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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 ngalaba nke ụlọ ọgwụ na Liviazella 1, Liviazella 1, Liviazella 1, na ngalaba nlekọta ahụike. Ọgwụ, Mahadum Catania, 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 Medicine Genetics, ASP, Syracuse, 96100, Italy; 6 Department of Biomedical and Biotechnology Sciences, University of Catania, Medical Genetics, Catania, Italy, 95123; 7Oasi Research Institute-IRCCS, Troina, 94018, Italy Communications: Stefania Stella, tel +39 095 378 1946, email [email protected]; [email protected] Nzube: Germline mutations na BRCA1 na BRCA2 na guzosie ike ara cancer (BC), ovary (OC) na ndị ọzọ metụtara a ndụ ndụ n'ihe ize ndụ nke cancer.Nlere maka BRCA gene bụ isi ihe na-enyocha onye ize ndụ, nakwa dị ka ịchọta ụzọ mgbochi na ahụike na-ebu na ịkwa akwa ọgwụgwọ na ọrịa cancer cancer. The prevalence nke gafee CABR a ọtụtụ mpaghara na CABR1 na mpaghara CABR1. dị na BRCA pathogenic variants na Sicily ezinụlọ, ọmụmụ kpọmkwem ezubere iche maka ndị bi n'ebe ọwụwa anyanwụ Sicily adịghị. Ebumnuche nke ọmụmụ anyị bụ iji nyochaa ọnọdụ na nkesa nke BRCA pathogenic germline mgbanwe na a otu ìgwè nke BC ọrịa si n'ebe ọwụwa anyanwụ Sicily na iji nyochaa ha mkpakọrịta na kpọmkwem BC àgwà site na-eji ọgbọ na-abịa na-abịaru nso nke akpụ na-eme ka akpụ akpụ. index.RESULTS: N'ozuzu, 35 ọrịa (9%) nwere BRCA pathogenic variant, 17 (49%) na BRCA1 na 18 (51%) na BRCA2.BRCA1 mgbanwe na-jupụtara na triple-na-adịghị mma BC ọrịa, ebe BRCA2 mutations na-na-emekarị na luminal luminal BC ndị ọrịa na-abụghị ndị na-arịa ọrịa 1. elu tumor grade and proliferative index.Nkwubi okwu: Nchọpụta anyị na-enye nkọwa nke ọnọdụ mgbanwe BRCA na ndị ọrịa BC si n'ebe ọwụwa anyanwụ Sicily ma kwado ọrụ nyocha NGS n'ịchọpụta ndị ọrịa nwere BC nketa.
Ọrịa ara ara (BC) bụ ọrịa ọjọọ na-emekarị n'ụwa nile na ọrịa cancer na-egbu egbu na ụmụ nwanyị.1 A na-enyocha ihe ndị dị ndụ nke na-achọpụta BC prognosis na omume ụlọ ọgwụ na-amụbawanye ma kọwaa n'ụzọ ụfọdụ n'ime oge. amplification, proliferation index Ki-67 na tumor grade (G) .2 Nchikota nke mgbanwe ndị a na-achọpụta ụdị BC ndị a: 1) Luminal tumors, na-egosi ER na / ma ọ bụ PgR okwu, ruru 75% nke BCs. A na-ekewakwa etuto ndị a na Luminal A, mgbe Ki-67 dị n'okpuru 20% ma ọ bụ HER2 na-adịghị mma, na Luminal 2% na-adịghị mma, na Luminal 20. na ọnụnọ nke HER2 amplification, n'agbanyeghị proliferation index; 2) HER2 + etuto ahụ bụ ER na PgR adịghị mma ma na-egosi mmụba HER2. Otu a bụ 10% nke ụbụrụ ara ara; 3) Ọrịa ara ara atọ na-adịghị mma (TNBC), nke na-egosighi okwu ER na PgR na mmụba HER2, na-akpata ihe dịka 15% nke ọrịa ara ara.2-4
N'ime subtypes BC ndị a, ọkwa tumor na proliferation index na-anọchite anya ndị na-ahụ maka biomarkers nke na-ejikọta ya na nke onwe ya na mkparị ike na prognosis.5,6
Na mgbakwunye na ndị e kwuru n'elu biological atụmatụ, ọrụ nke ketara eketa mkpụrụ ndụ ihe nketa mgbanwe na-eduga mmepe nke BC aghọwo esiwanye mkpa n'ime gara aga afọ ole na ole.7 About 1 na 10 ara etuto na-eketa ruru germline alterations na kpọmkwem mkpụrụ ndụ ihe nketa.8 Abụọ nnukwu epidemiological ọmụmụ metụtara ihe karịrị 180,000 ụmụ nwanyị nwere ihe karịrị 180,000 ụmụ nwanyị achọpụtala na nso nso a otu ìgwè nke BRie, BRie 10. BRCA2, CHK2, PALB2, RAD51C, na RAD51D) bụ isi na-ahụ maka eketa BC.N'ime mkpụrụ ndụ ihe nketa ndị a, BRCA1 na BRCA2 (nke a na-akpọ BRCA1/2) gosipụtara njikọ kachasị ike na mmepe nke etuto ara.9-12 N'ezie, germline mutation ndụ nke ọma na-abawanye CA1 / 2 n'ezie. Malignancies, gụnyere ovarian, prostate, pancreatic, colorectal, na melanoma.Site na afọ 13 ruo 80, ngụkọta oge nke BC bụ 72% na ụmụ nwanyị nwere BRCA1 pathogenic variant (PV) na 69% n'ime ụmụ nwanyị nwere BRCA2 PV.14
N'ụzọ doro anya, mbipụta na-adịbeghị anya na-egosi na ihe ize ndụ BC na-adabere n'ụdị PV. N'ezie, e jiri ya tụnyere pathogenic truncating variants, variants missense variants, karịsịa na BRCA1 gene, jikọtara ya na mbelata ihe ize ndụ nke BC, karịsịa na ndị inyom meworo agadi.15
Ọnụnọ nke BRCA1 ma ọ bụ BRCA2 PV jikọtara ya na ọdịdị dị iche iche nke ndụ na ụlọ ọgwụ.16,17 BRCA1-ejikọtara BC na-abụkarị ndị na-eme ihe ike, na-adịghị mma dị iche iche, na nke ukwuu. proliferative indices.Ụdị etuto ndị a na-adịkarị na lumen B ma na-emekarị na ndị okenye.16-18 N'ụzọ doro anya, mmụgharị na BRCA1 na BRCA2 na-amụba mmetụta maka ọgwụgwọ ụfọdụ, gụnyere salts platinum na ọgwụ ndị ezubere iche dị ka poly (ADP-ribose) polymerase inhibitors (PARPi).19,20
N'ime afọ ole na ole gara aga, mmejuputa usoro nke ọgbọ na-esote (NGS) na omume ahụike emeela ka ọnụ ọgụgụ na-arịwanye elu nke ndị ọrịa BC nwee ike ịnweta ule molecular maka ọrịa ọrịa cancer susceptibility, gụnyere BRCA1 / 2.21 N'otu oge ahụ, nkọwa ndị dabeere na kpọmkwem njirisi banyere akụkọ ihe mere eme ezinụlọ , igwe mmadụ, na clinicopathological e ji mara mma mara ndị mmadụ n'otu n'otu kwesịrị ịnwale, na CA12. na nyocha BRCA1 / 2 na ọnụ ọgụgụ dị iche iche, na-akọwapụta ọdịiche dị n'ofe mpaghara mpaghara.24-27 Ọ bụ ezie na e nwere akụkọ banyere òtù BC dị n'ebe ọdịda anyanwụ Sicily, ntakịrị data dị na nyocha BRCA1/2 n'ebe ọwụwa anyanwụ Sicily bi.28,29
Anyị na-akọwa ebe a nsonaazụ nke nyocha germline BRCA1/2 na ndị ọrịa BC si n'ebe ọwụwa anyanwụ Sicily, na-ejikọta ọnụnọ nke mmụgharị BRCA1 ma ọ bụ BRCA2 na isi njirimara clinicopathological nke etuto ndị a.
Emere nyocha nlọghachi azụ na "Center for Experimental Oncology and Hematology" na Ụlọ Ọgwụ Policlinico.Rodolico - San Marco dị na Catania. Site na January 2017 ruo March 2021, ngụkọta nke ndị ọrịa 455 nwere ara na ovarian, melanoma, pancreatic ma ọ bụ ọrịa prostate nke a na-ezo aka na nyocha mkpụrụ ndụ anyị CA2. dị ka nkwupụta Helsinki siri dị, yana ndị niile sonyere nyere nkwenye ederede tupu nyocha nke mkpụrụ ndụ ihe nketa.
A na-enyocha njirimara akụkọ ihe mere eme na ihe ndị dị ndụ (ER, PgR, HER2, Ki-67, na ọkwa) nke BC na isi biopsy ma ọ bụ ihe nlele ịwa ahụ, na-atụle naanị akụkụ ụbụrụ na-eme ihe ike. Dabere na njirimara ndị a, a na-ekewa BC dị ka ndị a: luminal A (ER + na / ma ọ bụ PgR +, HER2-, Ki-67/20%), ERluminal, 67/20% na B + . HER2-, Ki-67≥20%), luminal B-HER2+ (ER na/ma ọ bụ PgR +, HER2+), HER2+ (ER na PgR-, HER2+) ma ọ bụ atọ ọjọọ (ER na PgR-, HER2-).
Tupu nyochaa ọnọdụ mgbanwe BRCA1 na BRCA2, otu multidisciplinary gụnyere onye ọkà mmụta banyere oncologist, ọkà mmụta mkpụrụ ndụ ihe nketa, na onye ọkà n'akparamàgwà mmadụ mere nyocha mkpụrụ ndụ ihe nketa maka onye ọrịa ọ bụla iji chọpụta ọnụnọ BRCA1 na / ma ọ bụ BRCA1. ma ọ bụ ndị nwere nnukwu ihe ize ndụ nke PV na mkpụrụ ndụ BRCA2. A na-eme nhọrọ ndị ọrịa dịka ntụziaka nke Italian Society of Medical Oncology (AIOM) na ndụmọdụ Sicilian mpaghara.30,31 Usoro ndị a gụnyere: (i) akụkọ ihe mere eme ezinụlọ nke ụdị ọrịa nje a maara na mkpụrụ ndụ ihe nketa (dịka, BRCA1, BRCA2, TP53, PT); (ii) ụmụ nwoke nwere BC; (iii) ndị nwere BC na OC; (iv) ụmụ nwanyị nwere BC <36 afọ, TNBC <60 afọ, ma ọ bụ bilateral BC <50 afọ; (v) akụkọ ahụike onwe onye nke BC <50 afọ na opekata mpe otu onye ikwu nke mbụ: (a) BC <50 afọ; (b) OC na-abụghị mucinous na enweghị oke ala nke afọ ọ bụla; (c) nke abụọ BC; (d) nwoke BC; (e) ọrịa cancer pancreatic; (f) ọrịa kansa prostate; (vi) akụkọ ihe mere eme nkeonwe abụọ ma ọ bụ karịa nke BC> afọ 50 na akụkọ ihe mere eme ezinụlọ nke BC, OC, ma ọ bụ ọrịa cancer pancreatic maka ndị ikwu bụ ndị ikwu nke mbụ (gụnyere ndị ikwu ya na ndị ikwu nke mbụ); (vii) Akụkọ ihe mere eme nkeonwe nke OC na opekata mpe otu onye ikwu ogo mbụ: (a) BC <50 afọ; (b) NOC; (c) nke abụọ BC; (d) nwoke BC; (vii) nwanyi nwere ogo serous OC.
A na-enweta ihe nlele ọbara nke 20 mL site n'aka onye ọrịa ọ bụla wee chịkọta ya n'ime tubes EDTA (BD Biosciences) .Genomic DNA dịpụrụ adịpụ site na 0.7 mL ọbara zuru oke site na iji QIAsymphony DSP DNA Midi kit Isolation Kit (QIAGEN, Hilden, Italy) dị ka ntụziaka nke onye nrụpụta si kwuo ma gafere Qubitmo ® 3 . Waltham, MA, USA) Mee quantification. A na-eme nkwalite mmụta na nkwado ọbá akwụkwọ site n'aka Oncomine™ BRCA Research Assay Chef, dị njikere ibunye ya n'ime Ion AmpliSeq™ Chef Reagents DL8 Kit maka nkwadebe ọbá akwụkwọ akpaghị aka dị ka ntuziaka onye nrụpụta si dị. Ngwa ahụ nwere ọdọ mmiri abụọ multiplex PCR primer nke enwere ike iji mụọ BRCA1 (NM_030700) na BRCA1 niile. (NM_000059.3) genes.Na nkenke, 15 µL nke ọ bụla diluted sample DNA (10 ng) ka agbakwunyere na barcoded efere maka nkwadebe n'ọbá akwụkwọ na ihe niile reagents na consumable na-ejuru na Ion Chef™ ngwá. 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) dị ka ntuziaka onye nrụpụta si kwuo. N'ikpeazụ, a na-ejikọta ọba akwụkwọ n'ogo nha nha na Ion Chef ™ ọba akwụkwọ sample tubes (barcoded tubes) na kwajuru na Ion Chef™ instrument.Sequencing e rụrụ site na iji Ion Torrent S5 (Theficient Fisher) ngwá ọrụ. ihe Ion 510 Chip (Thermo Fisher Scientific) .Amplicon Suite (SmartSeq srl) na Ion Reporter Software mere nyocha data.
All variant nomenclature gbasoro ntuziaka dị ugbu a nke Human Genome Variation Consortium, dị na ntanetị (HGVS, http://www.hgvs.org/mutnomen) .Akọwapụtara uru ahụike nke BRCA1/2 dị iche iche site na iji nhazi ọkwa nke International Consortium ENIGMA (Network Based Network for Interpreting) https://www.hgvs.org/mutnomen. Na-enyocha ọdụ data dị iche iche dị ka ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, na UMD. Nhazi ahụ gụnyere ụdị ihe egwu ise dị iche iche: benign (category I), ma eleghị anya benign (ụdị II), variant nke na-ejighị n'aka (VUS, category III), eleghị anya pathogenic (ụdị IV), na pathogenic (ụdị IV) na-akpata protin. ọrụ, ngwá ọrụ na-enye ihe ọmụma nwere ohere ịnweta ọdụ data 30.32
Iji kenye uru ahụike nwere ike ịdị na VUS ọ bụla, a na-eji algọridim amụma amụma mgbako protein ndị a: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/) na Align-GVGD (http://agvgd.hci.utah.edu/agvgd_input.php) .Ndị dị iche iche nkewa dị ka klaasị 1 na 2 ka a na-ewere ụdị anụ ọhịa.
Sanger sequencing kwadoro ọnụnọ nke ọ bụla pathogenic variant.Na nkenke, a ụzọ nke kpọmkwem primers e mere maka onye ọ bụla achọpụtara variant site na iji BRCA1 na BRCA2 gene references (NG_005905.2, NM_007294.3 na NG_012772.3, NM_0300re PC) rụrụ. sochiri usoro Sanger.
A nwalere ndị ọrịa nwalere ihe na-adịghị mma maka mkpụrụ ndụ BRCA1/2 site na multiplex ligation-dependent probe amplification (MLPA) dị ka ntuziaka nke onye nrụpụta iji chọpụta ọnụnọ nke nnukwu nhazigharị genomic (LGR) .Na nkenke, DNA samples na-denaturered na ruo 60 BRCA1 na BRCA2 gene-specific na-eji ihe DNA nke ọ bụla kpọmkwem probe. nucleotides n'ogologo.Probe amplification ngwaahịa, nke nwere ihe pụrụ iche nke PCR amplicons, wee nyochaa site capillary electrophoresis na Cofalyser.Net software na njikọ kwesịrị ekwesị ogbe-kpọmkwem Cofalyser tables (www.mrcholland.com).
Achọpụtara mgbanwe nke clinicopathological (ọkwa histological na Ki-67% proliferation index) na ọnụnọ BRCA1/2 PV, gbakọrọ site na iji sọftụwia Prism v. 8.4 site na iji ule Fisher ziri ezi na-ewere p-uru <0.05 dị mkpa.
N'agbata Jenụwarị 2017 na Machị 2021, a na-enyocha ndị ọrịa 455 maka mgbanwe germline BRCA1/2. A na-anwale ule mutation na Ụlọ Ọgwụ Policlinico's Center for Experimental Oncology and Hematology. Dị ka ntụziaka Sicilian (http://www.gurs.regione.siciep1.ith0) 10 Gennaio 2020), na Rodolico nke Catania - San Marco "n'ozuzu, 389 ọrịa E nwere ọrịa ara ara, 37 ovarian cancer, 16 pancreatic cancer, 8 prostate cancer na 5 melanoma nkesa nke ndị ọrịa dị ka ọrịa cancer ụdị na analysis pụta gosiri na Figure 1.
Ọnụ ọgụgụ 1 na-egosi eserese na-asọpụta na-egosi nchịkọta nke ọmụmụ ihe. A nwalere ndị ọrịa nwere ara, melanoma, pancreatic, prostate, ma ọ bụ etuto ovarian maka mmụgharị na mkpụrụ ndụ BRCA1 na BRCA2.
Mbiri: PVs, ụdị ọrịa nje; VUS, dị iche iche nke na-ejighị n'aka; WT, ụdị anụ ọhịa BRCA1/2 usoro.
Anyị na-ahọrọ nke ọma lekwasịrị anya n'ọmụmụ ihe anyị na ndị otu ọrịa cancer ara. Ndị ọrịa ahụ nwere afọ 49 (nke dị na 23-89) ma bụrụkwa ndị inyom kachasị (n=376, ma ọ bụ 97%).
N'ime isiokwu ndị a, 64 (17%) nwere mgbanwe BRCA1 / 2 na ha niile bụ nwanyị. Iri atọ na ise (9%) nwere PV na 29 (7.5%) nwere VUS. Seventeen (48.6%) nke 35 pathogenic variants mere na BRCA1 na 18 (51.4%) na BRCA2, ebe 5CABR na 1.2. (82.8%) na BRCA2 (Njirimara 1 na 2) .LGR anọghị na nyocha MLPA.
Ọnụọgụ 2. Nyocha nke BRCA1 na BRCA2 mgbanwe na 389 ọrịa cancer ara. (B) 389 ọrịa cancer ara 35 (9%) nwere BRCA1 / 2 pathogenic variants (PVs) .N'ime ha, 17 (48.6%) bụ ndị na-ebu BRCA1 PV (acha uhie uhie na-acha uhie uhie) na 18 (51.4%) bụ ndị na-ebu BRCA2 (ọkụ uhie); (C) 29 (7.5%) nke isiokwu 389 bu VUS, 5 (17.2%) BRCA1 mkpụrụ ndụ ihe nketa (oroma gbara ọchịchịrị) na 24 (82.8%) BRCA2 mkpụrụ ndụ ihe nketa (oroma oroma).
Mbiri: PVs, ụdị ọrịa nje; VUS, dị iche iche nke na-ejighị n'aka; WT, ụdị anụ ọhịa BRCA1/2 usoro.
Anyị na-eme nchọpụta nyocha nke BC molecular subtypes na ndị ọrịa nwere BRCA1 / 2 PV. Nkesa gụnyere 2 (5.7%) luminal A, 15 (42.9%) luminal B, 3 (8.6%) luminal B-HER2 +, 2 (5.7%) HER2 + na 13 (ndị ọrịa 37.15%) Tmopositive B. (29.4%) nwere luminal B BC, 2 (11.8%) nwere ọrịa HER2 +, na 10 (58.8%) nwere TNBC. Tumor na-enweghị mgbanwe BRCA1 bụ ma ọ bụ luminal A ma ọ bụ luminal B-HER2 + (Nyocha 3) .Na BRCA2-positive subgroup, 10 (53%) bụ 10 (53%) bụ luminal . luminal B-HER2 +, 3 (16.7%) TNBC na 2 (11.1%) bụ luminal A (Nyocha 3) .Ọ dịghị etuto HER2 + dị na otu a. Ya mere, mgbanwe BRCA1 na-emekarị na ndị ọrịa TNBC, ebe mgbanwe BRCA2 na-abụkarị ndị lumen B ndị mmadụ.
Ọgụgụ 3 Ọnụ ọgụgụ nke ụdị ọrịa cancer ara ara na ndị ọrịa nwere ụdị ọrịa nje na BRCA1 na BRCA2.Histograms na-egosi nkesa BRCA1- (acha ọbara ọbara gbara ọchịchịrị) na BRCA2- (ọkụ uhie) PV n'etiti ụdị molecular subtypes nke ọrịa cancer ara. Ọnụ ọgụgụ ndị a kọrọ n'ime igbe ọ bụla na-anọchite anya pasent nke ndị ọrịa nwere BRCA1 na BRCA2 maka ọrịa cancer ara ọ bụla.
Mbiri: PVs, ụdị ọrịa nje; HER2 +, onye na-anabata ihe na-eto eto epidermal 2 ziri ezi; TNBC, ọrịa kansa ara na-adịghị mma atọ.
N'ikpeazụ, anyị nyochara ụdị na mkpụrụ ndụ ihe nketa nke BRCA1 na BRCA2 PVs. Na BRCA1 PV, anyị hụrụ 7 otu nucleotide variants (SNVs), 6 nhichapụ, 3 duplications na 1 ntinye. Naanị otu mutation (c.5522del PV) na-anọchite anya nchọpụta ọhụrụ. c.5035_5039delCTAAT. Nke a mgbanwe na-agụnye a ihichapụ nke ise nucleotides (CTAAT) na BRCA1 exon 15, butere na nnọchi nke amino acid leucine site tyrosine na codon 1679, na n'ihi na a translation frameshift na a buru amụma ọzọ nkwụsị codon na-eduga na akaghi aka protein trun. PV ndị a kọrọ nọ na mpaghara nkwenye saịtị splice (c.4357 + 1G> T) (Table 1).
Banyere BRCA2 PV, anyị hụrụ 6 nhichapụ, 6 SNV na 2 mbiputegharị. Ọ dịghị mgbanwe ọ bụla a chọtara bụ akwụkwọ akụkọ. Mmụgharị atọ na-emegharị ugboro ugboro na ọnụ ọgụgụ anyị, c.428dup na c.8487 + 1G> A hụrụ na isiokwu 3, sochiri c.5851_5854delAG na c.5851_5854delter. megharịa nke C na exon 5 nke BRCA2, buru amụma na-encode a truncated, na-adịghị arụ ọrụ protein.The c.8487+1G>Mmụgharị na-eme na intronic mpaghara nke BRCA2 intron 19 (± 1,2) na-emetụta splicing nkwenye usoro, na-eme ka a gbanwee splicing ma ọ bụ na-akpata protein na-adịghị. c.5851_5854delAGTT pathogenic variant bụ n'ihi na a 4-nucleotide nhichapụ si nucleotide ọnọdụ 5851 ka 5854 na codeing exon 10 nke BRCA2 gene na pụta na a translation frameshift na amụma ọzọ nkwụsị codon (p.S1951Wfs) kọrọ na mbụ, c.6. na c.7008-2A>T achọpụtara n'otu onye ọrịa ahụ.34 Mmụba nke mbụ gụnyere ngbanwe nke adenosine (A) na BRCA2 exon 7 na guanine (G) nwere nucleotide na-akpata mgbanwe nke valine na isoleucine na codon 211, isoleucine Amino acid bụ amino acid na-emetụta ọdịdị nke abụọ dị na RNA nke na-enwe mmetụta dị ukwuu. mpaghara intronic na nsonaazụ na-agbanwe okpukpu abụọ A na thymine (T) tupu exon 13 nke gene encoding BRCA2. Mgbanwe c.7008-2A>T nwere ike ịmepụta ọtụtụ transcript nke ogologo dị iche iche. Ọzọkwa, n'ime ìgwè BRCA2 PV, 4 n'ime 18 mgbanwe (22.2%) bụ intronic.
Mgbe ahụ, anyị na-edepụta BRCA1 / 2 deleterious mutations na ngalaba na-arụ ọrụ na mpaghara na-ejikọta protein (Fig 4) .Na gene BRCA1, 50% nke PV dị na mpaghara ụyọkọ ọrịa cancer ara (BCCR), ebe 22% nke mmụgharị dị na mpaghara ovarian cancer cluster (OCCR) (Fig. 35A. , BR) dị na mpaghara . na mpaghara BCCR na 42.8% nke mgbanwe dị na OCCR (Fig 4B) .N'ikpeazụ, anyị nyochara ebe PV dị n'ime BRCA1 na BRCA2 protein. Maka protein BRCA1, anyị chọtara PV atọ na akaghị na ngalaba coil coil, na ngbanwe abụọ na mpaghara BR4CTA2. na BRC megharịa ngalaba, ebe 3 intronic na 3 exonic mgbanwe achọpụtara na oligo / oligosaccharide-binding (OB) na ụlọ elu (T) ngalaba (Fig 4B).
Ọgụgụ 4 Ihe atụ nke atụmatụ nke BRCA1 na BRCA2 protein na localization nke pathogenic variants. Nke a na ọnụ ọgụgụ na-egosi nkesa nke BRCA1 (A) na BRCA2 (B) pathogenic variants na ara ọrịa cancer. Exonic mutations e gosiri na-acha anụnụ anụnụ, mgbe intronic variants na-egosi na oroma. The mmanya dị elu na-anọchi anya ọnụ ọgụgụ nke ikpe na ngalaba CA BRA. Protein BRCA1 nwere ngalaba loop (RING) na usoro nhazi mpaghara nuklia (NLS), ngalaba mkpuchi mkpuchi, ngalaba ngalaba SQ/TQ (SCD), na ngalaba BRCA1 C-terminal (BRCT) . folds, ngalaba ụlọ elu (T), na NLS dị n'akụkụ C. A na-egosi ebe a na-akpọ Breast Cancer Cluster Region (BCCR) na Ovarian Cancer Cluster Region (OCCR) na ala.* Na-anọchi anya mgbanwe ndị na-ekpebi nkwụsị codons.
Anyị wee nyochaa BC clinicopathological atụmatụ nke nwere ike imekọrịta na ọnụnọ nke BRCA1 / 2 PV. A na-enweta akwụkwọ ndekọ ụlọ ọgwụ zuru ezu maka ndị ọrịa 181 BRCA1 / 2 na-adịghị mma (ndị na-abụghị ndị na-ebu ibu) na ndị niile na-ebu (n = 35) .Enwere njikọ n'etiti ọnụ ọgụgụ mmụba tumor na ọkwa.
Anyị gbakọrọ nkesa nke Ki-67 dabere na median nke otu anyị (25%, nso <10-90%). A na-akọwa isiokwu ndị dị na Ki-67 <25% dị ka "ala Ki-67" , ebe ndị mmadụ nwere ụkpụrụ ≥ 25% bụ ndị a na-ewere "Ki-67" dị elu. Ndị na-ebu PV (Fig 5A).
Ọgụgụ 5 Mmekọrịta nke Ki-67 na ọkwa nkesa na ọrịa cancer ara ụmụ nwanyị nwere na-enweghị BRCA1 na BRCA2 PV. nke ndị ọrịa cancer BC banye na ọkwa ọkwa akụkọ ihe mere eme (G2 na G3) dị ka ọnọdụ BRCA1 na BRCA2 si dị (isiokwu WT, BRCA1 na BRCA2 PVs).
N'otu aka ahụ, anyị nyochara ma ọkwa ọkwa tumor jikọtara ya na ọnụnọ BRCA1 / 2 PV. Ebe ọ bụ na G1 BC adịghị na ọnụ ọgụgụ anyị, anyị kewara ndị ọrịa ahụ n'ime ìgwè abụọ (G2 ma ọ bụ G3) .N'ikwekọ na nsonaazụ Ki-67, nyocha ahụ gosipụtara ọnụ ọgụgụ dị ịrịba ama n'etiti ọkwa tumor na BRCA1 mutation, na ọnụ ọgụgụ dị elu nke ndị na-abụghị BRCA1 ma e jiri ya tụnyere ndị na-eme ihe na-adịghị mma nke BRCA1 na ndị na-emepụta ihe na-emepụta ihe na GCA3 na-adabere na ndị na-abụghị ndị na-emepụta ihe na-emepụta ihe na GCA1. (p<0.005) (Foto 5B).
Ọganihu na teknụzụ usoro DNA emeela ka ọganihu a na-enwetụbeghị ụdị ya na nyocha mkpụrụ ndụ ihe nketa BRCA1/2, na-enwe mmetụta dị oke mkpa maka ndị ọrịa nwere akụkọ ihe mere eme ezinụlọ nke ọrịa cancer. Ka ọ dị ugbu a, a chọpụtala ihe dị ka 20.000 BRCA1/2 variants dị ka American Society of Medical Genetics 35 na usoro ENIGMA si kwuo. gafee mpaghara mpaghara.37 N'ime Italy, ọnụ ọgụgụ nke BRCA1/2 PV sitere na 8% ruo 37%, na-egosi mgbanwe dị ukwuu n'ime obodo. agwaetiti.
Ọmụmụ ihe anyị bụ otu n'ime akụkọ mbụ banyere ọnọdụ BRCA1 / 2 PV na ndị ọrịa BC dị n'ebe ọwụwa anyanwụ Sicily.28 Anyị lekwasịrị anya nyocha anyị na BC, n'ihi na nke a bụ ọrịa na-ahụkarị n'òtù anyị.
Mgbe a na-anwale ndị ọrịa 389 BC, 9% na-ebu BRCA1 / 2 PV, kesara nke ọma n'etiti BRCA1 na BRCA2. Nsonaazụ ndị a kwekọrọ na ndị a kọrọ na mbụ na ndị Italy. Otú ọ dị, ọ dịghị nke ọ bụla n'ime ndị ikom a mepụtara BRCA1 / 2 PV, n'ihi ya, ha bụ ndị na-eme nchọpụta maka nyocha ọzọ nke molecular iji chịkwaa ọnụnọ nke mmụgharị ndị na-adịkarịghị adị dị ka PALB2, RAD51C na D, n'etiti ndị ọzọ. A na-eweghachite ụdị dị iche iche nke na-ejighị n'aka na 7% nke isiokwu ndị BRCA2 VUS pụtara, nke a na-egosi na 4.2.
Mgbe anyị nyochaa nkesa nke BC molecular subtypes na BRCA1 / 2 ụmụ nwanyị mutant, anyị kwadoro mkpakọrịta ndị a maara n'etiti TNBC na BRCA1 PV (58.8%) na n'etiti luminal B BC na BRCA2 PV (55.6%) .16,43 The luminal A na HER2 + etuto ahụ na BRCA1 na ụgbọ ala 3.1 data na-agbanwe agbanwe na BRCA1 na BRers4 data BRers.
Anyị na-elekwasị anya na ụdị na ọnọdụ nke BRCA1/2 PV. N'ime otu anyị, BRCA1 PV na-emekarị bụ c.5035_5039delCTAAT. Ọ bụ ezie na Incorvaia et al. akọwaghị nke a variant na ha Sicilian otu, ndị ọzọ na-ede akwụkwọ akọwo ya dị ka a germline BRCA1 PV.34 Ọtụtụ BRCA1 PV ndị a hụrụ na anyị otu - eg c.181T>G, c.514del, c.3253dupA na c.3253dupA na c.5266dupC - nke a hụrụ n'anya nke abụọ nke BRCA1. (c.181T>G na c.5266dupC) a na-ahụkarị na Ashkenazi ndị Juu nke Eastern na Central Europe (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian na German), 44,45 na, na United States na Argentina, na nso nso a kọwara dị ka a "na-emekarị germline variant" na ndị ọrịa Italian .5.4. na 8 ọrịa cancer ara ara si n'ebe ugwu Sicily na Palermo na Messina. N'ụzọ na-akpali mmasị, ọbụna Incorvaia et al. chọtara c.3253dupA variant na ụfọdụ ezinụlọ na Catania.28 Ndị kasị nnochite anya BRCA2 PV bụ c.428dup, c.5851_5854delAGTT na intronic variant c.8487+1G>A, nke a kọrọ n'ụzọ zuru ezu 28 na onye na-arịa ọrịa na Palermo na c.458585585585855. A hụrụ PV n'ụlọ ndị dị n'ebe ugwu ọdịda anyanwụ Sicily, tumadi na mpaghara Trapani na Palermo, ebe a na-ahụ c.5851_5854delAGTT PV n'ime ezinụlọ dị n'ebe ugwu ọdịda anyanwụ Sicily. 8487+ 1G> Ụdị dị iche iche na-adịkarị na isiokwu sitere na Messina, Palermo, na Caltanissetta.28 Rebbeck et al. A kọwara na mbụ c.5851_5854delAGTT mgbanwe na Colombia.37 Ọzọ BRCA2 PV, c.631 + 1G>A, ka a chọtara na BC na ndị ọrịa OC sitere na Sicily (Agrigento, Siracusa na Ragusa) .28 N'ụzọ doro anya, anyị hụrụ ịdị n'otu nke abụọ BRCA2 variants (BRCA2 variants) 631 + 8 c.28 c. n'otu onye ọrịa ahụ, nke anyị chere na a ga-ekewapụ ya na ọnọdụ cis, dị ka a kọrọ na mbụ.
Anyị dekwara BRCA1 na BRCA2 PV na mpaghara OCCR putative na BCCR nke ngalaba protein na mkpụrụ ndụ ihe nketa. A kọwara mpaghara ndị a Rebbeck et al. dị ka ebe dị ize ndụ maka mmepe nke ovarian na ọrịa ara ara, n'otu n'otu.49 Otú ọ dị, ihe àmà banyere njikọ dị n'etiti ọnọdụ nke germline variants na ara ma ọ bụ ovarian cancer ize ndụ na-anọgide na-arụ ụka. njikọ dị n'etiti mpaghara OCCR putative na BCCR na njirimara BC. Nke a nwere ike ịbụ n'ihi ọnụ ọgụgụ ndị ọrịa nwere mmụgharị BRCA1/2. Site na ngalaba protein, BRCA1 PV na-ekesa n'akụkụ protein dum, na mgbanwe BRCA2 na-akacha mma na mpaghara imegharị BRC.
N'ikpeazụ, anyị na-ejikọta BC clinicopathological features na BRCA1 / 2 PV. N'ihi ọnụ ọgụgụ dị nta nke ndị ọrịa gụnyere, naanị anyị chọtara njikọ dị ịrịba ama n'etiti Ki-67 na ọkwa tumor. Ọ bụ ezie na nyocha na nkọwa nke Ki-67 na-anọgide na-arụrịta ụka, ọ bụ ezie na ọnụ ọgụgụ dị elu nke proliferative na-ejikọta ya na ihe ize ndụ dị ukwuu nke nlọghachi ọrịa na-adịwanye elu, na-ebelata n'etiti ụbọchị ndụ na ịlanarị ọrịa. "Obere" Ki-67 bụ 20%. Otú ọ dị, ọnụ ụzọ a anaghị emetụta ọnụ ọgụgụ ndị ọrịa BRCA1 / 2 mutation anyị, nke nwere ọnụ ahịa Ki-67 nke etiti nke 25% . Nke a na-emekarị na ọnụ ọgụgụ Ki-67 dị elu nwere ike ịkọwa site na mgbasawanye na luminal B na TNBC cohorts anyị, nke ole na ole luminal A etuto dị na-egosi na-egosi na 6 ọ bụla. (25-30%) nwere ike ime ka ndị ọrịa dịkwuo mma dịka prognosis ha si dị.53,54 Site na nsonaazụ nke nyocha anyị, mmekọrịta dị ịrịba ama abụghị ihe mgbagwoju anya. Ọ na-eme n'etiti Ki-67 dị elu na akara ule na ọnụnọ nke BRCA1 PV. N'ezie, ụbụrụ ndị metụtara BRCA1 bụ ụdị TNBC ma gosipụta ihe ndị ọzọ na-eme ihe ike.16,17
N'ikpeazụ, ọmụmụ ihe a na-enye akụkọ banyere ọnọdụ mgbanwe nke BRCA1 / 2 na òtù BC si n'ebe ọwụwa anyanwụ Sicily. N'ozuzu, nchoputa anyị na-adabere na ihe àmà na-emebu, ma n'ihe gbasara mmụba ngbanwe na njirimara Clinicopathological na BC. Ọmụmụ ihe ọzọ na ọnụ ọgụgụ buru ibu nke BRCA1 / 2-mutant BC ndị ọrịa, dị ka iji nyocha nke multigenome na-amụbawanye, dị ka iji nyocha nke multigenome na-eme ka ndị na-arịa ọrịa BC gbasawanye. dị iche na nke na-erughị ugboro ugboro karịa BRCA1 / 2. Nke a ga-ekwe ka njirimara na njikwa kwesịrị ekwesị nke ọnụ ọgụgụ na-arịwanye elu nke isiokwu na-arịwanye elu nke ọrịa cancer n'ihi mgbanwe mkpụrụ ndụ ihe nketa.
Anyị kwadoro na ndị ọrịa bịanyere aka n'akwụkwọ nkwenye ka ha wepụta ihe nlele tumor ha n'amaghị aha maka ebumnuche nyocha. Ndị ọrịa niile bịanyere aka na nkwenye ederede dị ka nkwupụta nke Helsinki si kwuo. Dị ka amụma AOU Policlinico "G.Rodolico - S.Marco si kwuo, a gụpụrụ ọmụmụ ihe a site na nyocha usoro ziri ezi n'ihi na BRCA1/2 na-eme nyocha ndị ọrịa na-arụ ọrụ na-arụ ọrụ na-arụ ọrụ dị ka ndị na-ahụ maka nlekọta ahụike BRCA1/2 si mee ihe niile dị ka ndị ọrụ nlekọta ahụike si dị ka ndị na-eme nchọpụta BRCA1 / 2 si mee ihe niile dị ka ndị ọrụ nlekọta ahụike si dị. nkwenye iji data ha maka ebumnuche nyocha.
Anyị na-ekele Prof. Paolo Vigneri maka enyemaka ya na-elekọta ndị ọrịa ara ara dị ka Kọmitii Ethics rịọrọ.
Federica Martorana na-akọ nsọpụrụ sitere na Istituto Gentili, Eli Lilly, Novartis, Pfizer. Ndị edemede ndị ọzọ na-ekwupụta enweghị esemokwu nke mmasị na ọrụ a.
1. Sung H, Ferlay J, Siegel RL, et al.Global Cancer Statistics 2020: GLOBOCAN na-eme atụmatụ na ọrịa cancer 36 na-anwụ anwụ na mba 185 gburugburu ụwa.CA Cancer J Clin.2021;71 (3): 209-249.doi: 10.3322