake tsara kwayoyin halitta (LGR). zama samfuran ƙarawa, wanda ya ƙunshi keɓaɓɓen saiti na amplicon PCR, sannan an bincika su ta hanyar electrophoresis capillary da software na Cofalyser.Net tare da madaidaitan tebur na Cofalyser na musamman (www.mrcholland.com).
Zaɓuɓɓukan da aka zaɓa na likitan ilimin likitanci (ƙididdigar tarihin tarihi da Ki-67% proliferation index) an haɗa su tare da kasancewar BRCA1/2 PV, ƙididdiga ta amfani da software na Prism v. 8.4 ta amfani da ainihin gwajin Fisher yana ɗaukar p-darajar <0.05 don zama mahimmanci.
Tsakanin Janairu 2017 da Maris 2021, an bincika marasa lafiya 455 don germline BRCA1/2 maye gurbi. An yi gwajin maye gurbi a Cibiyar Nazarin Magungunan Oncology da Hematology na Asibitin Policlinico. Bisa ga ka'idar Sicilian (http://www.gurs.regione.sicilia.Vindic0.ith0. o 2020), Rodolico na Catania - San Marco” gabaɗaya, marasa lafiya 389 Akwai ciwon nono, kansar ovarian 37, kansar pancreatic 16, kansar prostate 8 da melanoma 5.Ana nuna rarraba marasa lafiya bisa ga nau'in ciwon daji da sakamakon bincike a cikin hoto na 1.
Hoto na 1 yana nuna ginshiƙi mai gudana wanda ke nuna bayyani na binciken. An gwada marasa lafiya tare da nono, melanoma, pancreatic, prostate, ko ciwace-ciwacen daji don maye gurbi a cikin kwayoyin BRCA1 da BRCA2.
Takaitacce: PVs, bambance-bambancen pathogenic;VUS, bambance-bambancen rashin tabbas;WT, jeri-nau'in BRCA1/2.
Mun zaɓi mayar da hankali kan karatunmu akan ƙungiyoyin ciwon daji na nono. Marasa lafiya suna da tsaka-tsakin shekaru 49 (na 23-89) kuma galibi mata ne (n=376, ko 97%).
Daga cikin waɗannan batutuwa, 64 (17%) suna da maye gurbi na BRCA1 / 2 kuma duk mata ne. Talatin da biyar (9%) suna da PV da 29 (7.5%) suna da VUS. Sha bakwai (48.6%) na 35 pathogenic bambance-bambancen ya faru a BRCA1 da 18 (51.4%) a cikin BRCA2, yayin da 51.4% (51.4%) a cikin BRCA2 (51.4%). BRCA2 (Hoto na 1 da 2) .LGR ba ya nan a cikin nazarin MLPA.
Hoto 2. Nazarin BRCA1 da BRCA2 maye gurbi a cikin 389 marasa lafiya na nono.(B) 389 marasa lafiya da ciwon nono talatin da biyar (9%) suna da BRCA1 / 2 pathogenic bambance-bambancen (PVs) . Daga cikinsu, 17 (48.6%) sun kasance masu ɗaukar BRCA1 PV (ja mai duhu) da 18 (51.4%) sun kasance masu ɗaukar BRCA2 (janye haske);(C) 29 (7.5%) na batutuwa 389 sun ɗauki VUS, 5 (17.2%) BRCA1 genes (duhu orange) da 24 (82.8%) BRCA2 genes (light orange).
Takaitacce: PVs, bambance-bambancen pathogenic;VUS, bambance-bambancen rashin tabbas;WT, jeri-nau'in BRCA1/2.
Mun yi bincike na gaba da yaduwar kwayoyin kwayoyin BC a cikin marasa lafiya tare da BRCA1 / 2 PV. Rarraba ya hada da 2 (5.7%) luminal A, 15 (42.9%) luminal B, 3 (8.6%) luminal B-HER2 +, 2 (5.7%) HER2 + da 13 (37.15%) luminal B. luminal B BC, 2 (11.8%) yana da cutar HER2 +, kuma 10 (58.8%) yana da TNBC. Tumor ba tare da maye gurbin BRCA1 ba ko dai luminal A ko luminal B-HER2 + (Hoto 3) . A cikin rukunin BRCA2-tabbatacce, 10 (55.6%), 3% luminal (55.6%) sun kasance luminal. 6.7%) TNBC da 2 (11.1%) sun kasance luminal A (Hoto 3) .Babu HER2 + ciwace-ciwacen da ke cikin wannan rukuni. Saboda haka, maye gurbin BRCA1 yana da yawa a cikin marasa lafiya na TNBC, yayin da BRCA2 gyare-gyare sun fi girma a cikin lumen B mutane.
Hoto 3 Ciwon daji na ciwon nono a cikin marasa lafiya tare da bambance-bambancen cututtuka a cikin BRCA1 da BRCA2.Histograms da ke nuna rarraba BRCA1- (duhu ja) da BRCA2- (janye haske) PVs a tsakanin nau'in kwayoyin halitta na ciwon nono.
Takaitacce: PVs, bambance-bambancen pathogenic;HER2 +, mai karɓar haɓakar haɓakar haɓakar ɗan adam 2 tabbatacce;TNBC, ciwon nono mara kyau sau uku.
Daga bisani, mun kimanta nau'in da kuma asalin halittar BRCA1 da BRCA2 PVs. A cikin BRCA1 PV, mun lura da 7 guda nucleotide bambance-bambancen (SNVs), 6 gogewa, 3 kwafi da shigar 1. Kawai maye gurbi (c.5522delG) yana wakiltar wani sabon ganowa.135 mafi yawan CT5 da aka gano a cikin c. AAT.Wannan canjin ya ƙunshi shafe biyar nucleotides (CTAAT) a cikin BRCA1 exon 15, sakamakon maye gurbin amino acid leucine ta tyrosine a codon 1679, kuma saboda fassarar frameshift tare da annabta madadin tasha codon gubar zuwa premature protein truncation. Duk sauran canje-canje da aka gano a cikin wani yanki na sputum. c.4357+1G>T) (Table 1).
Game da BRCA2 PV, mun lura da gogewar 6, 6 SNVs da 2 duplications. Babu wani canje-canje da aka samu ba sabon abu ba ne. Sauye-sauye guda uku sun sake dawowa a cikin yawan mu, c.428dup da c.8487 + 1G>A lura a cikin batutuwa 3, sannan kuma c.5851_5854delter a cikin C.5851_5854delter. a kan 5 na BRCA2, an annabta don encode wani tsattsauran ra'ayi, wanda ba ya aiki.C.8487 + 1G>A maye gurbi yana faruwa a cikin yankin intronic na BRCA2 intron 19 (± 1,2) kuma yana rinjayar jerin ra'ayi na splicing, wanda ya haifar da canzawa splicing wanda ya haifar da abnormal protein55 ko a.5. zuwa 4-nucleotide shafewa daga matsayi na nucleotide 5851 zuwa 5854 a cikin codeing exon 10 na BRCA2 gene kuma yana haifar da fassarar fassarar fassarar tare da tsinkayar madaidaicin tasha codon (p.S1951WfsTer) . ya haɗa da maye gurbin adenosine (A) a cikin BRCA2 exon 7 tare da guanine (G) dauke da nucleotide wanda ya haifar da canji na valine zuwa isoleucine a codon 211, isoleucine Amino acid amino acid ne mai kama da irin wannan canji. 2.Canjin c.7008-2A>T na iya haifar da kwafi da yawa na tsayi daban-daban. Bugu da ƙari, a cikin ƙungiyar BRCA2 PVs, 4 daga cikin 18 canje-canje (22.2%) sun kasance cikin ciki.
Sa'an nan kuma muka yi taswirar BRCA1 / 2 masu lalata maye gurbi a cikin yankuna masu aiki da yankunan da ke hade da furotin (Fig. 4) .A cikin jinsin BRCA1, 50% na PVs sun kasance a cikin yanki na ciwon nono na nono (BCCR), yayin da 22% na maye gurbi sun kasance a cikin gungun ciwon daji na ovarian (OCCR) (Fig. 4CA.7%). yanki da 42.8% na maye gurbi sun kasance a cikin OCCR (Fig. 4B) .Na gaba, mun kimanta wurin PV a cikin yankunan BRCA1 da BRCA2. Don furotin na BRCA1, mun sami PV guda uku a cikin madauki da yankunan coil coil, da kuma maye gurbi biyu a cikin yankin BRCT (Fig. 4CA2) . An gano canje-canje na intronic da 3 exonic a cikin oligo / oligosaccharide-binding (OB) da hasumiya (T) yankuna (Figure 4B).
Hoto 4 Tsarin tsari na BRCA1 da BRCA2 sunadaran da kuma ƙaddamar da bambance-bambancen ƙwayoyin cuta. Wannan adadi yana nuna rarraba BRCA1 (A) da BRCA2 (B) bambance-bambancen cututtuka a cikin marasa lafiya na nono. Ana nuna sauye-sauye na waje a cikin blue, yayin da bambance-bambancen intronic an nuna su a cikin orange. Tsawon mashaya yana wakiltar adadin lokuta da aikin CABRA1. furotin ya ƙunshi yanki na madauki (RING) da jerin ƙayyadaddun ƙayyadaddun makaman nukiliya (NLS), yanki na coiled-coil, yankin SQ/TQ cluster domain (SCD), da yankin BRCA1 C-terminal (BRCT) . da An NLS a gefen C. Yankunan da ake kira Yankin Ciwon Kankara na Nono (BCCR) da Yankin Ciwon daji na Ovarian (OCCR) ana nuna su a ƙasa.
Sa'an nan kuma mu bincika siffofin BC na asibiti wanda zai iya daidaitawa tare da kasancewar BRCA1 / 2 PV. An sami cikakkun bayanan asibiti don 181 BRCA1 / 2-marasa marasa lafiya (marasa masu ɗaukar nauyi) da duk masu ɗaukar kaya (n = 35) .Akwai daidaituwa tsakanin ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar cuta (n = 35).
Mun ƙididdige rarraba Ki-67 bisa ga matsakaici na ƙungiyarmu (25%, kewayon <10-90%). Abubuwan da ke da Ki-67 <25% an bayyana su a matsayin "ƙananan Ki-67", yayin da mutanen da ke da ƙima ≥ 25% suna dauke da "high Ki-67" . Muhimmancin Ki-67 . . Hoto 5A).
Hoto 5 Daidaitawar Ki-67 tare da rarraba daraja a cikin mata masu ciwon nono tare da kuma ba tare da BRCA1 da BRCA2 PVs ba. zuwa cikin rukunin tarihin tarihi (G2 da G3) bisa ga BRCA1 da matsayin maye gurbi na BRCA2 ( batutuwa WT, BRCA1 da BRCA2 PVs masu ɗaukar hoto).
Hakanan, mun bincika ko kumburin kumburi da kasancewar ƙididdigar ilimin tazari, da g3). 5b).
Ci gaban fasaha na jerin DNA ya ba da damar ci gaban da ba a taɓa gani ba a gwajin kwayoyin halitta na BRCA1/2, tare da mahimmancin tasiri ga marasa lafiya da tarihin iyali na ciwon daji. Ya zuwa yau, kusan 20.000 BRCA1/2 bambance-bambancen an gano kuma an rarraba su bisa ga American Society of Medical Genetics 35 da kuma tsarin ENIGMA sanannen yanki ne. 37 A cikin Italiya, adadin BRCA1 / 2 PV ya kasance daga 8% zuwa 37%, yana nuna bambancin cikin ƙasa.
Bincikenmu yana ɗaya daga cikin rahotanni na farko game da abin da ya faru na BRCA1 / 2 PV a cikin marasa lafiya na BC a gabashin Sicily.28 Mun mayar da hankali kan binciken mu akan BC, saboda wannan shine mafi yawan cututtuka a cikin ƙungiyarmu.
Lokacin gwada marasa lafiya na 389 BC, 9% sun ɗauki BRCA1 / 2 PVs, a ko'ina aka rarraba tsakanin BRCA1 da BRCA2. Waɗannan sakamakon sun yi daidai da waɗanda aka ruwaito a baya a cikin yawan mutanen Italiya. har abada, babu ɗayan waɗannan mutanen da suka haɓaka BRCA1 / 2 PV, don haka sun kasance 'yan takara don ƙarin nazarin kwayoyin halitta don kawar da kasancewar ƙananan maye gurbi kamar PALB2, RAD51C da D, da sauransu. An dawo da bambance-bambancen da ba su da tabbas a cikin 7% na batutuwa wanda BRCA2 VUS ya bayyana.
Lokacin da muka bincika rarraba nau'ikan kwayoyin halitta na BC a cikin BRCA1 / 2 mutant mata, mun tabbatar da sanannun ƙungiyoyi tsakanin TNBC da BRCA1 PV (58.8%) da kuma tsakanin luminal B BC da BRCA2 PV (55.6%) .16,43 The luminal A da HER2 + ciwace-ciwacen daji a cikin BRCA1 da kuma BRers4 data kasance wallafe-wallafen CA2.
Sa'an nan kuma mu mai da hankali kan nau'i da wurin BRCA1/2 PV. A cikin ƙungiyarmu, BRCA1 PV mafi yawan al'ada shine c.5035_5039delCTAAT.Ko da yake Incorvaia et al.Ba su bayyana wannan bambance-bambancen a cikin ƙungiyar Sicilian su ba, wasu mawallafa sun ba da rahoto a matsayin germline BRCA1 PV.34 An samo BRCA1 PV da yawa a cikin ƙungiyarmu - misali c.181T> G, c.514del, c.3253dupA da c.5266dupC - wanda aka samu a cikin Sicilia.1.1. T> G da c.5266dupC) ana samun su a cikin Yahudawa na Ashkenazi na Gabas da Tsakiyar Turai (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian da Jamusanci ), 44,45 da kuma, a Amurka da Argentina, an bayyana kwanan nan a matsayin "bambance-bambancen germline mai maimaitawa" a cikin marasa lafiya na Italiyanci tare da marasa lafiya na BC da 4c8 a baya an gano shi a cikin ciwon daji na 1. a Palermo da Messina. Abin sha'awa, har ma Incorvaia et al.sami bambance-bambancen c.3253dupA a wasu iyalai a cikin Catania.28 Mafi yawan wakilan BRCA2 PVs sune c.428dup, c.5851_5854delAGTT da bambance-bambancen intronic c.8487+1G>A, wanda aka ruwaito dalla-dalla 28 a cikin majiyyaci a Palermo tare da c.4555555555555555555555558 iyalai a arewa maso yammacin Sicily, galibi a cikin yankunan Trapani da Palermo, yayin da an lura da c.5851_5854delAGTT PV a gidaje a arewa maso yammacin Sicily. 8487+1G>Bambancin ya fi kowa a cikin batutuwa daga Messina, Palermo, da Caltanissetta.28 Rebbeck et al.A baya an kwatanta c.5851_5854delAGTT canji a Colombia.37 Wani BRCA2 PV, c.631 + 1G>A, an samo shi a cikin BC da marasa lafiya na OC daga Sicily (Agrigento, Siracusa da Ragusa) .28 Musamman, mun lura da haɗin kai na bambance-bambancen BRCA2 guda biyu (BRCA2 bambance-bambancen 317A) da c.8A. wanda muka zaci za a ware a yanayin cis, kamar yadda aka ruwaito a baya haka.34,46 Waɗannan sauye-sauyen BRCA2 da gaske ana lura da su a cikin yankin Italiya kuma an gano su gabatar da codons na dakatarwa da wuri, wanda ke shafar manzo RNA splicing kuma ya sa furotin BRCA2 ya kasa.47,48
Mun kuma tsara taswirar BRCA1 da BRCA2 PVs a cikin yankunan OCCR da BCCR na yankunan furotin da kwayoyin halitta.Rebbeck et al ya bayyana waɗannan yankuna.a matsayin wuraren haɗari don bunkasa ciwon daji na ovarian da nono. Yankunan OCCR da BCCR da sifofin BC. Wannan yana iya kasancewa saboda ƙarancin adadin marasa lafiya tare da maye gurbi na BRCA1/2. Daga ra'ayi na furotin, BRCA1 PVs ana rarraba tare da dukan furotin, kuma BRCA2 gyare-gyare sun fi dacewa a cikin yankin maimaita BRC.
A ƙarshe, mun haɗu da siffofi na asibiti na BC tare da BRCA1 / 2 PV. Saboda ƙarancin adadin marasa lafiya da aka haɗa, kawai mun sami daidaituwa mai mahimmanci tsakanin Ki-67 da ƙwayar ƙwayar cuta. Ko da yake ƙima da fassarar Ki-67 ya kasance da ɗan rikice-rikice, yana da tabbacin cewa yawan haɓakar haɓakawa suna haɗuwa da haɗarin haɗari na sake dawowa da cututtuka "tsakanin Ki-67" da kuma ragewa tsakanin Ki- 7 shine 20%. Duk da haka, wannan kofa ba ta shafi yawan mutation mutation na BRCA1 / 2, wanda ke da matsakaicin Ki-67 darajar 25% . Wannan yanayin a cikin babban Ki-67 rates za a iya bayyana ta da yawa a cikin mu luminal B da kuma TNBC cohorts, wanda 'yan luminal A ciwace-ciwacen daji sun kasance ba. Duk da haka, wasu shaidun da suka fi dacewa da su suna iya yankewa bisa ga Ki-6. gnosis.53,54 Daga sakamakon binciken mu, mahimmanci mai mahimmanci ba abin mamaki ba ne.Yana faruwa tsakanin babban Ki-67 da maki da kuma kasancewar BRCA1 PV. A gaskiya ma, ciwon daji na BRCA1 yana da alamun TNBC kuma yana nuna ƙarin siffofi masu banƙyama.16,17
A ƙarshe, wannan binciken ya ba da rahoto game da matsayi na maye gurbin BRCA1 / 2 a cikin ƙungiyar BC daga gabashin Sicily. Gabaɗaya, bincikenmu ya yi daidai da shaidar da aka rigaya ta kasance, duka cikin sharuddan maye gurbi da kuma sifofin asibiti a cikin BC. Ƙarin karatu a cikin manyan al'ummomi na BRCA1 / 2-mutant BC marasa lafiya, kamar yin amfani da garanti na mutage da yawa fiye da marasa lafiya na BC, wanda aka ba da garanti ga marasa lafiya da yawa. BRCA1 / 2. Wannan zai ba da damar ganewa da kulawa da kyau na yawan adadin batutuwa a cikin haɗarin ciwon daji saboda maye gurbin kwayoyin halitta.
Mun tabbatar da cewa marasa lafiya sun sanya hannu kan izini don sakin samfurorin ƙwayar cutar su ba tare da suna ba don dalilai na bincike. Duk marasa lafiya sun sanya hannu a kan takardar izinin da aka rubuta bisa ga sanarwar Helsinki. Bisa ga manufofin AOU Policlinico "G.Rodolico - S.Marco", an cire wannan binciken daga nazarin da'a saboda BRCA1 / 2 an ba da izini ga marasa lafiya da aka rubuta bisa ga binciken da aka yi amfani da su. na bayanan su don dalilai na bincike.
Mun gode wa Farfesa Paolo Vigneri saboda taimakon da ya bayar wajen kula da masu fama da ciwon nono kamar yadda Kwamitin Da'a ya nema.
Federica Martorana ta ba da rahoton karramawa daga Istituto Gentili, Eli Lilly, Novartis, Pfizer. Sauran marubutan sun ba da sanarwar wani rikici na sha'awa a cikin wannan aikin.
1. Sung H, Ferlay J, Siegel RL, et al.Kididdigar Ciwon Ciwon Kankara ta Duniya 2020: GLOBOCAN ta yi kiyasin kamuwa da cutar sankara 36 da mace-mace a kasashe 185 na duniya.CA Cancer J Clin.2021;71(3):209-249.doi: 16/03222
Lokacin aikawa: Afrilu-15-2022