BRCA1

BRCA1
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1JM7, 1JNX, 1N5O, 1OQA, 1T15, 1T29, 1T2U, 1T2V, 1Y98, 2ING, 3COJ, 3K0H, 3K0K, 3K15, 3PXA, 3PXB, 3PXC, 3PXD, 3PXE, 4IFI, 4IGK, 4JLU, 4OFB, 4U4A, 4Y18, 4Y2G

Identifikatori
AliasiBRCA1
Vanjski ID-jeviOMIM: 113705 MGI: 104537 HomoloGene: 5276 GeneCards: BRCA1
Lokacija gena (čovjek)
Hromosom 17 (čovjek)
Hrom.Hromosom 17 (čovjek)[1]
Hromosom 17 (čovjek)
Genomska lokacija za BRCA1
Genomska lokacija za BRCA1
Bend17q21.31Početak43,044,295 bp[1]
Kraj43,170,245 bp[1]
Lokacija gena (miš)
Hromosom 11 (miš)
Hrom.Hromosom 11 (miš)[2]
Hromosom 11 (miš)
Genomska lokacija za BRCA1
Genomska lokacija za BRCA1
Bend11 65.18 cM|11 DPočetak101,379,590 bp[2]
Kraj101,442,781 bp[2]
Obrazac RNK ekspresije


Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• vezivanje tubulina
• vezivanje iona metala
• vezivanje enzima
• vezivanje iona cinka
• oštećeno vezivanje sa DNK
• GO:0001948, GO:0016582 vezivanje za proteine
• GO:0001105 transcription coactivator activity
• androgen receptor binding
• vezivanje sa RNK
• ubiquitin protein ligase binding
• GO:0050372 aktivnost sa transferazom ubikvitina
• vezivanje sa DNK
• aktivnost sa transferazom
• RNA polymerase binding
• vezivanje identičnih proteina
Ćelijska komponenta• kompleks BRCA1-BARD1
• kondenzovani nuklearni hromosom
• kompleks BRCA1-A
• kompleks ubikvitin-ligaze
• ćelijska membrana
• nukleoplazma
• kondenzovani hromosom
• citoplazma
• hromosom
• jedro
• lateralni element
• GO:0009327 makromolekulani kompleks
• ribonukleoprotein
Biološki proces• response to ionizing radiation
• centrosome cycle
• hromosomska segregacija
• protein K6-linked ubiquitination
• intrinsic apoptotic signaling pathway in response to DNA damage
• ćelijski ciklus
• double-strand break repair via nonhomologous end joining
• GO:0097285 apoptoza
• regulation of apoptotic process
• regulation of gene expression by genetic imprinting
• GO:0009373 regulation of transcription, DNA-templated
• negative regulation of fatty acid biosynthetic process
• transcription, DNA-templated
• regulation of transcription by RNA polymerase III
• fatty acid biosynthetic process
• regulation of DNA methylation
• negative regulation of intracellular estrogen receptor signaling pathway
• protein autoubiquitination
• positive regulation of histone H3-K9 methylation
• DNA recombination
• positive regulation of angiogenesis
• response to estrogen
• cellular response to indole-3-methanol
• negative regulation of extrinsic apoptotic signaling pathway via death domain receptors
• GO:0045996 negative regulation of transcription, DNA-templated
• positive regulation of protein ubiquitination
• androgen receptor signaling pathway
• negative regulation of centriole replication
• Postreplikacijska reparacija
• lipid metabolism
• cellular response to tumor necrosis factor
• GO:1900404 positive regulation of DNA repair
• fatty acid metabolic process
• GO:1901313 positive regulation of gene expression
• negative regulation of histone H3-K4 methylation
• regulation of cell population proliferation
• negative regulation of reactive oxygen species metabolic process
• positive regulation of vascular endothelial growth factor production
• DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator
• GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II
• positive regulation of histone H4-K20 methylation
• DNA double-strand break processing
• double-strand break repair via homologous recombination
• negative regulation of histone acetylation
• protein ubiquitination
• positive regulation of histone H3-K4 methylation
• GO:0100026 Popravka DNK
• double-strand break repair
• positive regulation of histone acetylation
• dosage compensation by inactivation of X chromosome
• negative regulation of histone H3-K9 methylation
• positive regulation of histone H3-K9 acetylation
• GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated
• chordate embryonic development
• positive regulation of histone H4-K16 acetylation
• cellular response to DNA damage stimulus
• protein deubiquitination
• Replikacija DNK
• mitotic G2/M transition checkpoint
• GO:0044324, GO:0003256, GO:1901213, GO:0046019, GO:0046020, GO:1900094, GO:0061216, GO:0060994, GO:1902064, GO:0003258, GO:0072212 regulation of transcription by RNA polymerase II
• negative regulation of G0 to G1 transition
• transcription by RNA polymerase II
• mitotic G2 DNA damage checkpoint signaling
• regulation of signal transduction by p53 class mediator
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

672

12189

Ensembl

ENSG00000012048

ENSMUSG00000017146

UniProt

P38398

P48754

RefSeq (mRNK)
NM_007294
NM_007295
NM_007296
NM_007297
NM_007298

NM_007299
NM_007300
NM_007301
NM_007302
NM_007303
NM_007305
NM_007306

NM_009764

RefSeq (bjelančevina)

NP_009225
NP_009228
NP_009229
NP_009230
NP_009231

NP_033894

Lokacija (UCSC)Chr 17: 43.04 – 43.17 MbChr 11: 101.38 – 101.44 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Protein osjetljivosti na rak dojke tip 1 je protein koji je kod ljudi kodiran genom BRCA1.[5] Ortolozi su česti kod drugih kičmenjačkih vrsta, dok genomi beskičmenjaka mogu imati srodni gen.[6] BRCA1 je ljudski gen supresije tumora [7][8] (poznat i kao domarski gen) i odgovoran je za popravak DNK.[9]

BRCA1 i BRCA2 su nepovezani proteini,[10] ali oba se normalno eksprimiraju u ćelijama dojke i drugom tkivu, gdje pomažu u popravljanju oštećene DNK ili uništavanju ćelija, ako DNK nije moguće popraviti. Oni su uključeni u popravak hromosomskog oštećenja s važnom ulogom u nepogrešivim popravcima prekida dvolančana DNK.[11][12] Ako su BRCA1 ili BRCA2 sami oštećeni BRCA mutacijom, oštećena DNK se ne popravlja pravilno, a to povećava rizik za rak dojke.[13][14] BRCA1 i BRCA2 opisani su kao "geni osjetljivosti na rak dojke" i "proteini osjetljivosti na rak dojke". Prevladavajući alel ima normalnu funkciju supresije tumora, dok mutacije s visokom penetrabilnošću u ovim genima uzrokuju gubitak funkcije supresije tumora, što korelira s povećanim rizikom od raka dojke.[15]

BRCA1 se kombinira s drugim supresorima tumora, senzorima oštećenja DNK i pretvaračima signala da bi stvorio veliki kompleks multijedinica proteina poznat kao BRCA1-asocirani kompleks za nadzor genoma (BASC).[16] Protein BRCA1 povezuje se s RNK-polimerazom II, te putem C-terminalnog domena takođe komunicira sa kompleksima histon-deacetilaza. Dakle, ovaj protein ima ulogu u transkripciji i popravljanju prekida dvolančane DNK[14] ubikvitinaciji, transkripcijskoj regulaciji, kao i drugim funkcijamaa.[17]

Metodi za ispitivanje vjerovatnoće pacijenta sa mutacijama u BRCA1 i BRCA2 koje uzrokuju rak obuhvaćene su patentima u vlasništvu ili pod kontrolom Myriad Genetics. Myriadov poslovni model nuđenja dijagnostičkog testa vodio je isključivo od toga da je 1994. bio startup kompanija, koja je bila javna kompanija sa 1.200 zaposlenih i oko 500 miliona dolara godišnjeg prihoda u 2012.;[18][19] to je također dovelo do kontroverze oko visokih cijena i nemogućnosti dobivanja drugih mišljenja od drugih dijagnostičkih laboratorija, što je zauzvrat dovelo do značajne tužbe Udruženja za molekulsku patologiju protiv Association for Molecular Pathology v. Myriad Genetics.[20]

Otkriće

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Prve dokaze o postojanju gena koji kodira enzim za obnavljanje DNK, uključenog u osjetljivost na rak dojke pružio je laboratorij Mary-Claire King na University of California, Berkeley, 1990.[21] Četiri godine kasnije, nakon međunarodne utrke za pronalaženje ,[22] gen su 1994. godine klonirali naučnici sa Univerziteta u Utahu, Nacionalnog instituta za nauke o zdravlju i životnoj sredini (NIEHS) i Myriad Genetics.[23]

Lokacija gena

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Ljudski gen BRCA1 nalazi se na dugom (q) kraku hromosoma 17 u području 2, opseg 1, između baznih parova 41,196.312 i 41,277.500 (Build GRCh37/hg19)[24]Nacionalni centar za biotehnološke informacije, SAD, Nacionalna biblioteka za medicinu i [25] EntrezGene imaju referentne informacije za BRCA1 raka dojke 1, rani početak (Homo sapiens). Ortolozi BRCA1 identificirani su u većini kičmenjaka za koje su dostupni kompletni podaci o genomu.[6]

Struktura proteina

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Protein BRCA1 sadrži sljedeće domene:[26]

Ovaj protein takođe sadrži motive signala jedarne lokalizacije i signala jedarnog eksporta.[27]

Ljudski BRCA1 protein sastoji se od četiri glavna proteinska domena; Znf C3HC4- RING domen, domen BRCA1 i dva BRCT domena. Ovi domeni kodiraju približno 27% BRCA1 proteina. Poznato je šest izoformi BRCA1,[28] sa izoformama 1 i 2 koje sadrže po 1.863 aminokiseline.

BRCA1 nije povezan sa BRCA2, tj. oni nisu homolozi ili paralozi.[10]

text
Mapa domena BRCA1; označeni su RING-domeni koji sadrže serin (SCD) i BRCT. Horizontalne crne linije označavaju domene koji vežu proteine za navedene partnere. Crveni krugovi označavaju mjesta fosforilacije.[29]

Funkcija i mehanizam

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BRCA1 je dio kompleksa koji popravlja dvostruke niti u DNK. Lanci dvostruke zavojnice DNK neprekidno se lome jer se oštećuju. Ponekad je oštećen samo jedan polulanac, ponekad se oba prekidaju istovremeno. Sredstva za umrežavanje DNK važan su izvor oštećenja hromosoma/DNK. Dvolančane pukotine nastaju kao međuprodukti nakon uklanjanja umrežavanja i zaista su identificirane bialelne mutacije u BRCA1, odgovorne za Fanconijevu anemiju, komplementacijsku skupinu S,[30] genetiku bolest povezanu sa preosjetljivošću na agense za umrežavanje DNK. BRCA1 je dio proteinskog kompleksa koji popravlja DNK kad su oštećene obje niti. Kada se to dogodi, mehanizam za popravak teško može "znati" kako zamijeniti ispravnom sekvencom DNK, a postoji više načina za pokušaj popravka. Dvolančani mehanizam za popravak u kojem sudjeluje BRCA1 je homologmo usmjereni popravak, gdje popravni proteini kopiraju identičnu sekvencu iz netaknute sestrinske hromatide.[31]

U jedru mnogih tipova normalnih ćelija, protein BRCA1 tokom popravljanja dvonitnih preloma DNK komunicira sa RAD51.[32] Ti prekidi mogu biti uzrokovani prirodnim zračenjem ili drugim izlaganjem, ali se mogu dogoditi i kada hromosom razmijeni genetički materijal (homologna rekombinacija, npr."krosingover" tokom mejoze). Protein BRCA2, koji ima funkciju sličnu funkciji BRCA1, također djeluje s proteinom RAD51. Utičući na sanaciju oštećenja DNK, ova tri proteina imaju ulogu u održavanju stabilnosti ljudskog genoma.

BRCA1 je također uključen u drugi tip popravke DNK, zvani popravak neusklađenosti. BRCA1 stupa u interakciju s proteinom za popravak neusklađenosti DNK MSH2.[33] Objavljeno je da su MSH2, MSH6, PARP i neki drugi proteini koji su uključeni u popravak jednog lanca povišeni u tumorima dojke s nedostatkom BRCA1.[34]

Protein zvani valozin-sadržavajući protein (VCP, poznat i kao p97) ima ulogu u regrutaciji BRCA1 na oštećena mjesta DNK. Nakon ionizujućeg zračenja, VCP se regrutuje u lezije DNK i sudjeluje sa ubikvitin-ligazom RNF8, kako bi se orkestrirao sklop signalnih kompleksa za efikasnu popravku DSB.[35] BRCA1 komunicira sa VCP.[36] BRCA1 također komunicira i s c-Myc i drugim proteinima koji su presudni za održavanje stabilnosti genoma.[37]

BRCA1 se izravno veže za DNK, sa većim afinitetom za razgranate DNA strukture. Ova sposobnost vezanja za DNK doprinosi njenoj sposobnosti da inhibira aktivnost kompleksa nukleaza MRN, kao i aktivnost same nukleaze Mre11.[38] Ovo može objasniti ulogu BRCA1 u podsticanju popravka DNK manje vjernosti pomoću nehomolognog spajanja krajeva (NHEJ).[39] BRCA1 se također kolokalizira sa γ-H2AX (histon H2AX fosforiliran na serinu-139) u žarištima popravljanja dvostrukih lanaca DNK, što ukazuje da može imati ulogu u regrutovanju faktora popravka.[17][40]

Formaldehid i acetaldehid uobičajeni su izvori poprečnih prekida DNK, često zahtijevajući popravke posredovane putem BRCA1, koji sadrži puteve.[41]

Ova funkcija popravljanja DNK je ključna; miševi sa mutacijama gubitka funkcije u oba BRCA1 alela nisu održivi, a od 2015. godine poznato je da samo dvije odrasle osobe imaju takve mutacije; obje su imale urođene ili razvojne probleme, kao i kancer. Pretpostavljalo se da je jedna preživjela u odrasloj dobi, jer je jedna od mutacija BRCA1 bila hipomorfna.[42]

Transkripcija

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Pokazano je da BRCA1 ko-pročišćava s ljudskom RNK-polimerazom II, holoenzimom u ekstraktima HeLa, implicirajući da je komponenta holoenzima.[43] Kasnija istraživanja, međutim, proturječila su ovoj pretpostavci, umjesto da su pokazala da je dominantni kompleks koji uključuje BRCA1 u HeLa ćelijama kompleks od dva megadaltona koji sadrži SWI/SNF.[44] SWI / SNF je kompleks za remodeliranje hromatina. Pokazalo se da vještačko vezivanje BRCA1 za hromatin ne kondenzira heterokromatin, iako domen interakcije SWI / SNF nije bilo potreban za ovu ulogu.[40] BRCA1 stupa u interakciju s NELF-B (COBRA1 ) podjedinica kompleksa NELF.[40] BRCA1 je u interakciji sa NELF-B (COBRA1) podjedinicom NELF kompleksa.[40]

Mutacije i rizik od raka

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Određene varijacije gena BRCA1 dovode do povećanog rizika za raka dojke, kao dio nasljednog sindroma raka dojke-jajnika. Istraživači su identificirali stotine mutacija u genu BRCA1 , od kojih su mnoge povezane s povećanim rizikom od raka. Žene s abnormalnim genom BRCA1 ili BRCA2 imaju do 80% rizika od razvoja raka dojke do 90. godine; povećani rizik od razvoja raka jajnika je oko 55% za žene s BRCA1 mutacijama i oko 25% za žene s mutacijama BRCA2.[45]

Ove mutacije mogu biti promjene na jednom ili malom broju baznih parova DNK (građevni blokovi DNK) i mogu se identificirati pomoću PCR-a i sekvenciranja DNK.

U nekim slučajevima se preuređuju veliki segmenti DNK. Ti veliki segmenti, koji se nazivaju i velikim rearanžmanima, mogu biti delecija ili duplikacija jednog ili nekoliko egzona u genu. Klasični metodi za otkrivanje mutacija (sekvenciranje) nisu u stanju da otkriju ove tipove mutacija.[46] Predloženi su i drugi metodi: standardna kvantitativna PCR-analiza,[47] multipleks ligacijski-ovisne sonde (MLPA),[48] i kvantitativni multipleksni PCR kratkih fluorescentnih fragmenata (QMPSF).[49] Nedavno su predložene i novije metode: heterodupleksna analiza (HDA) multikapilarnom elektroforezom ili također namjenskim sekvenciranjem oligonukleotida, zasnovanom na upordnoj hibridizaciji genoma (mreža-CGH).[50]

Neki rezultati sugeriraju da bi se hipermetilacija promotora BRCA1, koji je prijavljen kod nekih karcinoma, mogao smatrati mehanizmom za inaktivaciju ekspresije BRCA1.[51]

Mutirani gen BRCA1 obično stvara protein koji ne funkcionira pravilno. Vjeruje se da neispravni protein BRCA1 nije u stanju pomoći u popravljanju oštećenja DNK, što dovodi do mutacija drugih gena. Ove mutacije mogu se akumulirati i omogućiti ćelijama nekontrolirani rast i dijeljenje, kako bi stvorile tumor. Dakle, inaktivacijske mutacije BRCA1 dovode do predispozicije za rak.

BRCA1 iRNK 3'UTR može biti vezana za miRNK, Mir-17 mikroRNK. Sugerira se da bi varijacije ove miRNA zajedno sa Mir-30 mikroRNK mogle izazvati osjetljivost na rak dojke.[52]

Pored karcinoma dojke, mutacije gena BRCA1 takođe povećavaju rizik od karcinoma jajnika i prostate. Šta više, prekancerozne lezije (displazija) unutar jajovoda povezane su s mutacijama gena BRCA1. Patogene mutacije bilo gdje u putevima modela koji sadrže BRCA1 i BRCA2 uveliko povećavaju rizike za podskupinu leukemija i limfoma.

Žene koje su naslijedile neispravan gen BRCA1 ili BRCA2 uveliko imaju povećan rizik od razvoja karcinoma dojke i jajnika. Njihov rizik od razvoja karcinoma dojke i/ili jajnika toliko je visok i toliko je specifičan za te karcinome da se mnogi nositelji mutacija odluče na profilaksnu operaciju. Bilo je mnogo nagađanja koja objašnjavaju tako očigledno zapanjujuću specifičnost tkiva. Glavne odrednice gdje se javljaju nasljedni karcinomi BRCA1/2 povezane su sa tkivnom specifičnošću patogena raka, agensa koji uzrokuje hroničnu upalu ili karcinogenezu. Ciljno tkivo može imati receptore za patogen, može biti selektivno izloženo upalnom procesu ili karcinogenu. Urođeni genomski u nedostatak gena za supresiju tumora narušava normalne reakcije i pogoršava osjetljivost na bolesti u organima- metama. Ova teorija također uklapa podatke za nekoliko tumorskih supresora izvan BRCA1 ili BRCA2. Glavna prednost ovog modela je u tome što sugerira da se uz profilaksnu operaciju mogu obaviti i neke druge opcije.[53]

Mutacija BRCA1 u raku dojke i jajnika

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Samo oko 3% –8% svih žena s rakom dojke ima mutaciju u BRCA1 ili BRCA2.[54] Slično tome, mutacije BRCA1 nađene su samo kod oko 18% karcinoma jajnika (13% mutacija zametnih linija i 5% somatskih mutacija).[55]

Prema tome, dok je ekspresija BRCA1 kod većine ovih karcinoma niska, mutacija BRCA1 nije glavni uzrok smanjene ekspresije. Određeni latentni virusi, koji se često otkrivaju u tumorima raka dojke, mogu smanjiti ekspresiju gena BRCA1 i izazvati razvoj tumora dojke.[56]

Karcinom dojke (uključujući i muški): Međuodnosi fenotip – genotip[57][58][59]

Lokacija Fenotip Fenotipski MIM broj Nasljeđivanje

+ oznaka mutacije

Ključ fenotipskog mapiranja Oznaka lokusa Genski/lokusni MIM broj
1p34.1 Invazivni duktusni 114480 AD*, SMu 3 RAD54L 603615
2q33.1 Zaštitni 114480 AD, SMu 3 CASP8 601763
2q35 Podložnost 114480 AD, SMu 3 BARD1 601593
3q26.32 Somatski 114480 3 PIK3CA 171834
5q34 Podložnost 114480 AD, SMu 3 HMMR 600936
6p25.2 Podložnost (?) 114480 AD, SMu 1 NQO2 160998
6q25 1-q25.2 Somatski 114480 3 ESR1 133430
8q11.23 Somatski 114480 3 RB1CC1 606837
11p15.4 Somatski 114480 3 SLC22A1L 602631
11q22.3 Podložnost 114480 AD, SMu 3 ATM 607585
12p12.1 Somatski 114480 3 KRAS 190070
13q13.1 Podložnost, muški 114480 AD, SMu 3 BRCA2 600185
14q32.33 Podložnost 114480 AD, SMu 3 XRCC3 600675
14q32.33 Somatski 114480 3 AKT1 164730
15q15.1 Podložnost 114480 AD, SMu 3 RAD51 179617
16p12.2 Podložnost 114480 AD, SMu 3 PALB2 610355
16q22.1 Režanjski 114480 AD, SMu 3 CDH1 192090
17q21.33 Podložnost 114480 AD, SMu 3 PHB 176705
17p13.1 Somatski 114480 3 TP53 191170
17q23.2 Somatski 114480 3 PPM1D 605100
17q23.2 Ranopojavna podložnost 114480 AD, SMu 3 BRIP1 605882
22q12.1 Podložnost 114480 AD, SMu 3 CHEK2 604373

Promotorska hipermetilacija BRCA1 u raku dojke i jajnika

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Promotorska hipermetilacija BRCA1 bila je prisutan u samo 13% neizabranih primarnih karcinoma dojke.[60] Slično tome, hipermetilacija promotora BRCA1 bila je prisutna u samo 5% do 15% slučajeva EOC-a.

Dakle, dok je ekspresija BRCA1 kod ovih karcinoma niska, metilacija promotora BRCA1 samo je manji uzrok smanjene ekspresije.

MikroRNK represija BRCA1 kod karcinoma dojke

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Postoji niz specifičnih mikroRNK, , koje, kada su prekomerno eksprimirane, direktno smanjuju ekspresiju specifičnih proteina koji popravljaju DNK (vidi mikroRNK, odjeljak: popravak DNK i rak). U slučaju raka dojke, mikroRNK-182 (miR-182) specifično cilja BRCA1.[61] Rak dojke može se klasificirati na osnovu statusa receptora ili histoloških obilježja, u trostruko negativni rak dojke (15% –25% karcinoma dojke), HER2 + (15% –30% karcinoma dojke), ER + / PR + (oko 70% karcinoma dojke) i Invazivni režanjski karcinom (oko 5% –10% invazivnog karcinoma dojke). Utvrđeno je da sva četiri tipa karcinoma dojke u prosjeku imaju oko 100 puta veći porast miR-182 u odnosu na normalno tkivo dojke.[62] U ćelijskim linijama karcinoma dojke postoji inverzna korelacija nivoa proteina BRCA1 sa ekspresijom miR-182. Stoga se čini da je velik dio smanjenja ili odsustva BRCA1 kod duktusnih karcinoma dojke visokog stepena prekomjerno eksprimirani miR-182.

Pored miR-182, par gotovo identičnih mikroRNK, miR-146a i miR-146b-5p, također potiskuju ekspresiju BRCA1. Ove dvije mikroRNK su prekomjerno eksprimirane u trostruko negativnim tumorima i njihova prekomjerna ekspresija rezultira inaktivacijom BRCA1. Dakle, miR-146a i / ili miR-146b-5p mogu također doprinijeti smanjenoj ekspresiji BRCA1 kod ovih trostruko negativnih karcinoma dojke.

MikroRNK represija BRCA1 kod karcinoma jajnika

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I u seroznim tubulskim intraepitelnim karcinomima (prethodnica lezije visokoeksprimiranog seroznog karcinoma jajnika (HG-SOC)), i u samom HG-SOC, miR- 182 je prekomjerno eksprimiran u oko 70% slučajeva.[63] Dakle, miR-146a i / ili miR-146b-5p mogu takođe doprinijeti smanjenoj ekspresiji BRCA1 kod ovih trostruko negativnih karcinoma dojke.

Još jedna mikroRNK za koju je poznato da smanjuje ekspresiju BRCA1 u ćelijamama raka jajnika je miR-9. Među 58 tumora pacijenata sa stadijem IIIC ili stadijem IV seroznog karcinoma jajnika (HG-SOG), pronađena je inverzna korelacija između ekspresija miR-9 i BRCA1, tako da povećani miR-9 kod ovih karcinoma jajnika također može doprinijeti smanjenoj ekspresiji BRCA1.

Nedostatak ekspresije BRCA1 – vjerovatno tumorogen

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Oštećenje DNK je primarni uzrok raka,[64] a izgleda da su nedostaci u popravljanju DNK u osnovi mnogih oblika raka.[65] Ako je popravak DNK nedostatan, oštećenje DNK se akumulira. Takav višak oštećenja DNK može povećati mutacijske greške tokom replikacije zbog sklonosti greškama sintezi translezije. Prekomjerna oštećenja DNK mogu također povećati epigenetičke promjene, zbog grešaka tokom popravka DNK.[66][67] Takve mutacije i epigenetičke promjene mogu dovesti do karcinoma. Česti nedostatak BRCA1 izazvan mikroRNK kod karcinoma dojke i jajnika vjerovatno pridonosi njihovom napredovanju.

Populacija ili podrrupa Mutacija BRCA1[68] Reference
Afroamerikanci 943ins10, M1775R [69]
Afrikanci E881X, 1374delC [70][71]
Aškenazi Jevreji 185delAG, 188del11, 5382insC [72][73]
Austrijanci 2795delA, C61G, 5382insC, Q1806stop [74]
Belgijanci 2804delAA, IVS5+3A>G [75][76]
Nizozemci Delecija egzona 2, delecija egzona 3, 2804delAA [75][77][78]
Finci 3745delT, IVS11-2A>G [79][80]
Francuzi 3600del11, G1710X [81]
Francuski Kanađani C4446T [82]
Nijemci 5382insC, 4184del4 [83][84]
Grci 5382insC [85]
Mađari 300T>G, 5382insC, 185delAG [86]
Italijani 5083del19 [87]
Japanci L63X, Q934X [88]
Autohtoni Amerikanci 1510insG, 1506A>G [89]
Sjeverni Irci 2800delAA [90]
Norvežani 816delGT, 1135insA, 1675delA, 3347delAG [91][92]
Pakistanci 2080insA, 3889delAG, 4184del4, 4284delAG, IVS14-1A>G [93]
Poljaci 300T>G, 5382insC, C61G, 4153delA [94][95]
Rusi 5382insC, 4153delA [96]
Škoti 2800delAA [90][97]
Španci R71G [98][99]
Šveđani Q563X, 3171ins5, 1201del11, 2594delC [69][100]

Hemoterapija kancera

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Nemaloćelijski rak pluća (NSCLC) vodeći je uzrok smrti od raka u svijetu. Pri dijagnozi, gotovo 70% osoba s NSCLC ima lokalno uznapredovalu ili metastatsku bolest. Osobe s NSCLC često se liječe terapijskim spojevima platine (npr. cisplatinom, karboplatinom ili oksaliplatinom) koji uzrokuju međulančane unakrsne veze u DNK. Među osobama s NSCLC, niska ekspresija BRCA1 u primarnom tumoru korelirala je s poboljšanim preživljavanjem nakon hemoterapije koja sadrži platinu.[101][102] Ova korelacija implicira da nizak BRCA1 u karcinomu i posljedično nizak nivo popravljanja DNK uzrokuju ranjivost raka na liječenje pomoću DNK agenasa za umrežavanje. Visok BRCA1 može zaštititi ćelije raka, djelujući na put koji uklanja oštećenja u DNK koju unose lijekovi od platine. Stoga je nivo ekspresije BRCA1 potencijalno važan alat za prilagođavanje hemoterapije u upravljanju karcinomom pluća.

Nivo ekspresije BRCA1 je također važan za liječenje raka jajnika. Pacijenti sa sporadičnim karcinomom jajnika koji su liječeni lijekovima od platine imali su duže medijane vremena preživljavanja ako je njihova ekspresija BRCA1 bila niska u odnosu na pacijente sa jačom ekspresijom BRCA1 (46 u odnosu na 33 mjeseca).[103]

Interakcije

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Pokazalo se da BRCA1 komunicira sa sljedećim proteinima:

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