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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 Lub Tsev Haujlwm Saib Xyuas Kev Noj Qab Haus Huv University of 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, Ltalis;4 Medical Genetics, ARNAS Garibaldi, Catania, 95123, Ltalis;5 Tshuaj Genetics, ASP, Syracuse, 96100, Ltalis;6 Department of Biomedical thiab Biotechnology Sciences, University of Catania, Medical Genetics, Catania, Ltalis, 95123;7Oasi Research Institute-IRCCS, Troina, 94018, Ltalis Kev Sib Txuas Lus: Stefania Stella, tel +39 095 378 1946, email [email tiv thaiv];[email tiv thaiv] Lub Hom Phiaj: Cov kab mob hloov pauv hauv BRCA1 thiab BRCA2 thiab tsim mob qog noj ntshav (BC), zes qe menyuam (OC) thiab lwm yam cuam tshuam nrog kev pheej hmoo ntawm kev mob qog noj ntshav hauv lub neej.Kev kuaj rau BRCA noob yog qhov tseem ceeb rau kev soj ntsuam tus neeg muaj kev pheej hmoo, nrog rau kev nrhiav kev tiv thaiv hauv kev noj qab haus huv cov neeg nqa khoom thiab kho cov kev kho mob hauv cov neeg mob qog noj ntshav BRCA.Qhov ntau thiab tsawg ntawm BRCA cov cheeb tsam. thiab txawm hais tias cov ntaub ntawv muaj nyob ntawm BRCA cov kab mob sib txawv hauv cov tsev neeg Sicilian, cov kev tshawb fawb tshwj xeeb tsom cov pej xeem nyob rau sab hnub tuaj Sicily yog qhov tsis muaj.Lub hom phiaj ntawm peb txoj kev tshawb fawb yog los tshawb xyuas qhov xwm txheej thiab kev faib tawm ntawm BRCA pathogenic germline alterations nyob rau hauv ib pawg ntawm BC cov neeg mob los ntawm sab hnub tuaj Sicily thiab ntsuam xyuas lawv cov koom haum nrog rau cov kab mob tshwj xeeb ntawm cov kab mob sib kis tom ntej. e thiab proliferation index.RESULTS: Zuag qhia tag nrho, 35 cov neeg mob (9%) muaj BRCA pathogenic variant, 17 (49%) hauv BRCA1 thiab 18 (51%) hauv BRCA2.BRCA1 kev hloov pauv tau nthuav dav hauv triple-negative BC cov neeg mob, whereas BRCA2 mutations muaj ntau dua nyob rau hauv cov neeg mob uas tsis muaj BRCA. Cov qog nqaij hlav ntau dua qib thiab qhov loj hlob index.Conclusions: Peb qhov kev tshawb pom muab ib qho kev nthuav dav ntawm BRCA kev hloov pauv hauv cov neeg mob BC los ntawm sab hnub tuaj Sicily thiab lees paub lub luag haujlwm ntawm NGS kev tshuaj xyuas hauv kev txheeb xyuas cov neeg mob uas muaj keeb kwm yav dhau los BC.Txhua yam, cov ntaub ntawv no zoo ib yam nrog cov pov thawj yav dhau los txhawb BRCA kev tshuaj ntsuam xyuas kom zoo thiab kho mob qog noj ntshav hauv mutation.
Mob qog noj ntshav mis (BC) yog qhov mob hnyav tshaj plaws thoob ntiaj teb thiab mob qog noj ntshav siab tshaj plaws hauv cov poj niam.1 Cov yam ntxwv lom neeg uas txiav txim siab BC prognosis thiab kev coj cwj pwm tau raug tshawb fawb ntau thiab ib nrab elucidated nyob rau lub sij hawm.Qhov tseeb, ntau tus surrogate markers yog tam sim no siv los faib BC rau hauv txawv molecular subtypes.Lawv yog estrogen receptor progesterone (ERR) thiab / receptor receptor malaria (ERR) ER2) amplification, proliferation index Ki-67 thiab qog grade (G).2 Kev sib xyaw ntawm cov kev hloov pauv no tau txheeb xyuas cov kab hauv qab no BC: 1) Luminal qog, qhia ER thiab/los yog PgR qhia, suav txog 75% ntawm BCs.Cov qog no tau muab faib ntxiv rau hauv Luminal A, Ki-70% hauv qab no Ki-6, thiab 2% Luminal A, thaum Ki-H2 tsis zoo. sib npaug los yog siab dua 20% thiab nyob rau hauv lub xub ntiag ntawm HER2 amplification, tsis hais txog kev loj hlob index;2) HER2+ cov qog uas yog ER thiab PgR tsis zoo tab sis qhia HER2 amplification.Cov pab pawg no suav txog 10% ntawm tag nrho cov qog mis;3) Triple-negative mis cancer (TNBC), uas tsis qhia ER thiab PgR qhia thiab HER2 amplification, suav txog li 15% ntawm cov qog nqaij hlav mis.2-4
Ntawm cov BC subtypes no, qog nqaij hlav qib thiab kev loj hlob Performance index sawv cev rau cov biomarkers cross-sectional uas ncaj qha thiab nws tus kheej cuam tshuam nrog qog aggressiveness thiab prognosis.5,6
Ntxiv nrog rau cov yam ntxwv hais txog kab mob lom neeg, lub luag haujlwm ntawm kev hloov pauv caj ces ua rau kev loj hlob ntawm BC tau dhau los ua qhov tseem ceeb nyob rau ob peb xyoos dhau los.7 Txog 1 ntawm 10 lub mis qog tau txais los ntawm kev hloov pauv ntawm cov noob caj noob ces.8 Ob qhov kev tshawb fawb loj ntawm kev kis kabmob uas muaj ntau dua 180,000 BA, ib pawg poj niam tsis ntev los no muaj ntau tshaj 180,000 BRD. CA1, BRCA2, CHK2, PALB2, RAD51C, thiab RAD51D) feem ntau yog lub luag haujlwm rau cov noob caj noob ces BC.Ntawm cov noob no, BRCA1 thiab BRCA2 (tom qab no hu ua BRCA1/2) pom qhov muaj zog tshaj kev sib raug zoo nrog kev loj hlob ntawm cov qog nqaij hlav hauv lub mis 1 / 2 BRCA2 qhov tseeb, qhov tseem ceeb tshaj plaws ntawm kev loj hlob ntawm cov qog nqaij hlav hauv lub mis 1. BC thiab lwm yam malignancies, xws li zes qe menyuam, prostate, pancreatic, colorectal, thiab melanoma.Los ntawm hnub nyoog 13 txog 80 xyoo, qhov tshwm sim ntawm BC yog 72% ntawm cov poj niam uas muaj BRCA1 pathogenic variant (PV) thiab 69% ntawm cov poj niam uas muaj BRCA2 PV.14.
Qhov tseem ceeb tshaj plaws, kev tshaj tawm tsis ntev los no qhia tias BC kev pheej hmoo yog nyob ntawm hom PV.Qhov tseeb, piv nrog cov kab mob sib kis kab mob, cov kab mob tsis pom kev txawv txav, tshwj xeeb tshaj yog nyob rau hauv BRCA1 noob, cuam tshuam nrog kev pheej hmoo ntawm BC, tshwj xeeb tshaj yog cov poj niam laus.15
Lub xub ntiag ntawm BRCA1 lossis BRCA2 PV tau cuam tshuam nrog cov kab mob lom neeg thiab cov kab mob sib txawv.16,17 BRCA1-koom nrog BCs zoo li kev kho mob hnyav, tsis zoo sib txawv, thiab loj heev.Cov qog no feem ntau yog triple tsis zoo thiab muaj lub hnub nyoog ntxov ntawm qhov pib.Tumors uas tshwm sim los ntawm cov neeg mob uas tsis zoo-BRCA2. Cov qib thiab qhov nce qib nce ntxiv.Cov qog no muaj ntau dua hauv lumen B thiab feem ntau tshwm sim hauv cov neeg laus.16-18 Tshwj xeeb, kev hloov pauv hauv BRCA1 thiab BRCA2 nce rhiab heev rau cov kev kho mob tshwj xeeb, suav nrog cov ntsev platinum thiab cov tshuaj tsom xws li poly(ADP-ribose) polymerase inhibitors (PARPi19).
Ob peb xyoos dhau los, kev ua raws li cov tiam tom ntej sequencing (NGS) hauv kev kho mob tau ua rau muaj coob tus neeg mob BC mus kuaj molecular rau mob qog noj ntshav, nrog rau BRCA1/2.21 Ib yam nkaus, cov ntsiab lus raws li cov qauv qhia meej txog tsev neeg keeb kwm , pej xeem, thiab CA 2 cov ntsiab lus zoo dua rau kev txheeb xyuas tus kheej. Cov pov thawj tau sib sau ua ke ntawm BRCA1/2 kev tshuaj xyuas hauv cov neeg tshwj xeeb, qhia txog qhov sib txawv ntawm thaj chaw thaj chaw.24–27 Txawm hais tias muaj cov lus ceeb toom ntawm BC pawg nyob rau sab hnub poob Sicily, cov ntaub ntawv tsawg dua muaj nyob rau ntawm BRCA1/2 kev tshuaj ntsuam nyob rau sab hnub tuaj Sicily cov pejxeem.28,29
Peb piav qhia ntawm no cov txiaj ntsig ntawm kev tshuaj ntsuam germline BRCA1/2 hauv BC cov neeg mob los ntawm sab hnub tuaj Sicily, txuas ntxiv cuam tshuam txog qhov muaj BRCA1 lossis BRCA2 kev hloov pauv nrog lub ntsiab lus kho mob ntawm cov qog no.
Kev tshawb nrhiav rov qab tau ua tiav ntawm "Center for Experimental Oncology thiab Hematology" ntawm Policlinico Tsev Kho Mob.Rodolico - San Marco hauv Catania.Txij Lub Ib Hlis 2017 txog Lub Peb Hlis 2021, tag nrho ntawm 455 tus neeg mob uas muaj lub mis thiab zes qe menyuam, melanoma, pancreatic lossis prostate CA txoj kev tshawb fawb no tau xa mus rau kev kuaj mob qog noj ntshav. tau ua raws li Kev Tshaj Tawm ntawm Helsinki, thiab txhua tus neeg koom nrog tau sau ntawv tso cai ua ntej kev soj ntsuam molecular.
Histological thiab biological yam ntxwv (ER, PgR, HER2 raws li txoj cai, Ki-67, thiab qib) ntawm BC raug soj ntsuam ntawm core biopsy los yog phais kuaj, txiav txim siab tsuas aggressive qog Cheebtsam.Raws li cov yam ntxwv, BCs tau muab faib raws li nram no: luminal A (ER + thiab / los yog PgR +, HER-2 / 0%), Ki. ER2-, Ki-67≥20%), luminal B-HER2+ (ER thiab/lossis PgR+, HER2+), HER2+ (ER thiab PgR-, HER2+) lossis triple negative (ER thiab PgR-, HER2-).
Ua ntej ntsuas BRCA1 thiab BRCA2 kev hloov pauv, pawg neeg ua haujlwm ntau yam suav nrog tus kws kho mob oncologist, kws kho caj ces, thiab tus kws kho mob hlwb tau ua kev sib tham txog qog caj ces rau txhua tus neeg mob txhawm rau txiav txim siab muaj BRCA1 thiab / lossis BRCA1.los yog cov neeg uas muaj kev pheej hmoo siab ntawm PV hauv BRCA2 gene. Cov neeg mob xaiv tau ua raws li Italian Society of Medical Oncology (AIOM) cov lus qhia thiab cov lus pom zoo hauv zos Sicilian.30,31 Cov txheej txheem no suav nrog: (i) tsev neeg keeb kwm paub txog kab mob sib txawv hauv cov noob muaj kev cuam tshuam (piv txwv li, BRCA1, BRCA2, PTEN );(ii) txiv neej nrog BC;(iii) cov BC thiab OC;(iv) cov poj niam uas muaj BC <36 xyoo, TNBC <60 xyoo, los yog ob sab BC <50 xyoo;(v) keeb kwm kev kho mob ntawm tus kheej ntawm BC <50 xyoo thiab tsawg kawg yog ib tus txheeb ze qib thib ib: (a) BC <50 xyoo;(b) tsis yog mucinous thiab tsis muaj ciam teb OC ntawm txhua lub hnub nyoog;(c) ob sab BC;(d) txiv neej BC;(e) mob qog noj ntshav pancreatic;(f) mob qog noj ntshav prostate;(vi) Ob los yog ntau tshaj Tus Kheej keeb kwm ntawm BC> 50 xyoo thiab tsev neeg keeb kwm ntawm BC, OC, lossis kab mob qog noj ntshav rau cov txheeb ze uas yog cov txheeb ze thawj zaug rau ib leeg (xws li cov txheeb ze uas nws yog thawj tus txheeb ze);(vii) Tus kheej keeb kwm ntawm OC thiab tsawg kawg yog ib tus txheeb ze qib thib ib: (a) BC <50 xyoo;(b) NCO;(c) ob sab BC;(d) txiv neej BC;(vii) poj niam nrog qib siab serous OC.
Ib qho 20 mL peripheral cov ntshav kuaj tau los ntawm txhua tus neeg mob thiab sau rau hauv EDTA hlab (BD Biosciences).Genomic DNA raug cais tawm ntawm 0.7 mL tag nrho cov ntshav kuaj siv QIAsymphony DSP DNA Midi cov khoom siv cais tawm (QIAGEN, Hilden, Ltalis) raws li cov chaw tsim khoom cov lus qhia thiab dhau los ntawm ib qho kev ntsuas ntawm 0.7 mL. am, MA, USA) Ua kom muaj nuj nqis.Lub hom phiaj kev txhawb nqa thiab kev npaj tsev qiv ntawv yog ua los ntawm Oncomine™ BRCA Kev Tshawb Fawb Kev Tshawb Fawb Tus Kws Ua Haujlwm, npaj kom thauj mus rau Ion AmpliSeq ™ Tus Kws Ua Haujlwm Reagents DL8 Cov Khoom Siv rau kev npaj lub tsev qiv ntawv zoo raws li cov chaw tsim khoom cov lus qhia.Cov khoom siv muaj ob lub multiplex PCR primer pas uas siv tau los kawm tag nrho BRCA0303N03MBR0.0. 3) genes.Briefly, 15 µL ntawm txhua tus qauv diluted DNA (10 ng) tau ntxiv rau cov ntawv barcoded rau kev npaj tsev qiv ntawv thiab tag nrho cov reagents thiab consumables tau loaded rau ntawm Ion Chef™ instrument.Automated library npaj thiab barcoded qauv tsev qiv ntawv pooling tau ua nyob rau hauv lub Ion Chef™ instrument.Tus naj npawb ntawm cov khoom siv li qub. er Scientific, Waltham, MA, USA) raws li cov chaw tsim khoom cov lus qhia.Thaum kawg, cov tsev qiv ntawv tau muab sib xyaw ua ke hauv qhov sib npaug ntawm Ion Chef™ lub tsev qiv ntawv cov qauv raj (barcoded tubes) thiab thauj mus rau Ion Chef™ instrument.Sequencing tau ua los ntawm kev siv Ion Torrent S5 (Thermo Fisher 0 Scientific) (Thermo Fisher 0 Scienti) rmo Fisher Scientific).Kev tsom xam cov ntaub ntawv tau ua los ntawm Amplicon Suite (SmartSeq srl) thiab Ion Reporter Software.
Txhua qhov sib txawv nomenclature tau ua raws li cov lus qhia tam sim no ntawm Human Genome Variation Consortium, muaj nyob hauv online (HGVS, http://www.hgvs.org/mutnomen).Qhov tseem ceeb ntawm kev kho mob ntawm BRCA1/2 variants tau txhais los ntawm kev faib tawm ntawm International Consortium ENIGMA (Evidence-Based Network for Interpreting Gems). Cov ntaub ntawv sib txawv xws li ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, thiab UMD.Qhov kev faib tawm suav nrog tsib yam kev pheej hmoo sib txawv: benign (category I), zoo li benign (category II), variant ntawm qhov tsis paub tseeb (VUS, qeb III), yuav muaj cov kab mob (qeb cov kab mob ntawm cov kab mob IV), thiab cov txiaj ntsig zoo ntawm cov kab mob (category VS). muaj nuj nqi, ib qho cuab yeej paub nrog kev nkag mus rau 30 databases.32
Txhawm rau muab qhov tseem ceeb hauv kev kho mob rau txhua VUS, cov txheej txheem hauv qab no suav nrog kev kwv yees protein ntau tau siv: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:///genetics.bwh.harvard.edu/pph-Gu/gut/) vgd_input.php).Variants cais raws li chav kawm 1 thiab 2 raug suav hais tias yog hom tsiaj qus.
Sanger sequencing tau lees paub qhov muaj ntawm txhua tus kab mob sib txawv.Rov luv, ib khub ntawm cov primers tshwj xeeb tau tsim los rau txhua qhov kev kuaj pom txawv los ntawm kev siv BRCA1 thiab BRCA2 gene references sequences (NG_005905.2, NM_007294.3 thiab NG_012772.3, NM_00), ua raws li Sanger. ua sequencing.
Cov neeg mob uas kuaj qhov tsis zoo rau BRCA1/2 noob tau sim los ntawm multiplex ligation-dependent probe amplification (MLPA) raws li cov chaw tsim khoom cov lus qhia los ntsuas qhov muaj cov genomic rearrangements (LGR) luv luv, cov qauv DNA yog denatured thiab txog li 60 BRCA1 thiab BRCA2 cov noob caj noob ces siv rau txhua qhov tshwj xeeb, kev tshawb nrhiav DNA. s nyob rau hauv length.Probe amplification cov khoom, uas muaj ib tug tshwj xeeb txheej ntawm PCR amplicons, ces soj ntsuam los ntawm capillary electrophoresis thiab los ntawm Cofalyser.Net software ua ke nrog cov tsim nyog batch-specific Cofalyser ntxhuav (www.mrcholland.com).
Kev xaiv clincopathological variables (histological qib thiab Ki-67% proliferation Performance index) tau txuam nrog lub xub ntiag ntawm BRCA1/2 PV, xam siv Prism software v. 8.4 siv Fisher qhov tseeb xeem piv txwv li p-value <0.05 yog qhov tseem ceeb.
Nyob nruab nrab ntawm Lub Ib Hlis 2017 thiab Lub Peb Hlis 2021, 455 tus neeg mob tau tshuaj xyuas cov kab mob BRCA1/2 kev hloov pauv.Mutation testing tau ua nyob rau ntawm Policlinico Tsev Kho Mob Lub Chaw rau Kev Tshawb Fawb Oncology thiab Hematology.Raws li Sicilian cov lus qhia (http://www.gurs.regione.0iht.sidicia. Naio 2020), Rodolico ntawm Catania - San Marco "tag nrho, 389 tus neeg mob Muaj mob qog noj ntshav mis, 37 mob qog noj ntshav zes qe menyuam, 16 mob qog noj ntshav, 8 mob qog nqaij hlav prostate thiab 5 melanoma.Kev faib tawm ntawm cov neeg mob raws li hom mob qog noj ntshav thiab kev soj ntsuam cov txiaj ntsig tau pom hauv daim duab 1.
Daim duab 1 qhia ib daim ntawv qhia kev khiav dej num uas qhia txog cov ntsiab lus ntawm txoj kev tshawb no.Cov neeg mob uas muaj lub mis, melanoma, pancreatic, prostate, los yog zes qe menyuam qog tau sim rau kev hloov pauv hauv cov noob BRCA1 thiab BRCA2.
Cov ntawv luv: PVs, kab mob sib txawv;VUS, qhov txawv ntawm qhov tsis paub meej;WT, hom tsiaj qus BRCA1/2 ib ntus.
Peb tau xaiv peb cov kev tshawb fawb txog kev mob qog noj ntshav mis.Cov neeg mob muaj hnub nyoog nruab nrab ntawm 49 xyoo (ntau 23-89) thiab feem ntau yog poj niam (n=376, lossis 97%).
Ntawm cov kev kawm no, 64 (17%) muaj BRCA1/2 kev hloov pauv thiab tag nrho cov poj niam.Peb caug-tsib (9%) muaj PV thiab 29 (7.5%) muaj VUS.Seventeen (48.6%) ntawm 35 cov kab mob sib txawv tshwm sim hauv BRCA1 thiab 18 (51.4%) hauv BRCA1.7 thiab 5% VUS. BRCA2 (Daim duab 1 thiab 2).LGR tsis muaj nyob rau hauv MLPA tsom xam.
Daim duab 2. Kev soj ntsuam ntawm BRCA1 thiab BRCA2 kev hloov pauv hauv 389 tus neeg mob qog noj ntshav mis.(A) Kev faib tawm ntawm cov kab mob pathogenic variants (PV) (liab), qhov txawv ntawm qhov tseem ceeb (VUS) (txiv kab ntxwv), thiab WT (xiav) hauv 389 tus neeg mob qog noj ntshav mis;(B) 389 tus neeg mob cancer mis Peb caug-tsib (9%) muaj BRCA1/2 pathogenic variants (PVs). Ntawm lawv, 17 (48.6%) yog BRCA1 PV cab (tsaus liab) thiab 18 (51.4%) yog BRCA2 cov cab (lub teeb liab);(C) 29 (7.5%) ntawm 389 yam kawm nqa VUS, 5 (17.2%) BRCA1 noob (txiv kab ntxwv tsaus) thiab 24 (82.8%) BRCA2 noob (lub teeb txiv kab ntxwv).
Cov ntawv luv: PVs, kab mob sib txawv;VUS, qhov txawv ntawm qhov tsis paub meej;WT, hom tsiaj qus BRCA1/2 ib ntus.
Peb tom ntej no tau tshawb xyuas qhov ntau ntawm BC molecular subtypes hauv cov neeg mob nrog BRCA1/2 PV.Cov kev faib tawm suav nrog 2 (5.7%) luminal A, 15 (42.9%) luminal B, 3 (8.6%) luminal B-HER2+, 2 (5.7%) HER2+ thiab 13 (posBC.CA.1%) cov neeg mob TNongitive (37.1%). luminal B BC, 2 (11.8%) muaj kab mob HER2+, thiab 10 (58.8%) muaj TNBC.Tumors tsis muaj BRCA1 kev hloov pauv yog luminal A lossis luminal B-HER2+ (Daim duab 3).Hauv pawg BRCA2-zoo, 10 (55.6%) BHER, 3% (3%). (16.7%) TNBC thiab 2 (11.1%) yog luminal A (Daim duab 3 ).Tsis muaj HER2+ qog nyob rau hauv pab pawg no. Yog li, BRCA1 kev hloov pauv tau tshwm sim nyob rau hauv cov neeg mob TNBC, qhov kev hloov pauv BRCA2 muaj feem ntau hauv cov neeg lumen B.
Daim duab 3 Prevalence ntawm cancer mis subtypes nyob rau hauv cov neeg mob uas muaj pathogenic variants nyob rau hauv BRCA1 thiab BRCA2.Histograms qhia kev faib ntawm BRCA1- (dub liab) thiab BRCA2- (lub teeb liab) PVs ntawm molecular subtypes ntawm cov neeg mob cancer mis.Numbers qhia nyob rau hauv txhua lub thawv sawv cev rau feem pua ​​ntawm cov neeg mob nrog BRCA2PV1 thiab BRCA subtypes.
Cov ntawv luv: PVs, kab mob sib txawv;HER2+, human epidermal growth factor receptor 2 zoo;TNBC, triple-negative mob cancer mis.
Tom qab ntawd, peb tau soj ntsuam hom thiab noob hauv cheeb tsam ntawm BRCA1 thiab BRCA2 PVs.In BRCA1 PV, peb pom 7 ib leeg nucleotide variants (SNVs), 6 deletions, 3 duplications thiab 1 insertion.Tsuas yog ib qho kev hloov pauv (c.5522delCA.5) sawv cev rau ob qho tib si kev tshawb pom tshiab. 5039delCTAAT.Qhov kev hloov pauv no suav nrog kev tshem tawm tsib nucleotides (CTAAT) hauv BRCA1 exon 15, uas ua rau hloov pauv ntawm cov amino acid leucine los ntawm tyrosine ntawm codon 1679, thiab vim muaj kev hloov pauv nrog kev kwv yees lwm txoj kev nres codon ua rau ntxov ntxov PV proteins tsuas yog ib qho kev hloov pauv hauv trun xwb. splice site consensus cheeb tsam (c.4357+1G>T) (Table 1).
Hais txog BRCA2 PV, peb tau pom 6 qhov kev tshem tawm, 6 SNVs thiab 2 duplications.Tsis muaj qhov kev hloov pauv uas pom yog tshiab.Peb qhov kev hloov pauv tau tshwm sim hauv peb cov pej xeem, c.428dup thiab c.8487+1G>A pom hauv 3 yam kev kawm, ua raws li c.5851_5854del rov ua dua ntawm ob qhov kev hloov pauv hauv AGTT. C nyob rau hauv exon 5 ntawm BRCA2, kwv yees kom encode ib tug truncated, uas tsis yog-functional protein.The c.8487+1G>A mutation tshwm sim nyob rau hauv lub intronic cheeb tsam ntawm BRCA2 intron 19 (± 1,2) thiab cuam tshuam rau lub splicing pom zoo ib theem zuj zus, ua nyob rau hauv altered altered proteins 8. TT pathogenic variant yog vim muaj 4-nucleotide deletion los ntawm nucleotide txoj haujlwm 5851 txog 5854 hauv coding exon 10 ntawm BRCA2 noob thiab ua rau muaj kev hloov pauv hloov pauv nrog kev kwv yees lwm txoj kev nres codon (p.S1951WfsTer).Notably, raws li yav dhau los tau tshaj tawm cT08-2. tib tus neeg mob.34 Qhov kev hloov pauv thawj zaug suav nrog kev hloov pauv ntawm adenosine (A) hauv BRCA2 exon 7 nrog guanine (G) uas muaj nucleotide uas ua rau muaj kev hloov pauv ntawm valine mus rau isoleucine ntawm codon 211, isoleucine Amino acid yog ib qho amino acid uas muaj cov khoom zoo sib xws.Qhov kev hloov pauv no cuam tshuam rau ib txwm mRNA qhov tshwm sim nyob rau hauv ib cheeb tsam thib ob vatronic. ) hloov ua ntej exon 13 ntawm cov noob encoding BRCA2.Qhov hloov pauv c.7008-2A>T tuaj yeem tsim ntau cov ntawv teev lus sib txawv ntawm qhov ntev sib txawv.Tsis tas li ntawd, hauv pawg BRCA2 PVs, 4 tawm ntawm 18 hloov pauv (22.2%) yog intronic.
Peb mam li piav qhia BRCA1/2 deleterious mutations nyob rau hauv functional domains thiab protein-binding regions (Fig. 4).In BRCA1 noob, 50% ntawm PVs nyob rau hauv lub mis mob cancer pawg (BCCR), thaum 22% ntawm cov kev hloov nyob rau hauv lub zes qe menyuam cancer pawg (OCCR) (Daim duab 7. BRCA 4). BCCR cheeb tsam thiab 42.8% ntawm qhov kev hloov pauv tau nyob hauv OCCR (Fig. 4B).Tom ntej no, peb tau soj ntsuam qhov chaw ntawm PV nyob rau hauv BRCA1 thiab BRCA2 protein domains.Rau BRCA1 protein, peb pom peb PVs nyob rau hauv lub voj thiab coiled coil domains, thiab ob tug mutations nyob rau hauv lub BRCA .Fi . mus rau BRC rov sau npe, thaum 3 intronic thiab 3 exonic hloov pauv tau kuaj pom hauv oligo/oligosaccharide-binding (OB) thiab ntauwd (T) domains (Daim duab 4B).
Daim duab 4 Schematic sawv cev ntawm BRCA1 thiab BRCA2 proteins thiab localization ntawm pathogenic variants.Cov duab no qhia txog kev faib tawm ntawm BRCA1 (A) thiab BRCA2 (B) pathogenic variants nyob rau hauv cov neeg mob cancer mis.Exonic mutations yog qhia nyob rau hauv xiav, thaum intronic variants yog qhia nyob rau hauv txiv kab ntxwv.Lub bar qhov siab qhia cov naj npawb ntawm cov neeg mob thiab BRCA. BRCA1 protein muaj ib lub voj domain (RING) thiab ib qho chaw hauv cheeb tsam nuclear (NLS), coiled-coil domain, SQ / TQ pawg domain (SCD), thiab BRCA1 C-terminal domain (BRCT).(B) Cov protein BRCA2 muaj yim BRC rov ua dua, DNA-binding domain nrog H helical binolacide (charcoal binolithic ide) 3. folds, ib tug pej thuam domain (T), thiab Ib NLS nyob rau sab C.Areas hu ua Lub Tsev Kho Mob Cancer Cluster Region (BCCR) thiab Ovarian Cancer Cluster Region (OCCR) yog qhia nyob rau hauv qab.
Tom qab ntawd peb tau tshawb xyuas BC clincopathological yam ntxwv uas yuav cuam tshuam nrog qhov muaj BRCA1/2 PV.Tag nrho cov ntaub ntawv kho mob muaj rau 181 BRCA1/2-cov neeg mob tsis zoo (tsis muaj tus cab) thiab txhua tus neeg nqa khoom (n = 35).Muaj kev sib raug zoo ntawm cov qog proliferation tus nqi thiab qib.
Peb xam qhov kev faib tawm ntawm Ki-67 raws li qhov nruab nrab ntawm peb pawg (25%, thaj tsam <10-90%).Cov ntsiab lus nrog Ki-67 < 25% tau txhais tias "qis Ki-67", thaum cov tib neeg uas muaj nuj nqis ≥ 25% raug suav tias yog "siab Ki-67".Ki-67 qhov sib txawv ntawm BR-10 (p < BR) thiab cov carriers (p< 10000 PV). g. 5A).
Daim duab 5 Kev sib raug zoo ntawm Ki-67 nrog qib kev faib tawm hauv cov poj niam mob qog noj ntshav nrog thiab tsis muaj BRCA1 thiab BRCA2 PVs.(A) Boxplot qhia qhov nruab nrab Ki-67 qhov tseem ceeb hauv 181 tus neeg tsis muaj tus kabmob BC piv rau BRCA1 (18) lossis BRCA2 (17) PV cov neeg mob . Kev xa mus rau BC cov neeg mob qog noj ntshav rau hauv cov qib histological (G2 thiab G3) raws li BRCA1 thiab BRCA2 kev hloov pauv (WT cov ntsiab lus, BRCA1 thiab BRCA2 PVs cov neeg nqa khoom).
Ib yam li ntawd, peb tau tshuaj xyuas seb cov qog qog puas cuam tshuam nrog qhov muaj BRCA1/2 PV.Vim tias G1 BC tsis nyob hauv peb cov pej xeem, peb tau faib cov neeg mob ua ob pawg (G2 lossis G3).Ua raws li cov txiaj ntsig Ki-67, qhov kev tshuaj ntsuam tau qhia txog kev sib raug zoo ntawm cov qog qog thiab BRCA1 cov kev hloov pauv ntau dua, piv rau cov qog nqaij hlav tsis sib haum nrog BRCA1 kev hloov pauv ntau dua. ers (p<0.005) (Daim duab 5B ).
Kev nce qib hauv DNA sequencing thev naus laus zis tau ua kom tsis muaj kev vam meej hauv BRCA1/2 kev kuaj caj ces, nrog rau kev cuam tshuam tseem ceeb rau cov neeg mob uas muaj keeb kwm mob qog noj ntshav.Tam sim no, kwv yees li 20.000 BRCA1/2 variants tau txheeb xyuas thiab cais raws li American Society of Medical Genetics 35. spectrum sib txawv thoob plaws cheeb tsam.37 Nyob rau hauv ltalis, tus nqi ntawm BRCA1/2 PVs ranged los ntawm 8% mus rau 37%, qhia dav intra-lub teb chaws variability.38,39 Nrog ib tug pej xeem ntawm yuav luag 5 lab, Sicily yog lub thib tsib cheeb tsam loj tshaj plaws nyob rau hauv ltalis nyob rau hauv cov nqe lus ntawm cov naj npawb ntawm inhabitants.Txawm hais tias cov ntaub ntawv muaj nyob rau hauv lub sab hnub poob ntawm BRCA. ern ib feem ntawm cov kob.
Peb txoj kev tshawb fawb yog ib qho ntawm thawj tsab ntawv ceeb toom txog qhov tshwm sim ntawm BRCA1/2 PV hauv BC cov neeg mob nyob rau sab hnub tuaj Sicily.28 Peb tsom peb qhov kev tshuaj ntsuam BC, vim qhov no yog nyob deb ntawm cov kab mob ntau tshaj plaws hauv peb pawg neeg.
Thaum kuaj 389 BC cov neeg mob, 9% nqa BRCA1/2 PVs, sib npaug ntawm BRCA1 thiab BRCA2.Cov txiaj ntsig no zoo ib yam nrog cov uas tau tshaj tawm yav dhau los hauv cov neeg Italians.28 Txaus siab, 3% (13/389) ntawm peb pawg yog txiv neej.Qhov tus nqi no siab dua li qhov xav tau rau txiv neej mob qog noj ntshav (1% ntawm tag nrho cov neeg mob ntshav qab zib hom 2 BC). Txawm li cas los xij, tsis muaj leej twg ntawm cov txiv neej no tau tsim ib qho BRCA1/2 PV, yog li lawv yog cov neeg sib tw rau kev tshuaj ntsuam xyuas molecular ntxiv los txiav txim qhov muaj cov kev hloov pauv tsis tshua muaj xws li PALB2, RAD51C thiab D, ntawm lwm tus.Variants ntawm qhov tsis paub tseeb tau muab rov qab rau hauv 7% ntawm cov ntsiab lus uas BRCA2 VUS tau ua pov thawj, 42 qhov pov thawj zoo sib xws.
Thaum peb txheeb xyuas qhov kev faib tawm ntawm BC molecular subtypes hauv BRCA1/2 cov poj niam mutant, peb paub tseeb tias cov koom haum paub txog ntawm TNBC thiab BRCA1 PV (58.8%) thiab nruab nrab ntawm luminal B BC thiab BRCA2 PV (55.6%).16,43 Lub luminal A thiab HER2+ qog hauv BRCA1 cov ntaub ntawv.1 thiab cov ntaub ntawv BRCA2 uas twb muaj lawm.
Peb mam li tsom ntsoov rau hom thiab qhov chaw ntawm BRCA1/2 PV.In peb pawg, feem ntau BRCA1 PV yog c.5035_5039delCTAAT.Txawm tias Incorvaia li al.tsis tau piav qhia txog qhov sib txawv no hauv lawv pawg Sicilian, lwm tus kws sau ntawv tau tshaj tawm tias nws yog germline BRCA1 PV.34 Ob peb BRCA1 PVs tau pom nyob rau hauv peb pawg - piv txwv li c.181T>G, c.514del, c.3253dupA thiab c.5266dupC hauv 1c. .181T>G thiab c.5266dupC) feem ntau pom muaj nyob rau hauv Ashkenazi cov neeg Yudais ntawm Eastern thiab Central Europe (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian thiab German), 44,45 thiab, nyob rau hauv lub tebchaws United States thiab Argentina, tsis ntev los no txhais tau tias yog ib tug "recurrent 4 germ" nyob rau hauv Italian variant. yav dhau los tau txheeb xyuas hauv 8 tus neeg mob qog noj ntshav ntawm lub mis los ntawm sab qaum teb Sicily hauv Palermo thiab Messina.Interestingly, txawm Incorvaia li al.pom cov c.3253dupA variant hauv qee tsev neeg hauv Catania.28 Cov neeg sawv cev tshaj plaws BRCA2 PVs yog c.428dup, c.5851_5854delAGTT thiab intronic variant c.8487+1G>A, uas tau tshaj tawm ntau yam ntxiv 28 hauv ib tus neeg mob hauv Palermo 4 c.5PV5 tau soj ntsuam, c. d nyob rau hauv cov tsev neeg nyob rau sab qaum teb hnub poob Sicily, feem ntau yog nyob rau hauv lub Trapani thiab Palermo cheeb tsam, whereas c.5851_5854delAGTT PV tau pom nyob rau hauv cov tsev neeg nyob rau sab qaum teb hnub poob Sicily.Lub 8487+1G>Ib qho txawv yog ntau dua nyob rau hauv cov kev kawm los ntawm Messina, Palermo, thiab Caltanissetta.28 Rebbeck.yav dhau los tau piav qhia txog kev hloov pauv c.5851_5854delAGTT hauv Colombia.37 Lwm BRCA2 PV, c.631+1G>A, tau pom nyob rau hauv cov neeg mob BC thiab OC los ntawm Sicily (Agrigento, Siracusa thiab Ragusa).28 Qhov tshwj xeeb, peb tau pom qhov sib koom ua ke ntawm ob lub vats.A-6BRCA2 thiab BRCA2. 2A>T) nyob rau hauv tib tus neeg mob, uas peb xav tias yuav tsum tau cais nyob rau hauv cis hom, raws li yav tas los qhia zoo li ntawd.34,46 Cov BRCA2 uble kev hloov pauv no tiag tiag nquag pom nyob rau hauv cheeb tsam Italian thiab tau pom los qhia ntxov ntxov nres codons, cuam tshuam tus xa xov RNA splicing thiab ua rau BRCA74 protein ua tsis tiav.
Peb kuj tau teeb tsa BRCA1 thiab BRCA2 PVs nyob rau hauv putative OCCR thiab BCCR cheeb tsam ntawm protein domains thiab noob.Cov cheeb tsam no tau piav qhia los ntawm Rebbeck li al.raws li thaj chaw muaj kev pheej hmoo rau kev loj hlob ntawm zes qe menyuam thiab mob qog noj ntshav, ntsig txog.49 Txawm li cas los xij, cov pov thawj hais txog kev sib koom ua ke ntawm qhov chaw ntawm cov kab mob sib txawv thiab kev pheej hmoo mob qog noj ntshav ntawm lub mis los yog zes qe menyuam tseem muaj teeb meem. ative OCCR thiab BCCR cheeb tsam thiab BC cov yam ntxwv.Qhov no tej zaum yuav yog vim muaj tsawg tus neeg mob nrog BRCA1/2 kev hloov pauv.Los ntawm qhov kev xav ntawm cov protein, BRCA1 PVs raug faib raws tag nrho cov protein, thiab BRCA2 kev hloov pauv tau zoo dua pom hauv BRC rov sau npe.
Thaum kawg, peb cuam tshuam txog BC clincopathological nta nrog BRCA1/2 PV.Vim muaj cov neeg mob tsawg, peb tsuas pom muaj kev sib raug zoo ntawm Ki-67 thiab qog nqaij hlav.Txawm hais tias qhov kev ntsuam xyuas thiab kev txhais ntawm Ki-67 tseem muaj teeb meem me ntsis, nws yog qhov tseeb tias qhov kev pheej hmoo loj ntawm cov kab mob muaj feem cuam tshuam rau hnub uas muaj kev cuam tshuam ntau ntxiv. ishing ntawm "siab" thiab "qis" Ki-67 yog 20%. Txawm li cas los xij, qhov pib no tsis siv rau peb cov BRCA1/2 hloov pauv cov neeg mob, uas muaj qhov nruab nrab Ki-67 tus nqi ntawm 25%. tawm (25–30%) yuav zoo dua stratify cov neeg mob raws li lawv cov prognosis.53,54 Los ntawm cov kev tshwm sim ntawm peb tsom xam, ib tug tseem ceeb correlation yog tsis xav tsis thoob.Ua nyob rau hauv siab Ki-67 thiab qib thiab muaj BRCA1 PV.Qhov tseeb, BRCA1-txog qog nqaij hlav yog ib yam ntawm TNBC thiab nthuav ntau yam.16.
Hauv kev xaus, txoj kev tshawb no muab ib daim ntawv qhia txog kev hloov pauv ntawm BRCA1/2 nyob rau hauv ib pawg BC los ntawm sab hnub tuaj Sicily.Zuag qhia tag nrho, peb cov kev tshawb pom tau zoo ib yam nrog cov pov thawj uas twb muaj lawm, ob qho tib si ntawm kev hloov pauv ntau thiab cov yam ntxwv kho mob hauv BC.Ntau cov kev tshawb fawb hauv cov pej xeem loj ntawm BRCA1/2-mutants BC cov neeg mob uas muaj kev sib ntaus sib tua, xws li kev sib ntaus sib tua BC. PVs uas txawv thiab tsis tshua muaj ntau dua li BRCA1/2.Qhov no yuav tso cai rau kev txheeb xyuas thiab kev tswj xyuas kom zoo ntawm cov neeg coob coob uas muaj feem yuav mob qog noj ntshav vim yog kev hloov ntawm caj ces.
Peb tau lees paub tias cov neeg mob tau kos npe rau kev tso cai tso tawm lawv cov qog qog tsis qhia npe rau kev tshawb fawb lub hom phiaj.Txhua tus neeg mob tau kos npe rau daim ntawv tso cai pom zoo raws li Kev Tshaj Tawm ntawm Helsinki.Raws li txoj cai ntawm AOU Policlinico "G.Rodolico - S.Marco", txoj kev tshawb fawb no raug zam los ntawm kev tshuaj xyuas kev coj ncaj ncees vim hais tias BRCA tau ua raws li txoj cai 1/2. kuj pom zoo siv lawv cov ntaub ntawv rau kev tshawb fawb.
Peb ua tsaug rau Prof. Paolo Vigneri rau nws txoj kev pabcuam hauv kev saib xyuas cov neeg mob qog noj ntshav mis raws li tau thov los ntawm Pawg Saib Xyuas Kev Ncaj Ncees.
Federica Martorana tshaj tawm Honoraria los ntawm Istituto Gentili, Eli Lilly, Novartis, Pfizer.Lwm cov kws sau ntawv tshaj tawm tias tsis muaj kev tsis sib haum xeeb ntawm txoj haujlwm no.
1. Sung H, Ferlay J, Siegel RL, thiab al.Global Cancer Statistics 2020: GLOBOCAN kwv yees qhov tshwm sim thiab kev tuag ntawm 36 mob qog noj ntshav hauv 185 lub teb chaws thoob ntiaj teb.CA Cancer J Clin.2021;71(3):209-2169.ac3.