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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 ntawm Chaw Kho Mob 6, thiab Kev sim tshuaj, University of Catania, Catania, 95123, Ltalis; 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, Ltalis; 5 Tshuaj Genetics, ASP, Syracuse, 96100, Ltalis; 6 Lub Tsev Haujlwm Saib Xyuas 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, xov tooj +39 095 378 1946, email [email protected]; [email protected] Lub Hom Phiaj: Kev hloov pauv ntawm cov noob caj noob ces hauv BRCA1 thiab BRCA2 thiab mob qog noj ntshav hauv lub mis (BC), zes qe menyuam (OC) thiab lwm yam uas cuam tshuam nrog kev pheej hmoo ntawm mob qog noj ntshav hauv lub neej. Kev kuaj rau BRCA gene yog qhov tseem ceeb rau kev ntsuam xyuas kev pheej hmoo ntawm tus kheej, nrog rau kev nrhiav cov txheej txheem tiv thaiv hauv cov neeg nqa khoom noj qab haus huv thiab kev kho mob rau cov neeg mob qog noj ntshav. Kev hloov pauv ntawm BRCA1 thiab BRCA2 sib txawv ntau thoob plaws thaj chaw, thiab txawm hais tias cov ntaub ntawv muaj nyob rau ntawm BRCA pathogenic variants hauv tsev neeg Sicilian, kev tshawb fawb tshwj xeeb tsom mus rau cov pej xeem hauv sab hnub tuaj Sicily tsis muaj. Lub hom phiaj ntawm peb txoj kev tshawb fawb yog los tshawb xyuas qhov tshwm sim thiab kev faib tawm ntawm BRCA pathogenic germline changes hauv ib pawg neeg mob BC los ntawm sab hnub tuaj Sicily thiab los ntsuam xyuas lawv txoj kev sib raug zoo nrog cov yam ntxwv BC tshwj xeeb siv cov cim tom ntej. Kev muaj kev hloov pauv cuam tshuam nrog qib qog thiab cov ntsuas kev loj hlob. COV TXiaj Ntsig: Tag nrho, 35 tus neeg mob (9%) muaj BRCA pathogenic variant, 17 (49%) hauv BRCA1 thiab 18 (51%) hauv BRCA2. BRCA1 kev hloov pauv yog qhov tshwm sim hauv cov neeg mob BC triple-negative, thaum BRCA2 mutations yog ntau dua hauv luminal Cov neeg mob BC. Piv nrog cov neeg tsis nqa cov noob caj noob ces, cov neeg mob uas muaj BRCA1 variants muaj qib qog nqaij hlav siab dua thiab cov ntsuas proliferative siab dua. Cov Lus Xaus: Peb cov kev tshawb pom muab kev pom dav dav ntawm BRCA mutational status 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 BC uas tau txais los ntawm noob caj noob ces. Zuag qhia tag nrho, cov ntaub ntawv no yog sib xws nrog cov pov thawj yav dhau los txhawb kev tshuaj ntsuam BRCA rau kev tiv thaiv thiab kho mob qog nqaij hlav hauv cov neeg nqa cov noob caj noob ces.
Mob qog noj ntshav hauv lub mis (BC) yog mob qog noj ntshav uas tshwm sim ntau tshaj plaws thoob ntiaj teb thiab yog mob qog noj ntshav uas ua rau cov poj niam tuag coob tshaj plaws.1 Cov yam ntxwv ntawm lub cev uas txiav txim siab txog kev kwv yees ntawm BC thiab tus cwj pwm kho mob tau raug kawm ntau yam thiab piav qhia ib feem dhau ib ntus. Qhov tseeb, ntau lub cim surrogate tam sim no siv los faib BC ua ntau hom molecular subtypes. Lawv yog estrogen (ER) thiab/lossis progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) amplification, proliferation index Ki-67 thiab tumor grade (G).2 Kev sib xyaw ua ke ntawm cov variables no tau txheeb xyuas cov pawg BC hauv qab no: 1) Luminal tumors, qhia ER thiab/lossis PgR expression, suav txog 75% ntawm BCs. Cov qog noj ntshav no tau muab faib ua Luminal A, thaum Ki-67 qis dua 20% thiab HER2 negative, thiab Luminal B, thaum Ki-67 sib npaug lossis siab dua 20% thiab nyob rau hauv qhov muaj HER2 amplification, tsis hais txog proliferation index; 2) Cov qog HER2+ uas yog ER thiab PgR tsis zoo tab sis qhia HER2 amplification.Pawg no suav txog 10% ntawm tag nrho cov qog mis; 3) Mob qog mis peb npaug tsis zoo (TNBC), uas tsis qhia ER thiab PgR qhia thiab HER2 amplification, suav txog li 15% ntawm cov mob qog mis.2-4
Ntawm cov BC subtypes no, qib qog nqaij hlav thiab qhov ntsuas kev loj hlob sawv cev rau cov cim qhia txog cov kab mob uas cuam tshuam ncaj qha thiab ywj pheej nrog kev loj hlob ntawm qog nqaij hlav thiab kev kwv yees.5,6
Ntxiv rau cov yam ntxwv ntawm lub cev uas tau hais los saum toj no, lub luag haujlwm ntawm kev hloov pauv caj ces uas ua rau muaj BC tau dhau los ua qhov tseem ceeb dua nyob rau ob peb xyoos dhau los.7 Kwv yees li 1 ntawm 10 tus qog nqaij hlav mis yog los ntawm kev hloov pauv ntawm cov noob caj ces hauv cov noob caj ces tshwj xeeb.8 Ob txoj kev tshawb fawb loj txog kev sib kis kab mob uas muaj ntau dua 180,000 tus poj niam nyuam qhuav txheeb xyuas ib pawg ntawm yim noob caj ces (piv txwv li, ATM, BARD1, BRCA1, BRCA2, CHK2, PALB2, RAD51C, thiab RAD51D) uas yog lub luag haujlwm tseem ceeb rau BC uas los ntawm kev yug los. Ntawm cov noob caj ces no, BRCA1 thiab BRCA2 (tom qab no hu ua BRCA1/2) tau qhia txog kev sib raug zoo tshaj plaws nrog kev loj hlob ntawm cov qog nqaij hlav mis.9-12 Qhov tseeb, kev hloov pauv ntawm cov noob caj ces BRCA1/2 ua rau muaj kev pheej hmoo ntawm BC hauv lub neej nrog rau lwm yam mob qog noj ntshav, suav nrog ovarian, prostate, pancreatic, colorectal, thiab melanoma. Txij li hnub nyoog 13 txog 80 xyoo, qhov tshwm sim ntawm BC yog 72% rau cov poj niam uas muaj BRCA1 pathogenic variant (PV) thiab 69% ntawm cov poj niam uas muaj BRCA2 PV.14
Qhov tseem ceeb, tsab ntawv tshaj tawm tsis ntev los no qhia tias qhov kev pheej hmoo ntawm BC nyob ntawm hom PV. Qhov tseeb, piv nrog cov kab mob pathogenic truncating variants, glaring missense variants, tshwj xeeb tshaj yog nyob rau hauv BRCA1 gene, yog txuam nrog kev pheej hmoo ntawm BC txo qis, tshwj xeeb tshaj yog rau cov poj niam laus.15
Qhov muaj BRCA1 lossis BRCA2 PV tau cuam tshuam nrog ntau yam kev hloov pauv ntawm lub cev thiab kev kho mob.16,17 BRCA1-cuam tshuam nrog BCs feem ntau yog cov neeg mob hnyav, tsis sib txawv, thiab loj hlob sai heev. Cov qog no feem ntau yog triple negative thiab muaj hnub nyoog thaum ntxov. Cov qog uas tshwm sim hauv cov neeg mob BRCA2-mutated feem ntau qhia txog qib nruab nrab mus rau qib sib txawv thiab cov ntsuas proliferative sib txawv. Cov qog no feem ntau tshwm sim hauv lumen B thiab feem ntau tshwm sim rau cov neeg laus.16-18 Qhov tseem ceeb, kev hloov pauv hauv BRCA1 thiab BRCA2 ua rau muaj kev nkag siab rau cov kev kho mob tshwj xeeb, suav nrog cov ntsev platinum thiab cov tshuaj tsom xws li poly (ADP-ribose) polymerase inhibitors (PARPi).19,20
Tau ob peb xyoos dhau los no, kev siv cov txheej txheem txheeb xyuas tiam tom ntej (NGS) hauv kev kho mob tau ua rau muaj ntau tus neeg mob BC los kuaj mob qog noj ntshav, suav nrog BRCA1 / 2.21 Tib lub sijhawm, cov lus txhais raws li cov qauv tseeb txog keeb kwm tsev neeg, cov neeg nyob hauv zej zog, thiab cov yam ntxwv ntawm kev kho mob kom paub zoo dua txog cov tib neeg tsim nyog rau kev kuaj BRCA1 / 2.22,23 Hauv qhov no, cov pov thawj tau sau los ntawm kev tshuaj ntsuam BRCA1 / 2 hauv cov pej xeem tshwj xeeb, qhia txog qhov sib txawv thoob plaws thaj chaw.24–27 Txawm hais tias muaj cov ntawv tshaj tawm txog BC cohort hauv sab hnub poob Sicily, tsawg dua cov ntaub ntawv muaj nyob rau ntawm kev tshuaj ntsuam BRCA1 / 2 hauv cov pej xeem sab hnub tuaj Sicily.28,29
Peb piav qhia ntawm no cov txiaj ntsig ntawm kev tshuaj ntsuam BRCA1/2 hauv cov neeg mob BC los ntawm sab hnub tuaj Sicily, ntxiv rau qhov muaj BRCA1 lossis BRCA2 mutations nrog cov yam ntxwv tseem ceeb ntawm cov qog no.
Ib txoj kev tshawb nrhiav rov qab tau ua tiav ntawm "Center for Experimental Oncology and Hematology" ntawm Policlinico Tsev Kho Mob. Rodolico - San Marco hauv Catania. Txij lub Ib Hlis 2017 txog lub Peb Hlis 2021, tag nrho 455 tus neeg mob uas muaj mob qog nqaij hlav mis thiab zes qe menyuam, melanoma, pancreatic lossis prostate tau raug xa mus rau peb lub chaw kuaj mob molecular rau kev kuaj mob BRCA / 2. Txoj kev tshawb fawb no tau ua raws li Daim Ntawv Tshaj Tawm ntawm Helsinki, thiab txhua tus neeg koom nrog tau muab kev pom zoo ua ntej kev tshuaj xyuas molecular.
Cov yam ntxwv ntawm keeb kwm thiab kab mob (ER, PgR, HER2 status, Ki-67, thiab qib) ntawm BC tau raug soj ntsuam ntawm cov qauv biopsy lossis phais, xav txog tsuas yog cov khoom qog nqaij hlav loj heev. Raws li cov yam ntxwv no, BCs tau raug faib ua raws li nram no: luminal A (ER+ thiab/lossis PgR+, HER2-, Ki-67<20%), luminal B (ER+ thiab/lossis PgR+, HER2-, 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 yuav soj ntsuam qhov xwm txheej ntawm BRCA1 thiab BRCA2 mutation, ib pab neeg ntau yam suav nrog tus kws kho mob qog nqaij hlav, tus kws kho mob caj ces, thiab tus kws kho mob hlwb tau ua kev sab laj txog kev kho mob qog nqaij hlav rau txhua tus neeg mob kom paub seb puas muaj BRCA1 thiab/lossis BRCA1. lossis cov tib neeg uas muaj feem yuav muaj PV ntau hauv BRCA2 gene. Kev xaiv neeg mob tau ua raws li Italian Society of Medical Oncology (AIOM) cov lus qhia thiab cov lus pom zoo hauv zos Sicilian.30,31 Cov qauv no suav nrog: (i) keeb kwm tsev neeg ntawm cov kab mob sib txawv uas paub hauv cov noob caj ces uas muaj kev phom sij (piv txwv li, BRCA1, BRCA2, TP53, PTEN); (ii) cov txiv neej uas muaj BC; (iii) cov neeg uas muaj BC thiab OC; (iv) cov poj niam uas muaj BC <36 xyoo, TNBC <60 xyoo, lossis ob sab BC <50 xyoo; (v) keeb kwm kho mob ntawm BC <50 xyoo thiab tsawg kawg yog ib tus txheeb ze thawj zaug: (a) BC <50 xyoo; (b) OC uas tsis mucinous thiab tsis ciam teb ntawm txhua lub hnub nyoog; (c) BC ob sab; (d) txiv neej BC; (e) mob qog nqaij hlav pancreas; (f) mob qog nqaij hlav prostate; (vi) ob lossis ntau dua keeb kwm tus kheej ntawm BC > 50 xyoo thiab keeb kwm tsev neeg ntawm BC, OC, lossis mob qog nqaij hlav pancreas rau cov txheeb ze uas yog cov txheeb ze thawj zaug rau ib leeg (suav nrog cov txheeb ze uas nws yog cov txheeb ze thawj zaug); (vii) Keeb kwm tus kheej ntawm OC thiab tsawg kawg yog ib tus txheeb ze thawj zaug: (a) BC <50 xyoo; (b) NOC; (c) ob sab BC; (d) txiv neej BC; (vii) poj niam nrog qib siab serous OC.
Tau txais cov qauv ntshav peripheral 20 mL los ntawm txhua tus neeg mob thiab sau rau hauv EDTA raj (BD Biosciences). Genomic DNA tau rho tawm los ntawm 0.7 mL tag nrho cov qauv ntshav siv QIAsymphony DSP DNA Midi kit Isolation Kit (QIAGEN, Hilden, Ltalis) raws li cov lus qhia ntawm cov chaw tsim khoom thiab dhau los ntawm Qubit® 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) Ua qhov ntsuas. Kev npaj cov ntaub ntawv thiab kev npaj cov ntaub ntawv hauv tsev qiv ntawv yog ua los ntawm Oncomine™ BRCA Research Assay Chef, npaj txhij rau kev thauj mus rau hauv Ion AmpliSeq™ Chef Reagents DL8 Kit rau kev npaj cov ntaub ntawv hauv tsev qiv ntawv raws li cov lus qhia ntawm cov chaw tsim khoom. Cov khoom siv muaj ob lub pas dej PCR primer uas siv tau los kawm txhua yam BRCA1 (NM_007300.3) thiab BRCA2 (NM_000059.3) noob. Hauv luv luv, 15 µL ntawm txhua tus qauv DNA diluted (10 ng) tau ntxiv rau cov phaj barcode rau kev npaj cov ntaub ntawv hauv tsev qiv ntawv thiab txhua yam reagents thiab cov khoom siv tau thauj mus rau ntawm Ion Chef™ instrument. Kev npaj cov ntaub ntawv hauv tsev qiv ntawv thiab kev sib sau ua ke ntawm cov qauv ntaub ntawv hauv tsev qiv ntawv tau ua tiav ntawm Ion Chef™ instrument. Tus naj npawb ntawm cov ntaub ntawv uas tau npaj lawm ces tau ntsuas los ntawm Qubit® 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) raws li cov lus qhia ntawm cov chaw tsim khoom. Thaum kawg, cov ntaub ntawv hauv tsev qiv ntawv tau muab tso ua ke hauv cov piv sib npaug hauv cov raj xa ntawv hauv tsev qiv ntawv Ion Chef™ (cov raj xa ntawv barcoded) thiab thauj mus rau hauv Ion Chef™ instrument. Kev txheeb xyuas tau ua tiav los ntawm kev siv Ion Torrent S5 (Thermo Fisher Scientific) instrument (Thermo Fisher Scientific) siv Ion 510 Chip (Thermo Fisher Scientific). Kev tshuaj xyuas cov ntaub ntawv tau ua los ntawm Amplicon Suite (SmartSeq srl) thiab Ion Reporter Software.
Txhua lub npe ntawm cov noob caj noob ces sib txawv 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 siv kev faib tawm ntawm International Consortium ENIGMA (Evidence-Based Network for Interpreting Germline Mutant Alleles, https://enigmaconsortium.org/) thiab sab laj nrog cov ntaub ntawv sib txawv xws li ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, thiab UMD. Kev faib tawm suav nrog tsib pawg kev pheej hmoo sib txawv: benign (qeb I), tej zaum benign (qeb II), variant ntawm qhov tsis paub meej tseem ceeb (VUS, qeb III), tej zaum yuav pathogenic (qeb IV), thiab pathogenic (qeb V). VarSome kuj tau tshuaj xyuas qhov cuam tshuam ntawm kev hloov pauv rau cov qauv protein thiab kev ua haujlwm, ib lub cuab yeej qhia txog kev nkag mus rau 30 lub ntaub ntawv.32
Yuav kom paub txog qhov tseem ceeb ntawm kev kho mob rau txhua tus VUS, cov txheej txheem kwv yees protein hauv qab no tau siv: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/) thiab Align-GVGD (http://agvgd.hci.utah.edu/agvgd_input.php). Cov variants uas tau muab faib ua pawg 1 thiab 2 tau suav tias yog hom qus.
Kev tshawb nrhiav Sanger sequencing tau lees paub tias muaj txhua yam kab mob sib txawv. Hauv luv luv, ib khub ntawm cov primers tshwj xeeb tau tsim rau txhua yam kab mob uas pom los ntawm kev siv cov kab mob BRCA1 thiab BRCA2 gene reference sequences (NG_005905.2, NM_007294.3 thiab NG_012772.3, NM_000059.3, feem). Yog li ntawd, targeted PCR tau ua raws li Sanger sequencing.
Cov neeg mob uas kuaj tsis pom muaj BRCA1/2 gene raug kuaj los ntawm multiplex ligation-dependent probe amplification (MLPA) raws li cov lus qhia ntawm cov chaw tsim khoom los ntsuas seb puas muaj kev hloov pauv loj ntawm genomic (LGR). Hauv luv luv, cov qauv DNA raug denatured thiab siv txog li 60 BRCA1 thiab BRCA2 gene-specific probes, txhua tus ntes tau ib qho DNA sequence tshwj xeeb kwv yees li 60 nucleotides ntev. Cov khoom Probe amplification, uas muaj ib pawg PCR amplicons tshwj xeeb, tom qab ntawd raug tshuaj xyuas los ntawm capillary electrophoresis thiab los ntawm Cofalyser.Net software ua ke nrog cov rooj Cofalyser tshwj xeeb (www.mrcholland.com).
Cov kev hloov pauv clinicopathological xaiv (qib histological thiab Ki-67% proliferation index) tau cuam tshuam nrog qhov muaj BRCA1/2 PV, xam siv Prism software v. 8.4 siv Fisher's exact test xav tias p-value <0.05 yog qhov tseem ceeb.
Nruab nrab ntawm Lub Ib Hlis 2017 thiab Lub Peb Hlis 2021, 455 tus neeg mob tau raug tshuaj xyuas rau cov kab mob BRCA1 / 2 mutations. Kev kuaj mob mutation tau ua tiav ntawm Policlinico Tsev Kho Mob Lub Chaw rau Kev Tshawb Fawb Oncology thiab Hematology. Raws li cov lus qhia Sicilian (http://www.gurs.regione.sicilia.it/Indicep1.htm, N. 02-Venerdì 10 Lub Ib Hlis 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 pancreatic, 8 mob qog noj ntshav prostate thiab 5 melanoma. Kev faib tawm ntawm cov neeg mob raws li hom mob qog noj ntshav thiab cov txiaj ntsig ntawm kev tshuaj xyuas tau pom hauv Daim Duab 1.
Daim Duab 1 qhia txog daim duab qhia txog kev tshawb fawb. Cov neeg mob uas muaj mob qog nqaij hlav hauv lub mis, melanoma, pancreatic, prostate, lossis ovarian tau raug kuaj xyuas seb puas muaj kev hloov pauv hauv cov noob BRCA1 thiab BRCA2.
Cov Lus Luv: PVs, pathogenic variant; VUS, variant ntawm uncertain significance; WT, wild-type BRCA1/2 sequence.
Peb xaiv peb txoj kev tshawb fawb rau cov neeg mob qog noj ntshav hauv lub mis. Cov neeg mob muaj hnub nyoog nruab nrab ntawm 49 xyoo (ntau ntawm 23-89) thiab feem ntau yog poj niam (n = 376, lossis 97%).
Ntawm cov neeg mob no, 64 (17%) muaj BRCA1/2 mutations thiab yog poj niam tag nrho. Peb caug tsib (9%) muaj PV thiab 29 (7.5%) muaj VUS. Kaum xya (48.6%) ntawm 35 qhov pathogenic variants tshwm sim hauv BRCA1 thiab 18 (51.4%) hauv BRCA2, thaum 5 VUS tshwm sim hauv BRCA1 (17.2%) thiab 24 (82.8%) hauv BRCA2 (Daim Duab 1 thiab 2). LGR tsis muaj nyob hauv MLPA kev tshuaj xyuas.
Daim Duab 2. Kev Tshuaj Xyuas Txog Kev Hloov Pauv BRCA1 thiab BRCA2 Hauv 389 Tus Neeg Mob Cancer Mis. (A) Kev Faib Tawm Cov Kab Mob Sib Txawv (PV) (liab), Cov Kab Mob Sib Txawv Tsis Paub Tseeb (VUS) (txiv kab ntxwv), thiab WT (xiav) Hauv 389 Tus Neeg Mob Cancer Mis; (B) 389 Tus Neeg Mob Cancer Mis Peb Caug Tsib (9%) Muaj Cov Kab Mob Sib Txawv BRCA1/2 (PVs). Ntawm lawv, 17 (48.6%) yog Cov Neeg Nqa BRCA1 PV (liab tsaus) thiab 18 (51.4%) yog Cov Neeg Nqa BRCA2 (liab dawb); (C) 29 (7.5%) ntawm 389 Tus Neeg Mob Nqa VUS, 5 (17.2%) BRCA1 noob (txiv kab ntxwv tsaus) thiab 24 (82.8%) BRCA2 noob (txiv kab ntxwv dawb).
Cov Lus Luv: PVs, pathogenic variant; VUS, variant ntawm uncertain significance; WT, wild-type BRCA1/2 sequence.
Tom ntej no peb tau tshawb nrhiav qhov muaj ntau ntawm BC molecular subtypes hauv cov neeg mob uas muaj BRCA1/2 PV. 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 (37.1%) TNBC cov neeg mob. Ntawm cov neeg mob BRCA1-zoo, 5 (29.4%) muaj luminal B BC, 2 (11.8%) muaj kab mob HER2+, thiab 10 (58.8%) muaj TNBC. Cov qog nqaij hlav uas tsis muaj BRCA1 mutations yog luminal A lossis luminal B-HER2+ (Daim Duab 3). Hauv BRCA2-zoo subgroup, 10 (55.6%) qog nqaij hlav yog luminal B, 3 (16.7%) yog luminal B-HER2+, 3 (16.7%) TNBC thiab 2 (11.1%) yog luminal A. (Daim Duab 3). Tsis muaj qog HER2+ nyob rau hauv pawg no. Yog li, BRCA1 mutations yog qhov tshwm sim ntau rau cov neeg mob TNBC, thaum BRCA2 alterations yog predominant rau cov neeg lumen B.
Daim Duab 3 Qhov muaj ntau hom mob qog noj ntshav hauv cov neeg mob uas muaj cov kab mob pathogenic hauv BRCA1 thiab BRCA2. Cov duab histograms qhia txog kev faib tawm ntawm BRCA1- (liab tsaus) thiab BRCA2- (liab sib dua) PVs ntawm cov hom molecular ntawm cov neeg mob qog noj ntshav hauv lub mis. Cov lej tshaj tawm hauv txhua lub thawv sawv cev rau feem pua ​​​​​​ntawm cov neeg mob uas muaj BRCA1 thiab BRCA2 PV rau txhua hom mob qog noj ntshav hauv lub mis.
Cov lus luv: PVs, pathogenic variant; HER2+, human epidermal growth factor receptor 2 positive; TNBC, triple-negative breast cancer.
Tom qab ntawd, peb tau soj ntsuam hom thiab qhov chaw nyob ntawm cov noob caj noob ces ntawm BRCA1 thiab BRCA2 PVs. Hauv BRCA1 PV, peb tau pom 7 qhov sib txawv ntawm cov nucleotide (SNVs), 6 qhov kev rho tawm, 3 qhov kev theej thiab 1 qhov kev ntxig. Tsuas yog ib qho kev hloov pauv (c.5522delG) sawv cev rau qhov kev tshawb pom tshiab. Qhov feem ntau pom ntawm BRCA1 PV hauv ob qho tib si yog c.5035_5039delCTAAT. Qhov kev hloov pauv no cuam tshuam nrog kev rho tawm tsib nucleotides (CTAAT) hauv BRCA1 exon 15, ua rau muaj kev hloov pauv ntawm cov amino acid leucine los ntawm tyrosine ntawm codon 1679, thiab vim yog kev hloov pauv ntawm lub thav duab nrog qhov kev kwv yees lwm txoj hauv kev nres codon ua rau muaj kev txiav cov protein ua ntej lub sijhawm. Tag nrho lwm yam kev hloov pauv tau pom hauv ib rooj plaub xwb. Qhov tseem ceeb, ib qho ntawm cov PVs tau tshaj tawm tau nyob hauv thaj chaw sib txuas ntawm qhov chaw sib koom ua ke (c.4357 + 1G> T) (Rooj 1).
Hais txog BRCA2 PV, peb pom 6 qhov kev rho tawm, 6 SNVs thiab 2 qhov kev rov ua dua. Tsis muaj qhov kev hloov pauv pom yog qhov tshiab. Peb qhov kev hloov pauv rov tshwm sim hauv peb cov pej xeem, c.428dup thiab c.8487 + 1G>A pom hauv 3 tus neeg mob, ua raws li c.5851_5854delAGTT tau rov qab los hauv ob kis. Qhov kev hloov pauv c.428dup cuam tshuam nrog kev rov ua dua ntawm C hauv exon 5 ntawm BRCA2, kwv yees tias yuav encode ib qho protein luv luv, tsis ua haujlwm. Lub c.8487 + 1G>A kev hloov pauv tshwm sim hauv thaj chaw intronic ntawm BRCA2 intron 19 (± 1,2) thiab cuam tshuam rau qhov kev sib txuas lus splicing, ua rau muaj kev hloov pauv splicing ua rau muaj cov protein tsis zoo lossis tsis muaj. Qhov c.5851_5854delAGTT pathogenic variant yog vim muaj 4-nucleotide deletion los ntawm nucleotide txoj haujlwm 5851 txog 5854 hauv coding exon 10 ntawm BRCA2 gene thiab ua rau ib qho kev hloov pauv ntawm lub thav duab nrog rau qhov kev kwv yees lwm txoj hauv kev nres codon (p.S1951WfsTer). Qhov tseem ceeb, raws li tau tshaj tawm ua ntej, ob qho kev hloov pauv c.631G>A thiab c.7008-2A>T tau pom nyob rau hauv tib tus neeg mob.34 Qhov kev hloov pauv thawj zaug cuam tshuam nrog kev hloov pauv ntawm adenosine (A) hauv BRCA2 exon 7 nrog guanine (G) muaj nucleotide ua rau muaj kev hloov pauv ntawm valine rau isoleucine ntawm codon 211, isoleucine Amino acid yog ib qho amino acid nrog cov khoom zoo sib xws heev. Qhov kev hloov pauv no cuam tshuam rau mRNA splicing ib txwm muaj. Qhov kev hloov pauv thib ob nyob hauv thaj chaw intronic thiab ua rau muaj ob chav A rau thymine (T) hloov pauv ua ntej exon 13 ntawm cov noob encoding BRCA2. Qhov kev hloov pauv c.7008-2A>T tuaj yeem tsim ntau cov ntawv sau ntawm qhov ntev sib txawv. Ntxiv mus, hauv pawg ntawm BRCA2 PVs, 4 ntawm 18 qhov kev hloov pauv (22.2%) yog intronic.
Tom qab ntawd peb tau kos duab BRCA1/2 cov kev hloov pauv tsis zoo hauv cov haujlwm thiab cov cheeb tsam khi protein (Daim Duab 4). Hauv BRCA1 gene, 50% ntawm PVs nyob hauv thaj chaw mob qog noj ntshav mis (BCCR), thaum 22% ntawm cov kev hloov pauv nyob hauv thaj chaw mob qog noj ntshav zes qe menyuam (OCCR) (Daim Duab 4A). Hauv BRCA2 PV, 35.7% ntawm cov variants nyob hauv thaj chaw BCCR thiab 42.8% ntawm cov kev hloov pauv nyob hauv OCCR (Daim Duab 4B). Tom ntej no, peb tau soj ntsuam qhov chaw ntawm PV hauv BRCA1 thiab BRCA2 protein domains. Rau BRCA1 protein, peb pom peb PVs hauv lub voj voog thiab coiled coil domains, thiab ob qho kev hloov pauv hauv BRCT domain (Daim Duab 4A). Rau BRCA2 protein, 4 PVs kos duab rau BRC rov ua dua domain, thaum 3 intronic thiab 3 exonic hloov pauv tau pom hauv oligo/oligosaccharide-binding (OB) thiab tower (T) domains (Daim Duab 4B).
Daim Duab 4 Daim duab kos ntawm cov protein BRCA1 thiab BRCA2 thiab qhov chaw ntawm cov kab mob sib txawv. Daim duab no qhia txog kev faib tawm ntawm BRCA1 (A) thiab BRCA2 (B) cov kab mob sib txawv hauv cov neeg mob qog noj ntshav mis. Kev hloov pauv exonic tau qhia ua xiav, thaum cov kab mob intronic tau qhia ua txiv kab ntxwv. Qhov siab ntawm cov kab sawv cev rau tus lej ntawm cov neeg mob. Cov protein BRCA1 thiab BRCA2 thiab lawv cov haujlwm tau tshaj tawm. (A) Cov protein BRCA1 muaj lub voj voog (RING) thiab lub hauv paus ntsiab lus nuclear (NLS), lub voj voog coiled-coil, lub voj voog SQ/TQ (SCD), thiab lub voj voog BRCA1 C-terminal (BRCT). (B) Cov protein BRCA2 muaj yim qhov rov ua dua BRC, lub voj voog DNA-binding nrog lub voj voog helical (Helical), peb lub voj voog oligonucleotide/oligosaccharide-binding (OB), lub voj voog tower (T), thiab NLS ntawm sab C. Cov cheeb tsam hu ua Lub Cheeb Tsam Cancer Cluster Mis (BCCR) thiab Lub Cheeb Tsam Cancer Cluster Ovarian (OCCR) tau qhia ntawm hauv qab.*Sawv cev rau kev hloov pauv uas txiav txim siab txog cov codons nres.
Tom qab ntawd peb tau tshawb nrhiav cov yam ntxwv ntawm BC clinicopathological uas yuav muaj feem cuam tshuam nrog qhov muaj BRCA1/2 PV. Cov ntaub ntawv kho mob tiav tau muaj rau 181 tus neeg mob BRCA1/2-negative (tsis yog tus nqa) thiab txhua tus neeg nqa (n = 35). Muaj kev sib raug zoo ntawm qhov nce ntawm qhov mob qog thiab qib.
Peb xam qhov kev faib tawm ntawm Ki-67 raws li qhov nruab nrab ntawm peb pawg neeg (25%, ntau yam <10-90%). Cov neeg uas muaj Ki-67 < 25% tau txhais tias yog "qis Ki-67", thaum cov tib neeg uas muaj tus nqi ≥ 25% tau suav tias yog "siab Ki-67". Qhov sib txawv tseem ceeb ntawm Ki-67 (p <0.01) tau pom ntawm cov neeg tsis nqa khoom thiab BRCA1 PV nqa khoom (Daim duab 5A).
Daim Duab 5 Kev sib raug zoo ntawm Ki-67 nrog kev faib qib hauv cov poj niam mob qog noj ntshav mis uas muaj thiab tsis muaj BRCA1 thiab BRCA2 PVs. (A) Boxplot qhia txog tus nqi nruab nrab Ki-67 hauv 181 tus neeg mob BC uas tsis yog tus nqa khoom piv rau BRCA1 (18) lossis BRCA2 (17) cov neeg mob PV. Cov nqi P qis dua 0.5 tau suav tias yog qhov tseem ceeb ntawm kev suav lej. (B) Histogram sawv cev rau kev muab cov neeg mob qog noj ntshav BC rau hauv cov pab pawg qib histological (G2 thiab G3) raws li BRCA1 thiab BRCA2 mutation xwm txheej (WT cov neeg mob, BRCA1 thiab BRCA2 PVs nqa khoom).
Ib yam li ntawd, peb tau tshuaj xyuas seb qib qog nqaij hlav puas muaj feem cuam tshuam nrog qhov muaj BRCA1/2 PV. Vim tias G1 BC tsis muaj nyob hauv peb cov pej xeem, peb tau faib cov neeg mob ua ob pawg (G2 lossis G3). Sib xws nrog cov txiaj ntsig Ki-67, qhov kev tshuaj xyuas tau qhia txog kev sib raug zoo ntawm qib qog nqaij hlav thiab kev hloov pauv BRCA1, nrog rau feem pua ​​​​​​ntau dua ntawm G3 qog nqaij hlav hauv BRCA1 cov neeg nqa khoom piv rau cov tsis nqa khoom (p < 0.005) (Daim Duab 5B).
Kev nce qib hauv thev naus laus zis DNA sequencing tau ua rau muaj kev nce qib tsis tau muaj dua hauv kev kuaj mob BRCA1/2, nrog rau qhov cuam tshuam tseem ceeb rau cov neeg mob uas muaj keeb kwm mob qog noj ntshav hauv tsev neeg. Txog niaj hnub no, kwv yees li 20.000 BRCA1/2 variants tau txheeb xyuas thiab faib raws li American Society of Medical Genetics 35 thiab ENIGMA system.35,36 Nws paub zoo tias BRCA1/2 mutational spectrum sib txawv ntau thoob plaws thaj chaw.37 Hauv Ltalis, tus nqi ntawm BRCA1/2 PVs yog txij li 8% txog 37%, qhia txog kev hloov pauv dav dav hauv lub tebchaws.38,39 Nrog rau cov pej xeem yuav luag 5 lab tus tib neeg, Sicily yog thaj chaw thib tsib loj tshaj plaws hauv Ltalis hais txog cov neeg nyob hauv. Txawm hais tias muaj cov ntaub ntawv ntawm kev faib tawm ntawm BRCA1/2 hauv sab hnub poob Sicily, tsis muaj pov thawj dav dav hauv sab hnub tuaj ntawm cov kob.
Peb txoj kev tshawb fawb yog ib qho ntawm thawj daim ntawv tshaj tawm txog qhov tshwm sim ntawm BRCA1/2 PV hauv cov neeg mob BC hauv sab hnub tuaj Sicily.28 Peb tau tsom peb qhov kev tshuaj xyuas rau BC, vim qhov no yog qhov kab mob feem ntau hauv peb pawg neeg.
Thaum kuaj 389 tus neeg mob BC, 9% nqa BRCA1/2 PVs, faib sib npaug ntawm BRCA1 thiab BRCA2. Cov txiaj ntsig no yog sib xws nrog cov uas tau tshaj tawm yav dhau los hauv cov pej xeem Italian.28 Qhov nthuav yog, 3% (13/389) ntawm peb pawg neeg yog txiv neej. Tus nqi no siab dua li qhov xav tau rau cov txiv neej mob qog noj ntshav mis (1% ntawm tag nrho cov BCs),40 qhia txog peb cov pej xeem xaiv raws li kev pheej hmoo ntawm BRCA1/2 mutation. Txawm li cas los xij, tsis muaj ib tug ntawm cov txiv neej no tau tsim BRCA1/2 PV, yog li lawv yog cov neeg sib tw rau kev tshuaj xyuas molecular ntxiv kom tshem tawm qhov muaj cov mutations tsawg dua xws li PALB2, RAD51C thiab D, ntawm lwm tus. Cov variants ntawm qhov tseem ceeb tsis paub meej tau rov qab tau hauv 7% ntawm cov neeg mob uas BRCA2 VUS tau pom tseeb. Txawm tias qhov tshwm sim no yog sib xws nrog cov pov thawj ua ntej.28,41,42
Thaum peb tshuaj xyuas qhov kev faib tawm ntawm BC molecular subtypes hauv cov poj niam BRCA1/2 mutant, peb tau lees paub qhov kev sib raug zoo ntawm TNBC thiab BRCA1 PV (58.8%) thiab ntawm luminal B BC thiab BRCA2 PV (55.6%).16,43 Cov qog luminal A thiab HER2+ hauv BRCA1 thiab BRCA2 PV carriers yog sib xws nrog cov ntaub ntawv sau uas twb muaj lawm.16,43
Tom qab ntawd peb tsom mus rau hom thiab qhov chaw ntawm BRCA1/2 PV. Hauv peb pawg neeg, BRCA1 PV feem ntau yog c.5035_5039delCTAAT. Txawm hais tias Incorvaia et al. tsis tau piav qhia txog qhov variant no hauv lawv cov Sicilian cohort, lwm tus kws sau ntawv tau tshaj tawm tias nws yog ib qho germline BRCA1 PV.34 Ntau BRCA1 PVs tau pom nyob rau hauv peb cov cohort - piv txwv li c.181T>G, c.514del, c.3253dupA thiab c.5266dupC - uas tau pom hauv Sicily.28 Ntawm cov no, ob qho BRCA1 founder mutations (c.181T>G thiab c.5266dupC) feem ntau pom muaj nyob rau hauv Ashkenazi Jews ntawm Eastern thiab Central Europe (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian thiab German), 44,45 thiab, hauv Tebchaws Meskas thiab Argentina, nyuam qhuav txhais tias yog "recurrent germline variant" hauv cov neeg mob Italian nrog BC thiab OC. Qhov 34c.514del variant tau txheeb xyuas yav dhau los hauv 8 tus neeg mob cancer mis los ntawm sab qaum teb Sicily hauv Palermo thiab Messina. Txaus siab, txawm tias Incorvaia et al. pom qhov c.3253dupA variant hauv qee tsev neeg hauv Catania.28 Cov BRCA2 PVs uas sawv cev tshaj plaws yog c.428dup, c.5851_5854delAGTT thiab qhov intronic variant c.8487+1G>A, uas tau tshaj tawm ntau ntxiv 28 hauv tus neeg mob hauv Palermo nrog c.428dup, c.5851_5854delAGTT PV tau pom hauv cov tsev neeg hauv sab qaum teb sab hnub poob Sicily, feem ntau hauv thaj chaw Trapani thiab Palermo, thaum c.5851_5854delAGTT PV tau pom hauv cov tsev neeg hauv sab qaum teb sab hnub poob Sicily. Qhov 8487+1G>A variant tau pom ntau dua hauv cov neeg mob los ntawm Messina, Palermo, thiab Caltanissetta.28 Rebbeck et al. yav dhau los piav qhia txog c.5851_5854delAGTT kev hloov pauv hauv Colombia.37 Lwm BRCA2 PV, c.631 + 1G>A, tau pom muaj nyob rau hauv BC thiab OC cov neeg mob los ntawm Sicily (Agrigento, Siracusa thiab Ragusa).28 Qhov tseem ceeb, peb tau pom qhov sib koom ua ke ntawm ob qho BRCA2 variants (BRCA2 c.631G>A thiab c.7008-2A>T) hauv tib tus neeg mob, uas peb xav tias yuav raug cais tawm hauv hom cis, raws li tau tshaj tawm ua ntej li ntawd.34,46 Cov kev hloov pauv BRCA2 uble no yeej pom ntau zaus hauv thaj av Italian thiab tau pom tias ua rau muaj kev nres codons ua ntej, cuam tshuam rau tus tub txib RNA splicing thiab ua rau BRCA2 protein ua tsis tiav.47,48
Peb kuj tau kos duab BRCA1 thiab BRCA2 PVs hauv cov cheeb tsam OCCR thiab BCCR uas muaj cov protein domains thiab cov noob caj noob ces. Cov cheeb tsam no tau piav qhia los ntawm Rebbeck et al. ua cov cheeb tsam muaj kev pheej hmoo rau kev mob qog noj ntshav hauv zes qe menyuam thiab mis, raws li.49 Txawm li cas los xij, cov pov thawj txog kev sib raug zoo ntawm qhov chaw ntawm cov kab mob sib txawv thiab kev pheej hmoo ntawm mob qog noj ntshav hauv mis lossis zes qe menyuam tseem muaj kev tsis sib haum xeeb.28,50-52 Hauv peb cov pej xeem, BRCA1 PVs feem ntau nyob hauv thaj tsam BCCR, thaum BRCA2 PVs feem ntau nyob hauv thaj tsam OCCR. Txawm li cas los xij, peb tsis tuaj yeem nrhiav tau kev sib raug zoo ntawm cov cheeb tsam OCCR thiab BCCR thiab cov yam ntxwv BC. Qhov no yuav yog vim muaj cov neeg mob tsawg uas muaj BRCA1/2 mutations. Los ntawm qhov pom ntawm cov protein domain, BRCA1 PVs tau faib raws tag nrho cov protein, thiab BRCA2 alterations feem ntau pom nyob rau hauv BRC rov ua dua domain.
Thaum kawg, peb tau sib piv cov yam ntxwv BC clinicopathological nrog BRCA1/2 PV. Vim muaj cov neeg mob tsawg, peb tsuas pom muaj kev sib raug zoo ntawm Ki-67 thiab qib qog. Txawm hais tias kev ntsuam xyuas thiab kev txhais lus ntawm Ki-67 tseem muaj kev tsis sib haum xeeb, nws yog qhov tseeb tias cov nqi proliferative siab cuam tshuam nrog kev pheej hmoo ntawm kev rov qab mob thiab txo qis kev ciaj sia. Txog niaj hnub no, qhov txiav rau qhov sib txawv ntawm "siab" thiab "qis" Ki-67 yog 20%. Txawm li cas los xij, qhov ntsuas no tsis siv rau peb cov neeg mob BRCA1/2 mutation, uas muaj tus nqi nruab nrab Ki-67 ntawm 25%. Qhov sib txawv no hauv cov nqi Ki-67 siab tuaj yeem piav qhia los ntawm qhov tshwm sim hauv peb cov luminal B thiab TNBC cohorts, uas muaj ob peb lub qog luminal A. Txawm li cas los xij, qee qhov pov thawj zoo li qhia tias qhov txiav Ki-67 siab dua (25-30%) yuav zoo dua stratify cov neeg mob raws li lawv qhov kev kwv yees.53,54 Los ntawm cov txiaj ntsig ntawm peb qhov kev tshuaj xyuas, qhov kev sib raug zoo tseem ceeb tsis yog qhov xav tsis thoob.Tshwm sim ntawm Ki-67 siab thiab qib thiab qhov muaj ntawm BRCA1 PV.Qhov tseeb, cov qog nqaij hlav BRCA1 yog cov yam ntxwv ntawm TNBC thiab qhia txog cov yam ntxwv hnyav dua.16,17
Xaus lus, txoj kev tshawb fawb no muab ib daim ntawv qhia txog qhov xwm txheej ntawm kev hloov pauv ntawm BRCA1/2 hauv ib pawg neeg BC los ntawm sab hnub tuaj Sicily. Zuag qhia tag nrho, peb cov kev tshawb pom yog sib xws nrog cov pov thawj uas twb muaj lawm, ob qho tib si hais txog kev hloov pauv thiab cov yam ntxwv clinicopathological hauv BC. Ntau txoj kev tshawb fawb hauv cov pej xeem loj dua ntawm cov neeg mob BRCA1/2-mutant BC, xws li siv ntau hom kev tshuaj xyuas kev hloov pauv ntau yam, yog qhov tsim nyog los ntsuas qhov muaj cov PVs uas sib txawv thiab tsawg dua li BRCA1/2. Qhov no yuav tso cai rau kev txheeb xyuas thiab kev tswj hwm kom zoo ntawm cov neeg mob uas muaj kev pheej hmoo ntawm mob qog noj ntshav vim yog kev hloov pauv caj ces.
Peb tau lees paub tias cov neeg mob tau kos npe rau kev pom zoo kom tso lawv cov qauv qog tsis qhia npe rau lub hom phiaj tshawb fawb. Txhua tus neeg mob tau kos npe rau kev pom zoo sau ntawv raws li Daim Ntawv Tshaj Tawm ntawm Helsinki. Raws li txoj cai ntawm AOU Policlinico "G.Rodolico - S.Marco", kev tshawb fawb no tau zam los ntawm kev tshuaj xyuas kev ncaj ncees vim tias kev tshuaj xyuas BRCA1/2 tau ua raws li kev xyaum kho mob thiab txhua tus neeg mob tau muab kev pom zoo sau ntawv. Cov neeg mob kuj pom zoo rau kev siv lawv cov ntaub ntawv rau lub hom phiaj tshawb fawb.
Peb ua tsaug rau Xibfwb Paolo Vigneri rau nws txoj kev pab hauv kev saib xyuas cov neeg mob qog noj ntshav hauv lub mis raws li Pawg Neeg Saib Xyuas Kev Ncaj Ncees tau thov.
Federica Martorana tshaj tawm cov nyiaj pub dawb los ntawm Istituto Gentili, Eli Lilly, Novartis, Pfizer. Cov kws sau ntawv lwm tus tshaj tawm tias tsis muaj kev tsis sib haum xeeb hauv txoj haujlwm no.
1. Sung H, Ferlay J, Siegel RL, thiab lwm tus. Cov Txheeb Xyuas Kab Mob Cancer Thoob Ntiaj Teb Xyoo 2020: GLOBOCAN kwv yees qhov tshwm sim thiab kev tuag ntawm 36 tus kab mob cancer hauv 185 lub teb chaws thoob ntiaj teb.CA Cancer J Clin.2021;71(3):209-249.doi: 10.3322/caac.21660