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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, 12 Sashen Liviazella 1 da Clinical Manuniya Magunguna, Jami'ar Catania, Catania, 95123, Italiya; 2 Cibiyar Gwajin Oncology da Hematology, AOU Policlinico "G.Rodolico - San Marco", Catania, 95123, Italiya; 3 Medical 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 a ko'ina cikin yankunan da CABR1 data kasance a ko'ina cikin CABR. wanzu a kan BRCA pathogenic bambance-bambancen karatu a Sicilian iyalai, nazarin musamman niyya yawan jama'a a gabashin Sicily sun rasa. Manufar binciken mu shi ne don bincika abin da ya faru da kuma rarraba BRCA pathogenic germline gyare-gyare a cikin wani rukuni na BC marasa lafiya daga gabashin Sicily da kuma tantance su hade tare da takamaiman BC halaye ta yin amfani da gaba-tsara na ci gaba da ci gaba da ci gaba da ci gaba da ci gaba da ci gaba da ci gaba da ci gaba. index.RESULTS: Gabaɗaya, marasa lafiya na 35 (9%) suna 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-negative, yayin da BRCA2 maye gurbi sun fi kowa a cikin luminal luminal BC tare da bambance-bambancen bambance-bambancen marasa lafiya tare da marasa lafiya na BC1. mafi girma ƙari grade da kuma haɓaka index.Kammalawa: Abubuwan da muka samo suna ba da bayyani game da matsayi na maye gurbin BRCA a cikin marasa lafiya na BC daga gabashin Sicily kuma sun tabbatar da muhimmancin nazarin NGS don gano marasa lafiya tare da gado na BC. Gabaɗaya, waɗannan bayanan sun yi daidai da shaidar da ta gabata da ke goyan bayan gwajin BRCA don dacewa da rigakafi da maganin ciwon daji a cikin masu ɗaukar maye gurbin.
Ciwon daji na nono (BC) shine mafi yawan mummunan cututtuka a duniya da kuma ciwon daji mafi muni 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. haɓakawa, haɓakar haɓakar Ki-67 da ƙwayar ƙwayar cuta (G) .2 Haɗin waɗannan sauye-sauye sun gano nau'ikan BC masu zuwa: 1) Ciwon daji na Luminal, yana nuna ER da / ko PgR magana, sun hada da 75% na BCs. Wadannan ciwace-ciwacen sun kara rarraba zuwa Luminal A, lokacin da Ki-67 ya kasance ƙasa da 20% ko kuma HER2 a sama, da kuma Luminal 2 a sama, da kuma Luminal 2 a sama da 20%. a gaban haɓakawar HER2, ba tare da la'akari da ƙididdigar haɓaka 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 sifofin halittun da aka ambata a baya, rawar da ke tattare da sauye-sauyen kwayoyin halitta wanda ke haifar da ci gaban BC ya zama mai mahimmanci a cikin 'yan shekarun da suka gabata.7 Game da 1 a cikin 10 ciwon nono ana gadon su saboda sauye-sauyen kwayoyin halitta a cikin takamaiman kwayoyin halitta.8 Manyan cututtukan cututtuka guda biyu da suka hada da fiye da 180,000 mata, BARD, BRie, 8, BRie, BRIE, BRIE, BRIE, BRIE, BRIE, BRIE, BRIE, BRIE, BRIE, BRD, BRIE, BRIE, BRIE, BRD, BR, BR, 1, BRD. BRCA2, CHK2, PALB2, RAD51C, da RAD51D) da farko alhakin gadon BC. Daga cikin wadannan kwayoyin halitta, BRCA1 da BRCA2 (nan gaba ake magana a kai a matsayin BRCA1 / 2) ya nuna mafi karfi dangantaka da ci gaban nono ciwace-ciwacen daji. Malignancies, ciki har da ovarian, prostate, pancreatic, colorectal, da melanoma.Daga shekaru 13 zuwa 80 shekaru, yawan abin da ya faru na BC shine 72% a cikin mata tare da BRCA1 pathogenic variant (PV) da 69% a cikin mata masu 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. alamun haɓakawa.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) polymerase inhibitors (PARPi).19,20
A cikin 'yan shekarun da suka gabata, aiwatar da tsarin tsarawa na gaba (NGS) a cikin aikin likita 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 danganta da ma'auni daidai game da tarihin iyali, alƙaluma, da halayen asibiti don mafi kyawun gano mutanen da suka cancanci gwadawa a cikin CA23. akan BRCA1 / 2 nunawa a cikin ƙayyadaddun 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 gwaji na Oncology da Hematology" a Asibitin Policlinico.Rodolico - San Marco a Catania.Daga Janairu 2017 zuwa Maris 2021, jimlar 455 marasa lafiya da nono da ovarian, melanoma, pancreatic ko prostate ciwon daji da aka gudanar a cikin binciken mu na kwayoyin CA2. daidai da sanarwar 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 core biopsy ko samfurori na tiyata, la'akari da abubuwan da ke tattare da ƙwayar cuta kawai. Bisa ga waɗannan halaye, an rarraba BCs kamar haka: luminal A (ER + da / ko PgR +, HER2-, Ki-67/20%), ER, 67/20% da B + luminal. HER2-, Ki-67≥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 (The QubitFicient 3). Waltham, MA, Amurka) Yi ƙididdigewa. Abubuwan wadatar da niyya da shirye-shiryen ɗakin karatu ana yin su ta hanyar Oncomine™ BRCA Research Assay Chef, a shirye don lodawa a 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 na PCR guda biyu waɗanda za a iya amfani da su don nazarin duk BRCA1 (NM_030730) (NM_000059.3) genes. A taƙaice, 15 µL na kowane samfurin DNA da aka diluted (10 ng) an saka shi a cikin faranti don shirya ɗakin karatu kuma an ɗora duk reagents da abubuwan amfani akan kayan aikin Ion Chef. 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, Amurka) bisa ga umarnin masana'anta. A ƙarshe, ana haɗa ɗakunan karatu daidai gwargwado a cikin bututun samfurin ɗakin karatu na Ion Chef™ (tubunan barcoded) kuma an ɗora su akan kayan aikin Ion Chef. wani Ion 510 Chip (Thermo Fisher Scientific) .An yi nazarin bayanai ta Amplicon 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 Fassarar Allegeni. tuntuɓar bayanai daban-daban kamar ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, da UMD. Rarraba ya ƙunshi nau'ikan haɗari daban-daban guda biyar: benign (category I), mai yiwuwa mara kyau (category II), bambance-bambancen rashin tabbas (VUS, nau'in III), mai yuwuwa pathogenic (category IV), da kuma Vutan sakamako na furotin. aiki, kayan aiki mai ba da labari tare da samun dama ga bayanan bayanai 30.32
Don sanya yuwuwar mahimmancin 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-GVGD (http://agvgd.hci.utah.edu/agvgd_input.php) .Bambance-bambancen da aka rarraba a matsayin aji na 1 da 2 an ɗauke su nau'in daji.
Tsarin Sanger 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). Sanger ya biyo baya.
Marasa lafiya waɗanda suka gwada mummunan ga ƙwayar BRCA1/2 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). nucleotides a tsayi.Kayayyakin haɓakawa, wanda ya ƙunshi saiti na musamman na amplicon PCR, sannan an bincika su ta hanyar electrophoresis capillary da software na Cofalyser.Net tare da takamaiman 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.siciep1.ith0). 10 Gennaio 2020), Rodolico na Catania - San Marco "gaba ɗaya, 389 marasa lafiya Akwai ciwon nono, ciwon daji na ovarian 37, ciwon daji na pancreatic 16, ciwon prostate 8 da melanoma 5. Ana nuna rarraba marasa lafiya bisa ga nau'in ciwon daji da sakamakon bincike a cikin Hoto 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 cikin BRCA1 da 18 (51.4%) a cikin BRCA2, yayin da 51.4% (51.4%) a cikin BRCA2. (82.8%) a cikin BRCA2 (Hoto na 1 da 2) .LGR bai kasance a cikin nazarin MLPA ba.
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.
Mu na gaba mun bincika yawancin nau'in kwayoyin halitta na 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%) Tmopositive B. (29.4%) yana da haske B BC, 2 (11.8%) yana da cutar HER2 +, kuma 10 (58.8%) yana da TNBC. Tumors ba tare da maye gurbin BRCA1 sun kasance ko dai luminal A ko luminal B-HER2 + (Figure 3) . A cikin BRCA2-tabbatacce subgroup, 10 (53%) sun kasance luminal. luminal B-HER2 +, 3 (16.7%) TNBC da 2 (11.1%) sun kasance luminal A (Figure 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 canje-canje sun kasance masu rinjaye 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. Mutation ɗaya kawai (c.5522del PV) yana wakiltar sabon ganowa. c.5035_5039delCTAAT. Wannan canjin ya ƙunshi shafe biyar nucleotides (CTAAT) a cikin BRCA1 exon 15, sakamakon maye gurbin amino acid leucine da tyrosine a codon 1679, kuma saboda fassarar frameshift tare da wani madadin tasha codeon gubar, ba a iya gano daya kawai wani protin. PVs da aka ruwaito sun kasance a cikin yanki na haɗin gwiwar yanki (c.4357 + 1G> T) (Table 1).
Game da BRCA2 PV, mun lura da gogewar 6, 6 SNVs da 2 kwafi. Babu wani canje-canjen da aka samu ba sabon abu ba ne. Sauye-sauyen maye gurbi guda uku sun sake faruwa a cikin yawan mu, c.428dup da c.8487 + 1G>A lura a cikin batutuwa 3, ya biyo bayan c.5851_5854delAG a cikin TT 8. sake maimaita C a cikin exon 5 na BRCA2, an annabta don shigar da wani tsattsauran ra'ayi, furotin da 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 sauye-sauyen furotin ko haifar da rashin lafiya. c.5851_5854delAGTT pathogenic bambance-bambancen ne saboda 4-nucleotide shafewa daga nucleotide matsayi 5851 zuwa 5854 a cikin codeing exon 10 na BRCA2 gene da kuma sakamakon a cikin wani fassarar frameshift tare da annabta madadin tasha codon (p.S1951Wfs) a baya, c. da c.7008-2A>T an gano su a cikin majiyyaci guda.34 Maye gurbin farko ya ƙunshi maye gurbin adenosine (A) a cikin BRCA2 exon 7 tare da guanine (G) mai dauke da nucleotide wanda ya haifar da canji na valine zuwa isoleucine a codon 211, isoleucine Amino acid shine amino acid wanda yake da tasiri mai mahimmanci a cikin nau'i na biyu. yankin intronic kuma yana haifar da sau biyu A zuwa thymine (T) maye gurbin kafin exon 13 na gene encoding BRCA2. Canjin c.7008-2A>T na iya haifar da rubutun da yawa na tsayi daban-daban. Bugu da ƙari, a cikin rukuni na BRCA2 PVs, 4 daga 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 yanki na ciwon daji na ovarian (OCCR) (Fig. 4CA.7%). a cikin yankin BCCR 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. Ga furotin na BRCA1, mun sami PV guda uku a cikin madauki da coiled coil domains, da kuma maye gurbi biyu a cikin yankin BR4CA2. zuwa yankin maimaita BRC, yayin da aka gano 3 intronic da 3 exonic canje-canje a cikin oligo/oligosaccharide-binding (OB) da hasumiya (T) domains (Hoto 4B).
Hoto 4 Tsarin tsari na BRCA1 da BRCA2 sunadaran da kuma ƙaddamar da bambance-bambancen cututtuka. 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 su na CABRA. Sunan furotin na BRCA1 ya ƙunshi yanki na madauki (RING) da jerin ƙayyadaddun ƙayyadaddun ƙayyadaddun makaman nukiliya (NLS), yanki mai naɗaɗɗen murɗa, yankin gungu na SQ / TQ (SCD), da yankin BRCA1 C-terminal (BRCT) . folds, a Tower domain (T), da An NLS a gefen C. Yankunan da ake kira Breast Cancer Cluster Region (BCCR) da Ovarian Cancer Cluster Region (OCCR) ana nuna su a kasa.
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 ƙimar ≥ 25% suna dauke da "high Ki-67" Masu ɗaukar PV (Fig. 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. na BC masu fama da ciwon daji a cikin rukunin tarihin tarihi (G2 da G3) bisa ga BRCA1 da matsayin maye gurbin BRCA2 ( batutuwa WT, BRCA1 da BRCA2 PVs masu ɗaukar hoto).
Hakanan, munyi nazari ko kumburin berca1 / 2 PV.Souse na ƙididdiga zuwa rukuni biyu (G2 ko g3). (p<0.005) (Hoto na 5B).
Ci gaban fasaha na jerin DNA ya ba da damar ci gaban da ba a taɓa gani ba a cikin gwajin kwayoyin halitta na BRCA1/2, tare da mahimman abubuwan da ke da alaƙa ga marasa lafiya da tarihin iyali na ciwon daji.Ya zuwa yau, an gano kusan 20.000 BRCA1/2 bambance-bambancen kuma an rarraba su bisa ga American Society of Medical Genetics 35 da kuma tsarin ENIGMA da aka sani da yawa. a fadin yankuna na geographic.37 A cikin Italiya, adadin BRCA1 / 2 PV ya kasance daga 8% zuwa 37%, yana nuna bambancin yanayi na cikin gida. tsibirin.
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 gwajin 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 Italiya. Duk da haka, babu ɗayan waɗannan mutanen da suka haɓaka BRCA1 / 2 PV, don haka sun kasance 'yan takara don ƙarin nazarin kwayoyin halitta don yin watsi da kasancewar ƙananan maye gurbi irin su PALB2, RAD51C da D, da sauransu. An dawo da bambance-bambancen da ba su da tabbas a cikin 7% na batutuwa a cikin abin da BRCA2 VUS ya kasance tabbatacce, yana da tabbacin 2.
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 su ta Sicilian ba, wasu mawallafa sun ba da rahoto a matsayin germline BRCA1 PV.34 An sami BRCA1 da yawa PVs a cikin ƙungiyarmu - misali c.181T>G, c.514del, c.3253dupA da c.5266dupC - waɗanda aka lura da su a cikin SiBR18. (c.181T>G da c.5266dupC) yawanci ana samun su a cikin Yahudawan Ashkenazi na Gabas da Tsakiyar Turai (Poland, Czech), Slovenia, Austrian, Hungarian, Belarusian da Jamusanci), 44,45 kuma, a cikin Amurka da Argentina, an bayyana kwanan nan a matsayin "bambance-bambancen germline mai maimaitawa" a cikin marasa lafiya na Italiyanci 4.5. a cikin 8 marasa lafiya na nono daga arewacin Sicily 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 ciki na c.8487+1G>A, wanda aka ruwaito daki-daki 28 a cikin majiyyaci a Palermo tare da c.458 An lura da PV a gidaje a arewa maso yammacin Sicily, musamman a 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 canjin c.5851_5854delAGTT 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 ma, mun lura da haɗin kai na bambance-bambancen BRCA2 guda biyu (BRCA2) da 3172 c. a cikin majiyyaci guda ɗaya, wanda muka ɗauka cewa za a ware shi a yanayin cis, kamar yadda aka ruwaito a baya kamar haka.34,46 Waɗannan sauye-sauyen BRCA2 na gaske ana lura da su akai-akai a cikin yankin Italiya kuma an gano su gabatar da codons na dakatarwa da wuri, yana rinjayar manzo RNA splicing kuma yana haifar da 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, bi da bi.49 Duk da haka, shaida game da haɗin gwiwa tsakanin wurin da bambance-bambancen germline da nono ko ciwon daji na ovarian ya kasance mai rikitarwa. haɗin gwiwa tsakanin yankunan OCCR da BCCR da aka saka da kuma siffofi na BC. Wannan yana iya zama saboda iyakanceccen adadin marasa lafiya tare da maye gurbi na BRCA1 / 2. Daga ra'ayi na furotin, BRCA1 PVs an rarraba tare da dukan furotin, kuma BRCA2 gyare-gyare an fi dacewa da samuwa 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 dangantaka mai mahimmanci tsakanin Ki-67 da ƙari. "ƙananan" Ki-67 shine 20%. Duk da haka, wannan kofa ba ta shafi yawan mutation na BRCA1 / 2 mutation na haƙuri ba, 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 TNBC cohorts, wanda 'yan luminal A ciwace-ciwacen daji sun kasance mafi girma shaida Ki-Ta yaya 6 ya nuna cewa 6. (25-30%) na iya ƙulla marasa lafiya mafi kyau bisa ga hasashen su.53,54 Daga sakamakon bincikenmu, babban mahimmanci ba abin mamaki ba ne.Yana faruwa tsakanin babban Ki-67 da maki da kuma kasancewar BRCA1 PV. A gaskiya ma, BRCA1 da ke da alaka da ciwace-ciwacen ƙwayoyi suna da alamun TNBC kuma suna nuna ƙarin siffofi masu tsanani.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 yawan jama'a na BRCA1 / 2-mutant BC marasa lafiya, kamar yin amfani da garanti na mutagenome na marasa lafiya na BC, kamar yadda aka yi amfani da mutagenome bincike. daban-daban da ƙasa da yawa fiye da BRCA1 / 2. Wannan zai ba da damar ganewa da kuma kula da yadda ya dace na yawan adadin batutuwa a cikin haɗarin ciwon daji saboda maye gurbin kwayoyin halitta.
Mun tabbatar da cewa marasa lafiya sun sanya hannu kan yarda don sakin samfuran 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 bita na ɗabi'a saboda BRCA1 / 2 an ba da rahoton aikin asibiti bisa ga bayanan asibiti. yarda da yin amfani da bayanansu 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
