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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, 6 Marco Fichera 2 Experimental Clinic, Maperitanial Clinic, 1 Department of 1 Medical Clinic , Catania, 95123, Italy;2 Center for Experimental Oncology and Hematology, AOU Policlinico "G.Rodolico - San Marco", Catania , 95123, Italy;3 Medical Oncology, AOU Policlinico “G.Rodolico - San Marco", Catania, 95123, Italy;4 Medical Genetics, ARNAS Garibaldi, Catania, 95123, Italy;5 Mankhwala Genetics, ASP, Syracuse, 96100, Italy;6 Dipatimenti ya Biomedical and Biotechnology Sciences, University of Catania, Medical Genetics, Catania, Italy, 95123;7Oasi Research Institute-IRCS, Troina, 94018, Italy Communications: Stefania Stella, telefoni +39 095 378 1946, imelo [imelo yotetezedwa];[imelo yotetezedwa] Cholinga: Kusintha kwa majeremusi ku BRCA1 ndi BRCA2 ndikukhazikitsa khansa ya m'mawere (BC), ovary (OC) ndi zina zomwe zimagwirizanitsidwa ndi chiopsezo cha moyo wonse wa khansa. BRCA pathogenic mitundu m'mabanja a ku Sicily, maphunziro okhudza makamaka anthu a kum'mawa kwa Sicily akusowa. Odwala a 5 (9%) anali ndi BRCA pathogenic variable, 17 (49%) mu BRCA1 ndi 18 (51%) mu BRCA2.BRCA1 zosintha ndizofala kwambiri mwa odwala atatu omwe alibe BC, pamene kusintha kwa BRCA2 kumakhala kofala kwambiri kwa odwala BC. BRCA mutational status in BC odwala ochokera kum'mawa kwa Sicily ndikutsimikizira udindo wa NGS kusanthula pozindikira odwala omwe ali ndi cholowa cha BC.Ponseponse, detayi ikugwirizana ndi umboni wam'mbuyo womwe umatsimikizira BRCA kuyesa kupewa ndi kuchiza khansa kwa onyamula masinthidwe.
Khansara ya m'mawere (BC) ndi matenda omwe amapezeka kwambiri padziko lonse lapansi komanso khansa yakufa kwambiri kwa amayi.1 Zomwe zimapangidwira zomwe zimatsimikizira kuti BC prognosis ndi khalidwe lachipatala zakhala zikuphunziridwa mozama ndipo zadziwika pang'ono pakapita nthawi.Zowonadi, zizindikiro zingapo zomwe zimagwiritsidwa ntchito popanga BC m'magulu osiyanasiyana a molecular subtypes.Iwo ndi estrogen (ER) ndi / kapena estrogen kukula kwa progesterone, epilife2 receptor (progestination) ration index Ki-67 ndi chotupa grade (G) .2 Kuphatikizika kwa mitunduyi kunazindikiritsa magulu otsatirawa a BC: 1) Zotupa za luminal, kusonyeza ER ndi / kapena PgR mawu, amawerengera 75% ya BCs. Zotupazi zinagawidwanso kukhala Luminal A, pamene Ki-67 inali pansi pa 20% ndi HER2 zoipa, ndipo Luminal B, pamene 0 ndi HER2 kukhalapo kwa HER2 inali yofanana ndi HER2%, pamene HER2 ndi HER2% , pamene HER2 analipo ndi 20% ya HER2. index;2) HER2 + zotupa zomwe ziri ER ndi PgR zoipa koma zimasonyeza HER2 kukulitsa. Gululi limapanga 10% ya zotupa za m'mawere;3) Khansa ya m'mawere ya katatu (TNBC), yomwe sikuwonetsa ER ndi PgR kufotokozera ndi HER2 kukulitsa, imakhala pafupifupi 15% ya khansa ya m'mawere.2-4
Pakati pa ma subtypes a BC awa, kalasi ya chotupa ndi index yowonjezereka imayimira ma biomarkers omwe amalumikizana mwachindunji ndi modziyimira pawokha ndi kuwopsa kwa chotupa ndi kuneneratu.5,6
Kuphatikiza pa zinthu zomwe tatchulazi, udindo wa kusintha kwa majini omwe amachokera ku chitukuko cha BC chakhala chofunikira kwambiri pazaka zingapo zapitazi.7 Pafupifupi 1 pa 10 zotupa za m'mawere zimatengera chifukwa cha kusintha kwa majeremusi m'majini enieni. K2, PALB2, RAD51C, ndi RAD51D) makamaka omwe ali ndi udindo wa cholowa cha BC. Pakati pa majiniwa, BRCA1 ndi BRCA2 (pambuyo pake amatchedwa BRCA1 / 2) adawonetsa mgwirizano wamphamvu kwambiri ndi kukula kwa zotupa za m'mawere.9-12 Ndipotu, majeremusi a BRCA1 / 2 monga kusintha kwa moyo, kusintha kwa moyo wa BRCA1 / 2, kuphatikizapo kusintha kwa moyo wa prognac, kusintha kwa moyo wapang'onopang'ono kumawonjezeka kwambiri. Ectal, ndi melanoma.Kuyambira zaka 13 mpaka zaka 80, kuchuluka kwa BC ndi 72% mwa amayi omwe ali ndi BRCA1 pathogenic variant (PV) ndi 69% mwa amayi omwe ali ndi BRCA2 PV.14
Zochititsa chidwi, zofalitsa zaposachedwa zikusonyeza kuti chiopsezo cha BC chimadalira mtundu wa PV. Ndipotu, poyerekeza ndi mitundu yosiyanasiyana ya pathogenic truncating, glaring missense mitundu, makamaka mu jini ya BRCA1, imagwirizana ndi kuchepetsa chiopsezo cha BC, makamaka kwa amayi achikulire.15
Kukhalapo kwa BRCA1 kapena BRCA2 PV kunkagwirizana ndi zinthu zosiyanasiyana zamoyo ndi zachipatala.16,17 BRCA1-zogwirizana ndi BCs zimakhala zaukali, zosiyanitsidwa bwino, komanso zowonjezereka.Zotupazi nthawi zambiri zimakhala zoipa katatu ndipo zimakhala ndi zaka zoyambira. se zotupa zimakhala zofala kwambiri mu lumen B ndipo nthawi zambiri zimachitika kwa okalamba.16-18 Mwachidziwitso, kusintha kwa BRCA1 ndi BRCA2 kumawonjezera kukhudzidwa kwa mankhwala apadera, kuphatikizapo mchere wa platinamu ndi mankhwala omwe akugwiritsidwa ntchito monga poly(ADP-ribose) polymerase inhibitors (PARPi) .19,20
Kwa zaka zingapo zapitazi, kukhazikitsidwa kwa mibadwo yotsatira (NGS) m'zachipatala kwathandiza kuti chiwerengero chowonjezeka cha odwala BC ayesedwe ndi maselo a khansa, kuphatikizapo BRCA1 / 2.21 Nthawi yomweyo, matanthauzo okhudzana ndi mbiri ya banja, chiwerengero cha anthu, ndi zizindikiro zachipatala kuti adziwe bwino anthu omwe ali ndi vuto la 23 BRCA1 / BRCA1 / 222. Kuwunika kwa BRCA1 / 2 m'magulu enaake, kuwonetsa kusiyana pakati pa madera.24-27 Ngakhale kuti pali malipoti a BC cohort kumadzulo kwa Sicily, deta yocheperapo ikupezeka pa BRCA1 / 2 kuyang'ana kummawa kwa anthu a ku Sicily.28,29
Tikufotokoza apa zotsatira za kuwunika kwa majeremusi a BRCA1/2 mwa odwala BC ochokera kum'mawa kwa Sicily, kulumikizanso kukhalapo kwa kusintha kwa BRCA1 kapena BRCA2 ndi mbali zazikulu zachipatala za zotupazi.
Kafukufuku wobwerezabwereza adachitika ku "Center for Experimental Oncology and Hematology" pachipatala cha Policlinico.Rodolico - San Marco ku Catania.Kuyambira Januwale 2017 mpaka Marichi 2021, odwala 455 omwe ali ndi khansa ya m'mawere ndi ovarian, melanoma, pancreatic kapena prostate adatumizidwa ku kafukufuku wathu wamamolekyulu a BRCA2. lsinki, ndipo onse omwe adatenga nawo mbali adapereka chilolezo chodziwitsidwa asanayambe kusanthula maselo.
Makhalidwe a histological and biological (ER, PgR, HER2 status, Ki-67, and grade) of BC adawunikidwa pa core biopsy kapena zitsanzo za opaleshoni, poganizira zigawo za chotupa zaukali zokha.Kutengera makhalidwe awa, BCs adasankhidwa motere: luminal A (ER+ ndi/kapena PgR+, HER2-, (ER2-, HER20, HER20, HER2, HER2), -67≥20%), kuwala kwa B-HER2+ (ER ndi/kapena PgR+, HER2+), HER2+ (ER ndi PgR-, HER2+) kapena katatu zoipa (ER ndi PgR-, HER2-).
Asanawunike kusintha kwa BRCA1 ndi BRCA2, gulu lamitundu yosiyanasiyana kuphatikiza katswiri wa oncologist, katswiri wa chibadwa, ndi katswiri wa zamaganizo adachita kafukufuku wamtundu wa chotupa kwa wodwala aliyense kuti adziwe kupezeka kwa BRCA1 ndi/kapena BRCA1.kapena anthu omwe ali ndi chiopsezo chachikulu cha PV mu jini ya BRCA2. Kusankhidwa kwa odwala kunkachitidwa motsatira malangizo a Italy Society of Medical Oncology (AIOM) ndi malangizo a ku Sicilian.(ii) amuna omwe ali ndi BC;(iii) omwe ali ndi BC ndi OC;(iv) amayi omwe ali ndi BC <36 zaka, TNBC <60 zaka, kapena mayiko awiri BC <50 zaka;(v) mbiri yachipatala ya BC zaka 50 ndi mbiri ya banja la BC, OC, kapena khansa ya pancreatic kwa achibale omwe ali pachibale choyamba kwa wina ndi mzake (kuphatikiza achibale omwe ali nawo pachibale);(vii) Mbiri yaumwini ya OC ndi wachibale wa digiri yoyamba: (a) BC Magazi a 20 mL otumphukira anapezedwa kuchokera kwa wodwala aliyense ndikusonkhanitsidwa mu machubu a EDTA (BD Biosciences).Genomic DNA inapatulidwa kuchokera ku 0.7 mL yamagazi athunthu pogwiritsa ntchito QIAsymphony DSP DNA Midi kit Isolation Kit (QIAGEN, Hilden, Italy) molingana ndi malangizo a wopanga ndikudutsa pa 3. , MA, USA) Chitani quantification.Kupititsa patsogolo chandamale ndi kukonza laibulale kumachitidwa ndi Oncomine™ BRCA Research Assay Chef, wokonzeka kukwezedwa mu Ion AmpliSeq™ Chef Reagents DL8 Kit pokonzekera laibulale yokhazikika molingana ndi malangizo a wopanga.Zidazi zimakhala ndi maiwe awiri oyambilira a PCR omwe angagwiritsidwe ntchito powerengera BRCA73300020 yonse (N5M0030). Mwachidule, 15 µL ya DNA iliyonse yosungunuka (10 ng) inawonjezedwa ku mbale za barcode zokonzekera laibulale ndipo zopangira zonse ndi zogwiritsira ntchito zidakwezedwa pa chida cha Ion Chef™. Kukonzekera kwa laibulale yodzichitira ndi kusanja kwa library ya barcode kudachitika pa chida cha Ion Chef™. cientific, Waltham, MA, USA) molingana ndi malangizo a wopanga. Pomaliza, malaibulale amaphatikizidwa molingana ndi machubu a laibulale ya Ion Chef™ (machubu a barcoded) ndikulowetsedwa pa chida cha Ion Chef™. Kutsata kunachitika pogwiritsa ntchito Ion Torrent S5 (Thermo Fisher Scientific) pogwiritsa ntchito chida cha Ion Chef (Thermo Fisher Scientific) pogwiritsa ntchito Chida Scientific) .Kusanthula deta kunachitidwa ndi Amplicon Suite (SmartSeq srl) ndi Ion Reporter Software.
Mitundu yonse ya mayina inatsatira ndondomeko zamakono za Human Genome Variation Consortium, zomwe zikupezeka pa intaneti (HGVS, http://www.hgvs.org/mutnomen).Kufunika kwachipatala kwa mitundu yosiyanasiyana ya BRCA1/2 kunatanthauzidwa pogwiritsa ntchito gulu la International Consortium ENIGMA (Evidence-Based Network for Interpreting Alemsline Database, https://www.interpreting Allemcond.org) monga ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, ndi UMD. Gululi limaphatikizapo magulu asanu owopsa: benign (gulu I), mwina benign (gulu II), kusiyana kofunikira kosadziwika bwino (VUS, gulu III), mwina pathogenic (gulu IV), ndi pathogenic (gulu lachidziwitso la V) kupeza 30 databases.32
Kupereka kufunikira kwachipatala ku VUS iliyonse, njira zolosera zam'mapuloteni zotsatirazi zidagwiritsidwa ntchito: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/G) ndi Align-Dg-Guta. d_input.php).Zosintha zomwe zidasankhidwa kukhala kalasi 1 ndi 2 zidawonedwa ngati zapathengo.
Kutsatizana kwa Sanger kunatsimikizira kukhalapo kwa mtundu uliwonse wa tizilombo toyambitsa matenda.Mwachidule, zoyambira zina zidapangidwa kuti zizipezeka mwanjira iliyonse pogwiritsa ntchito BRCA1 ndi BRCA2 gene reference sequences (NG_005905.2, NM_007294.3 ndi NG_012772.3, NM5_R030, NM9. nsi.
Odwala omwe adapezeka kuti alibe jini ya BRCA1/2 adayesedwa ndi multiplex ligation-dependent probe amplification (MLPA) molingana ndi malangizo a wopanga kuti awone ngati pali ma genomic rearrangements (LGR) ma nucleotides muutali.Probe amplification product, yopangidwa ndi ma PCR amplicon apadera, adawunikidwa ndi capillary electrophoresis ndi mapulogalamu a Cofalyser.Net molumikizana ndi matebulo oyenera a batch-specific Cofalyser (www.mrcholland.com).
Zosintha zosankhidwa zachipatala ( histological grade ndi Ki-67% proliferation index) zinagwirizanitsidwa ndi kukhalapo kwa BRCA1 / 2 PV, kuwerengedwa pogwiritsa ntchito pulogalamu ya Prism v. 8.4 pogwiritsa ntchito mayeso enieni a Fisher poganiza kuti p-value <0.05 ndi yofunika.
Pakati pa Januware 2017 ndi Marichi 2021, odwala 455 adawunikiridwa kuti ali ndi kusintha kwa majeremusi a BRCA1/2. Kuyezetsa kosinthika kunachitika ku Policlinico Hospital's Center for Experimental Oncology and Hematology.Malinga ndi malangizo a Sicilian (http://www.gurs.regione.sicilia.it.it.00100mIt-indicepneipne. 2020), Rodolico waku Catania - San Marco” onse, odwala 389 Panali khansa ya m'mawere, khansa ya m'mawere 37, khansa ya m'mawere 16, khansa ya prostate 8 ndi melanoma 5.Kugawidwa kwa odwala molingana ndi mtundu wa khansa ndi zotsatira za kusanthula zikuwonetsedwa pa Chithunzi 1.
Chithunzi cha 1 chikuwonetsa tchati chotsatira chomwe chikuwonetsa mwachidule phunziroli.Odwala omwe ali ndi chifuwa, melanoma, pancreatic, prostate, kapena ovarian tumors adayesedwa kuti asinthe ma jini a BRCA1 ndi BRCA2.
Mafupipafupi: PVs, mitundu yosiyanasiyana ya pathogenic;VUS, kusiyanasiyana kosadziwika bwino;WT, mtundu wakuthengo wa BRCA1/2 mndandanda.
Tinasankha mosamala maphunziro athu pamagulu a khansa ya m'mawere. Odwalawo anali ndi zaka zapakati pa 49 (zosiyanasiyana 23-89) ndipo makamaka anali akazi (n = 376, kapena 97%).
Mwa maphunzirowa, 64 (17%) anali ndi masinthidwe a BRCA1 / 2 ndipo onse anali akazi. Makumi atatu ndi asanu (9%) anali ndi PV ndipo 29 (7.5%) anali ndi VUS. Seventeen (48.6%) mwa mitundu 35 ya pathogenic inachitika mu BRCA1 ndi 18 (51.4%) mu BRCA2, pamene . (Zithunzi 1 ndi 2) LGR sinalipo pakuwunika kwa MLPA.
Chithunzi 2. Kusanthula kwa kusintha kwa BRCA1 ndi BRCA2 kwa odwala khansa ya m'mawere a 389. (A) Kugawidwa kwa mitundu yosiyanasiyana ya pathogenic (PV) (yofiira), mitundu yosiyanasiyana ya kufunikira kosadziwika (VUS) (lalanje), ndi WT (buluu) mu 389 odwala khansa ya m'mawere;(B) 389 odwala khansa ya m'mawere Makumi atatu ndi asanu (9%) anali ndi BRCA1 / 2 mitundu ya pathogenic (PVs) . Pakati pawo, 17 (48.6%) anali BRCA1 PV zonyamulira (zofiira zakuda) ndi 18 (51.4%) zinali zonyamula BRCA2 (zofiira zofiira);(C) 29 (7.5%) mwa maphunziro 389 ananyamula VUS, 5 (17.2%) BRCA1 majini (mdima lalanje) ndi 24 (82.8%) BRCA2 majini (kuwala lalanje).
Mafupipafupi: PVs, mitundu yosiyanasiyana ya pathogenic;VUS, kusiyanasiyana kosadziwika bwino;WT, mtundu wakuthengo wa BRCA1/2 mndandanda.
Kenako tidafufuzanso kuchuluka kwa ma BC molecular subtypes mwa odwala omwe ali ndi BRCA1/2 PV. Kugawa kunaphatikizapo 2 (5.7%) luminal A, 15 (42.9%) luminal B, 3 (8.6%) luminal B-HER2+, 2 (5.7%) HER2+ ndi 13 (37.1%) pakati pa odwala 9 BRCA 9, 5-19 TNBC odwala. , 2 (11.8%) anali ndi matenda a HER2 +, ndipo 10 (58.8%) anali ndi TNBC. Zotupa zopanda kusintha kwa BRCA1 zinali zowala A kapena luminal B-HER2 + (Chithunzi 3). Mu gulu laling'ono la BRCA2, zotupa 10 (55.6%) zinali luminal B, 3 (16) 16 BBC ndi 16 HER2% B, 3 (16) BBC ndi 16 HER2%. .1%) anali kuwala kwa A (Chithunzi 3) .Palibe zotupa za HER2 + zomwe zinalipo mu gulu ili.Choncho, kusintha kwa BRCA1 kumakhala kofala kwa odwala TNBC, pamene kusintha kwa BRCA2 kumakhala kwakukulu kwa anthu a lumen B.
Chithunzi cha 3 Kuchuluka kwa khansa ya m'mawere kwa odwala omwe ali ndi mitundu yosiyanasiyana ya pathogenic mu BRCA1 ndi BRCA2.Histograms yosonyeza kugawa kwa BRCA1- (mdima wofiira) ndi BRCA2- (wofiira owala) PVs pakati pa ma molecular subtypes a odwala khansa ya m'mawere.Nambala zomwe zafotokozedwa mkati mwa bokosi lililonse zimayimira chiwerengero cha odwala omwe ali ndi BRCA1 ndi BRCA2 ya khansa ya m'mawere.
Mafupipafupi: PVs, mitundu yosiyanasiyana ya pathogenic;HER2 +, epidermal kukula factor receptor 2 zabwino;TNBC, khansa ya m'mawere yopanda katatu.
Pambuyo pake, tinayesa mtundu ndi jini za BRCA1 ndi BRCA2 PVs.Mu BRCA1 PV, tinawona mitundu 7 ya nucleotide c (SNVs), kuchotsedwa kwa 6, kubwereza kwa 3 ndi kuyika kwa 1. Kusintha kumodzi kokha (c.5522delG) kumaimira kupezedwa kwatsopano 553V zonse zomwe zapezeka 530 zodziwika bwino za P530. 9delCTAAT.Kusinthaku kumaphatikizapo kuchotsedwa kwa ma nucleotide asanu (CTAAT) mu BRCA1 exon 15, zomwe zimapangitsa kuti amino acid leucine alowe m'malo mwa tyrosine pa codon 1679, ndipo chifukwa cha kumasulira kwazithunzi ndi njira ina yodziwikiratu yoyimitsa codon kutsogolere ku kuchepetsedwa kwa mapuloteni asanafike nthawi, palibe kusintha komwe kunadziwika mu PtaV imodzi yokha. splice site consensus region (c.4357+1G>T) (Table 1).
Ponena za BRCA2 PV, tinawona kufufutidwa kwa 6, 6 SNVs ndi kubwereza kwa 2. Palibe zosintha zomwe zapezeka ndi zatsopano.Kusintha kutatu kunabweranso mwa anthu athu, c.428dup ndi c.8487 + 1G>A adawona m'mitu ya 3, kutsatiridwa ndi c.5851_5854kubwereza kwawiri2AGdup kubwereza kwa c. 5 ya BRCA2, yonenedweratu kuti idzalowetsa mapuloteni ochepa, osagwira ntchito. The c.8487 + 1G> Kusintha kumachitika m'chigawo cha intronic cha BRCA2 intron 19 (± 1,2) ndipo kumakhudza ndondomeko ya splicing consensus, zomwe zimapangitsa kusintha kwa splicing kumapangitsa kuti absent581 proteinoid absent581. kupita ku 4-nucleotide kuchotsedwa kwa nucleotide malo 5851 mpaka 5854 mu coding exon 10 ya jini ya BRCA2 ndipo imapangitsa kuti pakhale chithunzithunzi chomasulira ndi codon yodziwikiratu (p.S1951WfsTer) . Kusintha koyamba kumaphatikizapo kusintha kwa adenosine (A) mu BRCA2 exon 7 ndi guanine (G) yomwe ili ndi nucleotide zomwe zimapangitsa kusintha kwa valine kukhala isoleucine pa codon 211, isoleucine Amino acid ndi amino acid omwe ali ndi katundu wofanana kwambiri. 13 ya jini encoding BRCA2.Kusintha kwa c.7008-2A>T kungapangitse zolemba zambiri zautali wosiyana.Kuonjezera apo, mu gulu la BRCA2 PVs, 4 kuchokera ku 18 kusintha (22.2%) inali intronic.
Kenako tinajambula masinthidwe a BRCA1/2 m'magawo ogwirira ntchito komanso zigawo zomanga mapuloteni (mkuyu. 4) .Mu jini ya BRCA1, 50% ya PVs inali m'chigawo cha masango a khansa ya m'mawere (BCCR), pomwe 22% ya masinthidwewo anali m'chigawo cha ovarian cancer cluster region (OCCR) (Fig. 30 BRCA5A) mu chigawo cha BRCA52 BC. ndi 42.8% ya masinthidwewo anali mu OCCR (mkuyu 4B) .Kenako, tinayang'ana malo a PV mkati mwa BRCA1 ndi BRCA2 madera a mapuloteni.Kwa mapuloteni a BRCA1, tinapeza ma PV atatu mu madera ozungulira ndi coil coil, ndi masinthidwe awiri mu dera la BRCT (Mkuyu, kubwereza kwa BRCA 4A). Kusintha kwa intronic ndi 3 exonic kunapezeka mu madera a oligo / oligosaccharide-binding (OB) ndi nsanja (T) (Chithunzi 4B).
Chithunzi cha 4 Schematic kuyimira kwa BRCA1 ndi BRCA2 mapuloteni ndi kumasulira kwa mitundu yosiyanasiyana ya matenda.Chiwerengerochi chikuwonetsa kugawa kwa BRCA1 (A) ndi BRCA2 (B) mitundu ya pathogenic mwa odwala khansa ya m'mawere. Kusintha kwachilendo kumawonetsedwa mumtambo wa buluu, pamene zosiyana zowoneka bwino zimasonyezedwa mu lalanje. Kutalika kwa bar kumaimira chiwerengero cha milandu.Mapuloteni a BRCA21 omwe amanenedwa. malo ozungulira (RING) ndi ndondomeko ya nyukiliya (NLS), malo ozungulira-coil, SQ / TQ cluster domain (SCD), ndi BRCA1 C-terminal domain (BRCT) . NLS kumbali ya C. Madera otchedwa Breast Cancer Cluster Region (BCCR) ndi Ovarian Cancer Cluster Region (OCCR) akuwonetsedwa pansi.* Amaimira masinthidwe omwe amatsimikizira ma codon oyimitsa.
Kenako tinafufuza za BC clinicopathological features zomwe zingagwirizane ndi kukhalapo kwa BRCA1 / 2 PV. Complete clinic records was available for 181 BRCA1 / 2-negative odwala (osakhala onyamula) ndi onse onyamula (n = 35) .
Tinawerengera kugawidwa kwa Ki-67 kutengera zapakati pa gulu lathu (25%, range <10-90%). Nkhani zomwe zili ndi Ki-67 <25% zimatanthauzidwa ngati "otsika Ki-67", pamene anthu omwe ali ndi makhalidwe ≥ 25% ankaonedwa kuti ndi "high Ki-67" .Significant0 (CAp-607) kusiyana (CAp-607). onyamula (mkuyu 5A).
Chithunzi 5 Kulumikizana kwa Ki-67 ndi kugawa kwamagulu mu amayi omwe ali ndi khansa ya m'mawere omwe alibe BRCA1 ndi BRCA2 PVs. odwala khansa m'magulu a histological grade (G2 ndi G3) malinga ndi BRCA1 ndi BRCA2 mutation status (mitu ya WT, BRCA1 ndi BRCA2 PVs carriers).
Momwemonso, tinapenda ngati kalasi ya chotupa ikugwirizana ndi kukhalapo kwa BRCA1/2 PV. Popeza G1 BC kunalibe m’chiŵerengero chathu, tinagawa odwalawo m’magulu awiri (G2 kapena G3). Mogwirizana ndi zotsatira za Ki-67, kusanthula kunavumbula kugwirizana kwakukulu pakati pa kalasi ya chotupa ndi kusintha kwa BRCA1, ndi gawo lapamwamba la 01 chonyamula chotupa cha 01 BRCA <0 BRCA                             ) (Chithunzi 5B).
Kupita patsogolo kwa ukadaulo wotsatizana wa DNA kwathandiza kupita patsogolo kopitilira muyeso pakuyezetsa majini kwa BRCA1/2, zomwe ndizofunikira kwambiri kwa odwala omwe ali ndi mbiri ya banja la khansa. 37 M'dziko la Italy, mlingo wa BRCA1/2 PVs unachokera ku 8% kufika ku 37%, kusonyeza kusiyana kwakukulu pakati pa mayiko.38,39 Ndi anthu pafupifupi 5 miliyoni, Sicily ndi dera lachisanu lalikulu kwambiri ku Italy malinga ndi chiwerengero cha anthu okhalamo.
Phunziro lathu ndi limodzi mwa lipoti loyamba la zochitika za BRCA1 / 2 PV kwa odwala BC kum'maŵa kwa Sicily.28 Tinayang'ana kafukufuku wathu pa BC, chifukwa ichi ndi matenda omwe amapezeka kwambiri m'gulu lathu.
Poyesa odwala 389 BC, 9% ananyamula BRCA1 / 2 PVs, yogawidwa mofanana pakati pa BRCA1 ndi BRCA2. Zotsatirazi zimagwirizana ndi zomwe zinanenedwa kale mu chiwerengero cha Italy.28 Chochititsa chidwi, 3% (13 / 389) ya gulu lathu anali amuna.Chiwerengero ichi ndi chapamwamba kuposa kuyembekezera kwa khansa ya m'mawere yamphongo BC (1% 4 BR) yosankhidwa ndi khansa ya m'mawere yamphongo (1% 4 BR). Komabe, palibe mmodzi mwa amunawa omwe adapanga BRCA1 / 2 PV, kotero iwo anali oyenerera kuti apitirize kufufuza ma molekyulu kuti athetse kukhalapo kwa masinthidwe ang'onoang'ono monga PALB2, RAD51C ndi D, pakati pa ena.Kusiyanasiyana kwa kufunikira kosadziwika kunapezedwa mu 7% ya maphunziro omwe BRCA2 VUS inali yoonekera.
Pamene tidasanthula kagawidwe ka BC molecular subtypes mu BRCA1/2 akazi osinthika, tidatsimikizira mayanjano odziwika pakati pa TNBC ndi BRCA1 PV (58.8%) komanso pakati pa luminal B BC ndi BRCA2 PV (55.6%).16,43 Zotupa za luminal A ndi HER2+ mu BRCA1 ndi BRCA1 zonyamulira za BRCA2 ndi zonyamula 6 zonyamula BRCA2 zomwe zilipo.
Kenako timaganizira za mtundu ndi malo a BRCA1/2 PV. Mu gulu lathu, BRCA1 PV yodziwika kwambiri inali c.5035_5039delCTAAT.Ngakhale Incorvaia et al.sanafotokoze kusiyana kumeneku mu gulu lawo la Sicilian, olemba ena adanena kuti ndi kachilombo ka BRCA1 PV.34 Ma PV angapo a BRCA1 adapezeka m'gulu lathu - mwachitsanzo c.181T>G, c.514del, c.3253dupA ndi c.5266dupC - zomwe zapezeka 1BRCA1 mu 28 mu Sici. G ndi c.5266dupC) amapezeka kawirikawiri ku Ashkenazi Ayuda a Kum'maŵa ndi Pakati pa Ulaya (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian ndi German ), 44,45 ndipo, ku United States ndi Argentina, posachedwapa anatanthauzidwa kuti "kusiyana kwa majeremusi" kwa odwala a ku Italy omwe ali ndi odwala omwe ali ndi khansa ya BC ndi OC 34cant poyamba anali odwala khansa ya kumpoto. mu Palermo ndi Messina.Chochititsa chidwi, ngakhale Incorvaia et al.anapeza kusiyana kwa c.3253dupA m'mabanja ena ku Catania.28 Oimira kwambiri BRCA2 PVs ndi c.428dup, c.5851_5854delAGTT ndi intronic kusiyana c.8487+1G>A, zomwe zafotokozedwa mwatsatanetsatane 28 mwa wodwala ku Palermo ndi 52AG5 C_528 C. kumpoto chakumadzulo kwa Sicily, makamaka m'madera a Trapani ndi Palermo, pamene c.5851_5854delAGTT PV inkawoneka m'mabanja kumpoto chakumadzulo kwa Sicily.Kusiyana kwa 8487 + 1G>Kusiyana kunali kofala kwambiri pa maphunziro ochokera ku Messina, Palermo, ndi Caltanissetta.28 Rebbeck et al.m'mbuyomu adalongosola kusintha kwa c.5851_5854delAGTT ku Colombia.37 Wina BRCA2 PV, c.631 + 1G>A, wapezeka mu BC ndi OC odwala ochokera ku Sicily (Agrigento, Siracusa ndi Ragusa) .28 Mwachidziwitso, tinawona kukhalapo kwa mitundu iwiri ya BRCA2 c.6 ndi 8 c.8>odwala omwewo (BRCA2> 31G0) ofanana (BRCA2> 31G2) ofanana. , zomwe tinkaganiza kuti zasiyanitsidwa mu cis mode, monga momwe tafotokozera kale.34,46 Kusintha kwa BRCA2 uble kumawoneka kawirikawiri m'chigawo cha Italy ndipo kunapezeka kuti kumayambitsa ma codons oima msanga, kukhudza mthenga wa RNA splicing ndikupangitsa kuti mapuloteni a BRCA2 alephere.47,48
Tinapanganso mapu a BRCA1 ndi BRCA2 PVs m'magawo a OCCR ndi BCCR a zigawo za mapuloteni ndi majini. Maderawa adafotokozedwa ndi Rebbeck et al.monga malo owopsa a khansa ya ovari ndi khansa ya m'mawere, motero.49 Komabe, umboni wokhudzana ndi kugwirizana pakati pa malo a mitundu yosiyanasiyana ya majeremusi ndi chiopsezo cha khansa ya m'mawere kapena yamchiberekero imakhalabe yotsutsana. Madera a BCCR ndi zizindikiro za BC.Izi zikhoza kukhala chifukwa cha chiwerengero chochepa cha odwala omwe ali ndi kusintha kwa BRCA1 / 2. Kuchokera ku chigawo cha mapuloteni, BRCA1 PVs imagawidwa pamodzi ndi mapuloteni onse, ndipo kusintha kwa BRCA2 kumapezeka makamaka mu BRC kubwereza domain.
Potsirizira pake, tinagwirizanitsa mbali za BC clinicopathological ndi BRCA1 / 2 PV. Chifukwa cha chiwerengero chochepa cha odwala omwe akuphatikizidwa, tinangopeza kugwirizana kwakukulu pakati pa Ki-67 ndi kalasi ya chotupa. Ki-67 ndi 20%.Komabe, malirewa sagwira ntchito kwa odwala athu osinthika a BRCA1/2, omwe ali ndi mtengo wapakatikati wa Ki-67 wa 25%.Mchitidwewu m'magulu apamwamba a Ki-67 ukhoza kufotokozedwa ndi kufalikira kwa magulu athu a luminal B ndi TNBC, omwe zotupa zochepa za luminal A zinalipo. ku zotsatira zawo.53,54 Kuchokera ku zotsatira za kusanthula kwathu, mgwirizano wofunikira sizodabwitsa.Zimachitika pakati pa Ki-67 yapamwamba ndi magiredi ndi kukhalapo kwa BRCA1 PV. Ndipotu, zotupa zokhudzana ndi BRCA1 ndizofanana ndi TNBC ndipo zimasonyeza zinthu zowopsya.16,17
Pomaliza, phunziroli limapereka lipoti la kusintha kwa kusintha kwa BRCA1 / 2 mu gulu la BC kuchokera kummawa kwa Sicily.Ponseponse, zomwe tapeza zikugwirizana ndi umboni womwe ulipo kale, pokhudzana ndi kusintha kwa masinthidwe ndi zochitika zachipatala mu BC. ndizosiyana komanso zochepa kwambiri kuposa BRCA1 / 2. Izi zidzalola kuzindikiritsa ndi kuyang'anira bwino chiwerengero cha anthu omwe ali pachiopsezo cha khansa chifukwa cha kusintha kwa majini.
Tidatsimikizira kuti odwala adasaina chilolezo chodziwitsidwa kuti atulutse zitsanzo zawo zotupa mosadziwika bwino pazolinga zofufuza. Odwala onse adasaina chilolezo chodziwitsidwa molingana ndi Declaration of Helsinki. Mogwirizana ndi ndondomeko ya AOU Policlinico "G.Rodolico - S.Marco", kafukufukuyu sanakhululukidwe kuwunikiranso zamakhalidwe chifukwa kusanthula kwa BRCA1/2 kunachitikanso molingana ndi zomwe odwala adagwiritsa ntchito pofufuza komanso kusanthula kwawoko kunachitika molingana ndi zomwe odwala adagwiritsa ntchito. .
Tikuthokoza Prof. Paolo Vigneri chifukwa cha thandizo lake posamalira odwala khansa ya m'mawere monga momwe Komiti ya Ethics inapempha.
Federica Martorana akufotokoza ulemu kuchokera ku Istituto Gentili, Eli Lilly, Novartis, Pfizer.Olemba ena amalengeza kuti palibe mikangano ya chidwi pa ntchitoyi.
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