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Ding Jingnuo, Zhao Weifeng, Dhipatimendi rezvirwere zvinotapukira, Suzhou University First Affiliated Hospital, Suzhou City, Jiangsu Province, 215000 Tel.mamota emudumbu system ane makore mashanu ekurarama kwe 14.1%.Varwere vazhinji vane HCC vanoonekwa padanho repamusoro, saka kuongororwa kwekutanga kwakakosha kudzikisa kufa kubva kuHCC.Pamusoro pezvinowanzo shandiswa zviratidzo zvekuona seserum alpha-fetoprotein (AFP), lens lectin-reactive alpha-fetoprotein (AFP-L3), uye abnormal prothrombin (vitamin K kushomeka-induced protein II, PIVKA-II), fluid biopsy maitiro. Yakaratidzwa kuva yehutano hwekuongorora mukuonekwa kweHCC.Kuenzaniswa nemaitirwo ekupinda, fluid biopsy inogona kuona kutenderera kwakashata metabolites.Fluid biopsy matekiniki anoona kutenderera bundu masero, kutenderera bundu DNA, kutenderera RNA, uye exosomes uye anoshandiswa kwekutanga kuongororwa, kuongororwa, uye kuongororwa kweHCC.Ichi chinyorwa chinoongorora mamorekuru biology uye kushandiswa kweakasiyana siyana emvura biopsy matekiniki ekuparadzanisa anovimbisa biomarkers angave anoshanda sarudzo dzekutanga ongororo yeHCC yekuvandudza yekutanga kuongororwa kwemapoka ane njodzi yakanyanya HCC.Keywords: fluid biopsy technique, hepatocellular carcinoma, high-risk group .
Hepatocellular carcinoma (HCC) ibundu rakajairika remudumbu rekugaya, riri pachitanhatu pakati pezviitiko zvitsva zvemamota akaipa muvarume nevakadzi.1 Pasi rose, kenza yechiropa ndiyo yechitatu inokonzera kufa kwegomarara mushure mekenza yemapapu uye colorectal, inoverengera 8.3% yerufu dzine chekuita negomarara kubva kune ese anouraya neoplasms.1 The prognosis yeHCC yakanyatsoenderana nedanho rekuongororwa.Zvikonzero zvikuru zvekupona murombo muHCC intrahepatic metastases, portal venous tumor thrombi, uye kure metastases inodzivirira kubviswa, uye mazhinji ehunhu aya atovepo muvarwere panguva yekuongororwa.
Zvichienderana nekuongorora uye nhungamiro yekurapa, izvo zvinonyanya kuisa njodzi yekuvandudza HCC ndeye cirrhosis yechiropa, hutachiona hweH hepatitis B (HBV) kana hutachiona hweH hepatitis C (HCV), chirwere chedoro chemafuta echiropa, uye isiri-doro fatty chiropa chirwere (NAFLD). )2 Uyezve, zvinogona kukonzera njodzi yeHCC zvinosanganisira kudya kwakasvibiswa neaflatoxin, schistosomiasis, zvimwe zvinokonzera cirrhosis, nhoroondo yemhuri yekenza yechiropa, chirwere cheshuga, kufutisa, kusvuta, uye kukuvara kwechiropa kunokonzerwa nezvinodhaka.Mapoka ane makore 35 ne45 ekuberekwa ane njodzi huru anofanira kugara achiongororwa nanachiremba.Kuongororwa kwekutanga inzira yakakosha yekurapa kwekutanga kuvandudza hupenyu hwese hwevarwere vane HCC.
Biomarkers yakadai seAFP, AFP-L3 uye PIVKA-II inokurudzirwa kuongororwa kwekutanga kweHCC3,4.Liquid biopsy matekiniki akaratidza mhedzisiro inovimbisa mukutanga kuongororwa uye kuongororwa kwekurapa.5,6 Kufambira mberi kwakakosha kwakaitwa muHCC liquid biopsy, iyo inogona kunge iine kunzwisiswa kwepamusoro uye yakananga kupfuura inowanzoshandiswa serum markers seAFP (Table 1).
AFP inonzi biomarker inoshandiswa zvakanyanya muHCC uye parizvino ndiyo yakanyanya kutsanangurwa biomarker inoshandiswa zvakanyanya kuongororwa, kuongororwa, uye kuongororwa kwechirwere.Iyo inoramba yakakwira AFP nhanho inoonekwa senjodzi yekuenderera mberi kweHCC.7,8 Nhamba yekuona yehepatocellular carcinoma (sHCC) iri kuwedzera nekugadzirwa kwe ultrasound uye computed tomography, uye AFP yakawanikwa ichinyanya kusava nehanya nekuona hHCC mumakiriniki maitiro.Zvinoenderana neretrospective multicentre study9, AFP yakanaka yakawanikwa mu46% (616/1338) yeHCC kesi uye 23.4% (150/641) yesHCC kesi.Mukuwedzera, mazinga eAFP anokwidziridzwa kune varwere vane chirwere chisingaperi chechiropa uye cirrhosis.10 Saka, AFP ine shoma yekutarisa maitiro eSHCC.11 Maererano neAsia-Pacific Clinical Practice Guidelines for Hepatocellular Carcinoma, kushandiswa kweAFP hakukurudzirwi.12 Uchapupu hwekliniki hunoratidza kuti PIVKA-II yakakwirira kupfuura AFP mukurapa HCC uye kuti kusanganiswa kwePIVKA-II neAFP kune kukosha kwepamusoro kwekuongorora muHCC.13 Kuenzaniswa netishu biopsy, fluid biopsy inonyanya kuona tumor-inosanganisirwa metabolites mumvura yemuviri (ropa, mate, pleural fluid, cerebrospinal fluid, kana weti) uye haina kupindira kune tishu.14 Uye zvakare, mvura biopsies inogona kuratidza yakashata maficha asiripo mune yekutanga bundu tishu.15 Liquid biopsies haisati yaongororwa mukiriniki yekudzidzira kune ese marudzi emamota, asi kugona kwavo kuongororwa mugomarara kuri kukwezva kutarisisa kwevanorapa.16 Fluid biopsy inogona kuona kutenderera bundu masero (CTCs), kutenderera bundu DNA (cDNA), inotenderera yemahara RNA (ecRNA), uye exosomes.Muchikamu chino, tichakurukura hunhu, basa, uye mashandisirwo emhando dzakasiyana dzebiopsy tekinoroji mukutarisisa kwekutanga kwemapoka ane njodzi yeHCC.
Extracellular DNA (cfDNA) mumasampuli eropa kubva kuvanhu vane hutano yakatanga kutsanangurwa muna 1948 naMandel et al.17 cfDNA chimedu chisina sero cheDNA chinenge 160-180 bp pakureba, chichibva kunyanya kubva kumalymphocytes uye myeloid cells.ctDNA ndeye chaiyo mutant DNA fragment yakaburitswa nebundu maseru muropa reperipheral, inomiririra iyo genomic ruzivo rwemamota maseru mushure memamwe maitiro epathophysiological, anosanganisira necrosis, apoptosis, uye excretion.Chikamu che ctDNA mu cfDNA yakazara chinosiyana zvakanyanya nerudzi rwebundu, uye zvimedu zvecDNA zvinonzi zvinogara zvisingasviki 167 bp pakureba.18 Ongororo yakaitwa naUnderhill yakaratidza kuti cfDNA zvidimbu kazhinji zvipfupi pane zvakajairika cfDNA.19 Zvichienzaniswa nevanhu vane hutano, hurefu hwese hwezvimedu zvecfDNA muropa revarwere vegomarara hupfupi, saka cfDNA inogona kushandiswa sechiratidzo chekutanga kuongorora bundu.Kupfumiswa kwemamwe ma subsets ecfDNA chidimbu kureba kunogona kuvandudza kuwonekwa kwecDNA ine chekuita neasina-metastatic akasimba mabundu.Zvidzidzo zvakaratidza kuti ctDNA inowanikwa mune inopfuura makumi manomwe neshanu muzana epamusoro pancreatic, colon, dundira, gastrointestinal, chiropa, ovarian, zamu, melanoma, uye musoro nemutsipa kenza.20,21 Zvakadaro, huwandu hwectDNA muropa hunoenderana nenzvimbo yebundu.22 Muongororo yakaitwa naBettegoud, varwere vane cancer yeruvara rweganda, zamu, chiropa, mapapu, neprostate vakaonekwa vaine mwero wepamusoro wecDNA muropa ravo kupfuura mamwe makomarara.Kusiyana neizvi, kune varwere vane kenza yemuromo, kenza yepancreatic, kenza yemudumbu, uye glioma, cDNA kusungwa muropa kwakaderera.makumi maviri nerimwe
Nekuti ctDNA ine ma genetic mutations seyekutanga bundu masero, cDNA inogona kushandiswa kuona heterogeneous tumor-chaiyo shanduko uye epigenetic shanduko, kusanganisira methylation, hydroxymethylation, single nucleotide kusiyana, uye kopi nhamba kusiyana.makumi maviri nenhatu
DNA methylation ndeimwe yeakajairika epigenetic shanduko inokonzera kudzvinyirirwa kwemajini.Kuenzaniswa nemasero akajairwa, kune misiyano muhuwandu hwemethylation ye tumor cell genome, kunyanya mumethylation ye tumor suppressor genes, iyo inogona kuonekwa padanho rekutanga, zvichiratidza kuti shanduko muDNA methylation inogona kunge iri chiratidzo chekutanga. kuonekwa kwe tumorigenesis.Tumor suppressor genes inobatanidza neHCC inogona kuvharwa nekusimudzira methylation, nokudaro inokurudzira tumorigenesis.24 DNA methylation mucherechedzo wakakodzera wekuongororwa kwekutanga kwemamota nekuda kwehunhu hwayo hwematishu, kuonekwa, uye kusununguka kwezera.Pamusoro pezvo, DNA methylation inonyanya kuwanda kana ichienzaniswa nekuchinja kwe somatic nekuti kune mamwe matunhu anotariswa uye akati wandei akachinja CpG nzvimbo munzvimbo imwe neimwe yechinangwa genome.25 Pamusoro penzvimbo dzakawanda dzeCpG, nhamba huru yeyakazvimirira hypermethylated loci mu ctDNA yakaonekwa muDBX2, THY1, MT1M, INK4A, VIM, FBLN1, uye RGS10.26 Xu et al.Kuenzanisa kwemasampunzi ecfDNA kubva kuvarwere ve1098 HCC uye 835 hutano hunodzora hwakanga huri majini akabatana neHCC akawanikwa achienderana zvakanyanya neinowirirana plasma cDNA methylation siginecha.25 Zvichienderana nekuongorora kwarabhoritari, modhi yekufungidzira yakagadziridzwa iine gumi methylation mamaki ane sensitivity uye chaiyo ye85.7% uye 94.3%, zvichiteerana, uye mamaki aya aive akabatana zvakanyanya nehuremu hwebundu, bundu nhanho, uye mhinduro pakurapwa.Mhedzisiro iyi inoratidza kuti kushandiswa kwecDNA methylation mamaki ane vimbiso huru mukuongororwa, kutarisa, uye kufungidzira kweHCC.Mune methylation modhi ine matatu aberrantly methylated genes (APC, COX2, RASSF1A) uye imwe miRNA (miR203) yakaratidzwa naLu et al27, kunzwisiswa uye kujeka kwemuenzaniso 27 yekuongorora HBV-yakabatana HCC yaifananidzwa.80%.Mukuwedzera, iyo modhi inogona kuona 75% yevarwere vasina kuongororwa HCC vane AFP level ye20 ng/mL.Jeni reRas-associated domain mhuri 1A protein (RASSF1A) ndiyo huru inodzokorora DNA kutevedzana mugenome remunhu.Araujo et al.akagumisa kuti hypermethylation yemusimudziri weRASSF1A inogona kuva yakakosha biomarker yekuongorora kwekutanga kweHCC uye inogona kunge iine molecular target for epigenetic therapy.28 Mune imwe ongororo, serum RASSF1A inokurudzira hypermethylation yakawanikwa mu73.3% yevarwere vane HCC.29 Yakareba yakapindirwa nucleotide element 1 (LINE-1) imwezve inoshanda zvakanyanya retrotransposition murevereri.Hypomethylation yeLINE-1 yakawanikwa muDNA ye66.7% yeHCC serum samples uye yaisanganiswa nekudzoka kwekutanga uye kupona kwakashata mushure mekurasika resection.29 Hypermethylation yakajairika genetic maitiro anoita basa rakasiyana mukukura kwechiropa cirrhosis uye HCC.30 Kusiyana neizvi, hydroxymethylation inzira ye demethylation inoita kuti gene reactivation uye kutaura, uye kuonekwa kwe5-hydroxymethylcytosine (5-hmC) chigadzirwa mune iyi nzira inogona kushandiswa kuona bundu.Methylation uye hydroxymethylation yecDNA yakabatana ne tumorigenesis uye inogona kubatsira mukutanga kuongororwa kweHCC.Muchidzidzo chezvidzidzo zve2554, 31 genome-wide 5-hmCs yakawanikwa mu cfDNA samples, uye 32 majini akaonekwa nekuenzanisa 5-hmC sequences muHCC varwere uye mapoka ane ngozi akadai seaya ane zvirwere zvisingaperi.Diagnostic mhando dzezvirwere zvechiropa.uye cirrhosis.Iyi modhi yaive yepamusoro kune AFP mukusiyanisa HCC kubva kune isiri-bundu tishu.
Shanduko mumatunhu ekodha inogona kutungamira kune zvinyorwa zvisiri izvo, izvo zvinogona kutungamira kune shanduko mukutevedzana kweprotein uye pakupedzisira gomarara.Single nucleotide akasiyana akakosha genomic mamaki ekutanga kutariswa bundu nekuda kwekuvimbika kwavo kwetishu uye bundu rakakura uye hunhu hwematishu.Zvidzidzo zvakawanda zvine chekuita neHCC vachishandisa chizvarwa chinotevera sequencing (NGS) yekubuda uye yakazara genome kutevedzana kwegomarara zvakaratidza zvakajairika mutated cellular genes seTP53 uye CTNNB1, pamwe nemamwe akati wandei anosanganisira ARID1A, MLL, IRF2.Iwo majini matsva, ATM, CDKN2A, FGF19, PIK3CA, RPS6KA3 uye JAK1 inoratidza mwero mutation. Mutant gene function analysis inoratidza kuti kuchinja kwechromatin remodeling, Wnt/β-catenin uye JAK/STAT signal transduction, P53-cell cycle pathway, epigenetic modifiers, oxidative stress pathways, PI3K/AKT/MTOR nzira uye RAS/RAF/ MAPK kinase pathway inobata basa rinokosha muHCC oncogenesis.32,33 Muchidzidzo umo kuchinja kwakabatana nebundu kwakaonekwa, Huang et al akawana kuti kuwanda kwemararamiro anokonzerwa nechirwere zvichienderana nectDNA yaiva 19.5%, uye chaiyo yaiva 90% .34 Mukuwedzera, varwere vakawana vascular invasion vaiwanzoita ctDNA mutations (P = 0.041) uye kupfupika kwekudzoka-kusina kupona (P <0.001). Mutant gene function analysis inoratidza kuti kuchinja kwechromatin remodeling, Wnt/β-catenin uye JAK/STAT signal transduction, P53-cell cycle pathway, epigenetic modifiers, oxidative stress pathways, PI3K/AKT/MTOR nzira uye RAS/RAF/ MAPK kinase pathway inobata basa rinokosha muHCC oncogenesis.32,33 Muchidzidzo umo kuchinja kwakabatana nebundu kwakaonekwa, Huang et al akawana kuti kuwanda kwemararamiro anokonzerwa nechirwere zvichienderana nectDNA yaiva 19.5%, uye chaiyo yaiva 90% .34 Mukuwedzera, varwere vakawana vascular invasion vaiwanzoita ctDNA mutations (P = 0.041) uye kupfupika kwekudzoka-kusina kupona (P <0.001).Mutant gene function analysis inoratidza kuti kuchinja kwechromatin remodeling, Wnt/β-catenin uye JAK/STAT signing, P53 cell cycle pathway, epigenetic modifiers, oxidative stress pathways, PI3K/AKT/MTOR nzira, uye RAS/RAF/ MAPK kinase nzira inotamba. basa rinokosha muHCC tumorigenesis.32,33 Muchidzidzo chakawana kuchinja kwakabatana ne tumor, Huang et al.vakawana kuti kuwanda kwe ctDNA-inotsamira tumor-yakabatana mutations yaive 19.5% uye chaiyo yaive 90%..34 Кроме того, у пациентов сосудистой инвазией чаще мстречались мутации цДНК (P=0,041) uye более короткая безрецивыдижи Господ, короткая безрецивыдижи (P=0,041). .34 Mukuwedzera, varwere vane vascular invasion vaiva nekazhinji cDNA mutations (P = 0.041) uye kupfupika kwechirwere-pasina kupona (P <0.001).Kushanda kuongororwa kwemajini anochinja anoratidza chromatin remodeling, Wnt/β-catenin uye JAK/STAT kusaina, iyo P53 cell cycle nzira, epigenetic modifiers, iyo oxidative stress nzira, iyo PI3K/AKT/MTOR nzira, uye iyo RAS/RAF/MAPK. kinase nzira inoita basa rakakosha mune oncogenesis yeHCC. 32,3 3 在 项 检测 肿瘤 肿瘤 相关 相关 的 的 发现 发现 发现 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 肿瘤 相关 相关 相关 相关 相关 相关突变(P=0.041)和更短的无复发生存期(P<0.001). 32.33 在 一 检测 到 到 到 突变 突变 肿瘤 肿瘤 ,,5%, 特异性 为 90% .34 此外 经历 血管 侵犯 的 更 可能 发生 CTDNA 突变 (P = 0.041)短的无复发生存期(P<0.001).32,33 Muchidzidzo chakawana kuchinja kwakabatana nebundu, Huang et al.akawana kuti kushanduka kwakabatana ne-tumor kwaiva 19.5% zvichienderana necDNA ine ruzivo rwe90% 34. Mukuwedzera, varwere vakanga vapinda mutsinga vaiwanzoita cDNA.мутация (P = 0,041) uye более короткая безрецидивная выживаемость (P <0,001). mutation (P=0.041) uye kupfupika kwechirwere-pasina kurarama (P<0.001).Imwe yakajairika HCC mutyairi gene ndeye TP53, iyo ine mutation rate inopfuura 30%.Zvidzidzo zvakaratidza kuti kuwanda kwe TP53 shanduko mu ctDNA muropa uye weti inotangira pa5% kusvika 60%.35 Ongororo yaJohan yakaratidza kuti ctDNA mutation spectrum munguva yekupedzisira HCC ine chiyero chakafanana chekuchinja kune yekutanga HCC, kusanganisira iyo TERT mutsigiri (51%), TP53 (32%), CTNNB1 (17%), PTEN (8%), shanduko AXIN1 ., ARID2, KMT2D uye TSC2 (6% imwe neimwe).36 Iyo β-catenin (CTNNB1) oncogene inoita basa rinokosha muWnt signing pathway.Iyo transcription coactivator CTNNB1 inogona kukurudzira gene kutaura, izvo zvinogona kutungamirira kukuwedzera kwesero, inhibition yeapoptosis, uye angiogenesis.CTNNB1 inogona zvakare kudyidzana neTERT kukurudzira hepatocyte shanduko.33 Mutsigiri weTERT anowanzo shandurwa mune mamwe mamota akasimba.Kuchinja muTERT, imwe yepakutanga kushanduka kwemajini mukuchinja kwakashata kweHCC, kunogona kutungamirira ku telomerase reactivation mu cirrhotic hepatocytes uye inogona kukurudzira kupararira nekudzivirira kukwegura.Kuchinja-chinja mu33-37 TERT mutsigiri anonzi akaitika mu59-90% yevarwere vane proliferative chiropa nodules uye yekutanga HCC uye inobatanidzwa nekupona.38
Copy nhamba shanduko (CNA) yakakosha subtype ye somatic mutations.Tsvagiridzo yakaratidza kuti kupararira uye kutarisisa kuremerwa kweCNA igenomic siginecha inokwanisa kufanotaura bundu immune kupinza uye kusabatanidzwa mune mamwe marudzi egomarara.39 Active infiltration signing, yakakwira cytolytic basa, kuzvimba kwakanyanya uye ma genetic markers anoenderana neantigen mharidzo muHCC.Ongororo yedhata array ye single nucleotide polymorphisms mune 477 zvidzidzo zvakaratidza mutoro wakaderera paCNS.Kusiyana neizvi, mapundu asina kugadzikana echromosomally ane yakakura yakakura CNA mutoro wakaratidza zviratidzo zvekurambwa kwekudzivirira uye zvakabatanidzwa nekupararira, kugadzirisa DNA, uye TP53 kusagadzikana.Xu et al.yakaratidza kuti boka reHCC raiva nepamusoro peCNA scores kupfuura chirwere chisingaperi chechiropa boka.40 Kushandisa yose-genome sequencing yesero rimwe chete, CNAs dzakawanikwa dzichioneka kare muhepatocarcinogenesis uye dzinoramba dzakagadzikana panguva yekufambira mberi kwebundu.41 Chung et al.vakawana kuti cfDNA mazinga akakwidziridzwa zvakanyanya muvarwere veHCC uye kuti genome-wide CNAs mucfDNA yaive yakakosha yakazvimirira prognostic marker muHCC varwere vanorapwa sorafenib.42 Varwere vane mutoro wakakwirira weCNA vainyanya kuve nekufambira mberi kwechirwere uye kufa pane avo vane mutoro wakaderera weCNA.Ollerich et al.akawana kuti kopi nhamba instability index (CNI) inogona kushandiswa kuongorora CNA mucfDNA yevarwere vegomarara.Vakacherekedza kuti varwere vane gomarara repamusoro vaive nepamusoro zvakanyanya CNI zvibodzwa pane boka rinodzora, iro rinoongorora mhinduro yemurwere kune systemic chemotherapy uye immunotherapy.43 Mhedzisiro iyi inoratidza kuti maCNA anowanikwa mune yemvura biopsy mienzaniso inogona kushanda sechiratidzo chezviratidzo muvarwere vane gomarara repamusoro.HCC pamashure ehurongwa hwekurapa.
Parizvino, nzira dzinoshandiswa kuona ctDNA dzinogona kukamurwa kuita nzira dzakanangwa uye dzisiri dzakatariswa.Muchidimbu, nzira dzakanangwa dzakadai sedhijitari polymerase chain reaction (dPCR), BEAMing digitaalinen PCR, Amplification Refractory Mutation System-PCR, Capp-Seq uye Tam-Seq vane hanya zvakanyanya kune akafanotsanangurwa majini.Nzira dzekunze-dzakavavarira dzakadai seyese genome sequencing uye NGS inopa maonero akakwana eiyo genomic landscape.44 Kana ichienzaniswa nemapaneru ekunangwa, kutevedzana kwegenome hakugone kungoona shanduko uye kuiswa, asiwo kurongazve uye kukopa nhamba dzakasiyana.prognosis, uye CTC uye cfDNA zviratidzo zvakanaka zvinogona kushandiswa kusimba kwekutarisa kweHCC.45 Pamusoro pezvo, cfDNA ongororo inogona kubatsira zvakanyanya pakuona HCC.Yan et al.yakaratidza kuti cfDNA muplasma yevarwere vane HCC yakanga yakanyanya kukwirira kupfuura kune varwere vane chiropa fibrosis uye kutonga kwakanaka.Kuenzaniswa neAFP, ctDNA inotarisirwa kuve iri nani yekutarisa chiratidzo chekutanga HCC.46 Muchidzidzo chinotarisirwa chemakumi mana nemanomwe emvura biopsies akaedza cfDNA uye mapuroteni muhuwandu hwevanhu, akaratidzwa kuve anoshanda mukusiyanisa varwere vane HCC nevarwere vasina HCC.Mukutevera kwe331 ultrasound yakajairika uye AFP-negative varwere, kunzwisiswa uye kujeka kwecfDNA yekuongorora HCC yaive 100% uye 94%, zvichiteerana, saka cDNA yaigona kuona HCC mune asymptomatic HBsAg seropositive vanhu.Muchidzidzo cheYeo48, yakakwira frequency (92.5%) ye hypermethylation yeRASSF1A inosimudzira yakawanikwa mune varwere vane HCC.Mukuwedzera, Xu et al.yakagadzira diagnostic modhi yekufanotaura HCC vachishandisa pani yeyakananga methylation mamaki ane chaiyo uye sensitivity ye90.5% uye 83.3%, zvichiteerana.Iyo pani inobvumira varwere vane HCC kuti vasiyane nevarwere vane zvimwe zvirwere zvechiropa, izvo zviri nani pane AFP.Vakaona zvakare kuti zvidzoreso zvakajairwa zvakaongororwa zvakanaka zvinogona kunge zvine njodzi yeHCC, senge HBV kutapukirwa kana nhoroondo yekunwa doro.25 Isu tinofungidzira kuti zvinhu zvine njodzi zvakanyanya kuHCC zvinogona kukurudzira hypermethylation yecfDNA, iyo inobva yabatsira mukufambira mberi kweHCC, uye nekudaro cfDNA inogona kuita basa rakakosha pakuongorora mapoka ane njodzi.Cai et al.pfupikisa iyo yakazara yakazara ctDNA shanduko uye inopa yakasimba zano rekuongorora bundu mutoro muvarwere.49 Iyi nzira inogona kuziva tumorigenesis yepakati yemwedzi 4.6 isati yashanduka kuchinja uye yakaratidza kushanda kwepamusoro kwekuongorora kuenzaniswa ne serum biomarkers AFP, AFP-L3, uye PIVKA-II.Kukosha kwekuongorora kwekuongorora kwecDNA kwakaratidzwa kana kuongororwa kwemufananidzo kusipo, saka kuongororwa kwecDNA kunokosha mukuongororwa kwekutanga kweHCC mumapoka ane ngozi.Munguva pfupi yapfuura, masayendisiti akashandisa tekinoroji yeNGS kuongorora zviratidzi zve multivariate genetic variation (kusanganisira 5-hydroxymethylcytosine, 5'-motif, fragmentation, nucleosome trace, HIFI) mu3204 kliniki samples uye cfDNA.50 Yakadzokororwazve HIFI modhi ine matatu yakazvimirira chitima, bvunzo, uye bvunzo seti yakaratidza yakagadzikana uye yakavimbika rusarura pakati peHCC nevasiri HCC vanhu vane 95.79% uye 95.42% sensitivity muHCC-chaiyo bvunzo uye bvunzo seti, zvichiteerana.Varume vacho vaive 95.00% uye 97.83%, zvichiteerana.Kukosha kwekuongorora kweHIFI nzira yakakwirira kudarika yeAFP mukusiyanisa HCC kubva kune cirrhosis.Mukuwedzera, ctDNA inoshandiswawo mukuvhiya kurapwa.Atsushi et al.yakasarudza preoperative serum mazinga e ctDNA muvarwere vane HCC uye akawana kuti chiyero chekudzoka uye extrahepatic metastasis rate mu cDNA yakanaka boka yakanga yakakwirira zvikuru kupfuura muboka re cDNA risina kunaka, uye mazinga ecDNA akabatanidzwa zvakanyanya.nekukura kwebundu.51 Kuve inocherekedza biomarker, ctDNA inogona kufanotaura kugona kweHCC kupinda mungarava.Wang et al.yakaita yese genome sequencing yevarwere makumi mana nevatanhatu vane HCC, uye kuongororwa kwakawanda kwakaratidza kuti kukosha kwechikumbaridzo cheiyo allele frequency ye cDNA musiyano wekupinda mumamicrovessels i0.83%, senitivity 89.7% uye chaiyo 80.0%.yakazvimiririra njodzi yekupinda microvascular in rectable HCC, zvichiratidza kuti cDNA inogona kubatsira kutungamira kurapwa kwakaringana.Mukupedzisa, ctDNA inobatanidzwa zvizere mukuitika uye kuvandudzwa kweHCC uye inogona kushandiswa kutanga kuongororwa, kuongororwa kwekuvhiya, uye kuongorora chirwere.
CTCs masero akashata anotorwa kubva kumapundu ekutanga kana metastases anokura kusvika muropa.Tumor cell secrete matrix metalloproteinases (MMPs), iyo inopwanya membrane yepasi, ichibvumira masero ebundu kuti apinde zvakananga muropa uye lymph midziyo.Nekudaro, mazhinji maCTC anokurumidza kubviswa neanoikis, immune kurwisa, kana shear stress.53 Iyo epithelial-mesenchymal transition (EMT) inobvumira maCTC kuti angove ari ega kubva kune yekutanga bundu tishu, apinde nechisimba capillaries, uye kuwana zvakanyanya kunatsiridza kupona, metastasis, invasiveness, uye kuramba zvinodhaka.Zvidzidzo zvakaratidza kuti kune yakadzama heterogeneity pakati peakasiyana masero ebundu mune ekutanga metastatic tumors.Nekudaro, kuongororwa kweCTC kunogona kutungamira mukunzwisisa kwakazara kwe tumor cell heterogeneity.54
Mavara chaiwo eHCC-akabatanidzwa CTCs anosanganisira glypican-3 (GPC3), asialoglycoprotein receptor (ASGPR), epithelial cell adhesion molecule (EpCAM) uye stem cell-associated mamaki akadai seCD44, CD90, 55 uye intercellular adhesion molecule 1 (ICAM1).) .56 Mucherechedzo weGPC3 ipuroteni yesero membrane-anchored iyo inoshandiswa nekiriniki pakuongorora chirwere uye kuratidza chimiro cheHCC.57 Maonero eGPC3 anowanzoonekwa muHCC tumor cell ane pakati uye yakaderera kusiyana uye inokurudzira extrahepatic migration;uyezve, kuvapo kweGPC3+ CTCs kunoratidza metastatic HCC.58 ASGPR inonzi transmembrane protein inoratidzwa chete pamusoro pehepatocytes uye inoratidzirwa zvakanyanya muHCC yakanyatsosiyana.EpCAM ndeimwe yeanonyanya kushandiswa membrane-akabatanidzwa mapuroteni kutora CTCs.EpCAM yakaonekwa sechiratidzo chepamusoro chemasero eHCC ane stem cell maitiro, 59 ayo anoenderana neakasiyana siyana ekiriniki yeHCC, senge vascular invasion, yakaongororwa mazinga eAFP, uye nhanho yepamusoro yekenza yechiropa paBarcelona Hospital (BCLC).Iyo 60 CTC EMT phenotype yakanyanya metastatic.54 EMT maitiro muCTC anokurudzira HCC metastasis.Mataurirwo eEMT mamakisi akadai se vimentin, twist, E-box zinc finger binding (ZEB) 1, ZEB2, hozhwa, slug, uye E-cadherin zvakadzidzwa muCTC dzakatorwa nechiropa kubva kuvarwere veHCC.58 Iyo CanPatrol™ sisitimu yakagadziridzwa naCheng [61] yakarongedza maCTC muzvikamu zvitatu zvephenotypic zvichibva pane zvinonyanya kuratidzwa mamaki: epithelial phenotype (EpCAM, CK8/18/19), mesenchymal phenotype (vimentin, coiled), uye yakasanganiswa phenotypes.Muvarwere ve176, CTC yakazara yaive yepamusoro kune AFP mukusiyanisa HCC kubva kune benign chiropa chirwere.Huwandu hweAUC hweCTC yakazara, AFP, uye yakasanganiswa yakazara CTC neAFP yaive 0.774 (95% CI, 0.704–0.834), 0.669 (95% CI, 0.587–0.750), uye 0.821 (95% CI, 0.886-0.886). )), zvichiteerana.CTC classification yakavakirwa paEMT inogona kufanotaura kuongororwa kweHCC, kudzoka kwekutanga, metastasis, uye ipfupi nguva yese.
Parizvino, nzira dzekuona maCSC dzinosanganisira nzira dzemuviri uye nzira dzebiological.Nzira dzemuviri, dzinowanzonzi hupfumi hwakavakirwa pane biophysical zvimiro, zvinonyanya zvinoenderana nehunhu hweCSC, senge saizi, density, charge, kufamba uye kuremara.Zvichienderana nemamiriro emuviri, kune nzira dzakasiyana-siyana dzakadai sefiltration-based systems, dielectrophoresis, nezvimwewo. Iyo yekupedzisira, inozivikanwawo se immunoaffinity-based enrichment, inonyanya kuenderana neantigen-antibody kusunga sezvo nzira inoshandisa masoja ekudzivirira zvirwere kubva kune tumor-specific biomarkers. zvakadai seEpCAM, ASGPR, epidermal growth factor receptor 2 (HER2), prostate specific antigen (PSA), pancytokeratin yevanhu (P-CK) uye carbamoyl phosphate synthase 1 (CPS1).62 Imwe mhando, inonzi no-enrichment method, inoshandisa flow cytometry kusiyanisa CTCs kubva leukocytes zvichienderana nepamusoro nuclear-to-cytoplasmic ratio uye saizi.Parizvino, iyo chete FDA-yakatenderwa bvunzo yekuonekwa kweCTCs ndiyo Cell-Search™ system, inoshandisa EpCAM cell surface marker. Zvisineyi, zvicherechedzo zvakasanganiswa-based CTC kuonekwa zvinogona kuwedzera positivity rate.54 Musanganiswa wemasoja ekudzivirira chirwere anorwisa ASGPR neCPS1 akawana CTC yekuona chiyero che91% muvarwere veHCC.63 Zhang et al akashandisa CTC-Chip ine masoja ekudzivirira chirwere anorwisa ASGPR, P. -CK neCPS1, uye vakasiyanisa varwere veHCC kubva kune avo vane chirwere chechirwere chechiropa kana kuti isiri-HCC kenza pamwero we100%.64 Ongororo yakaitwa naWang yakaona EpCAM + CTCs mu60% yevarwere ve42 HCC uye yakawana kuwirirana kwakakosha pakati pezvose zviri positivity. chiyero uye nhamba yeCTCs neTNM stage.65 Guo et al vakawana kuti CTC-yakatorwa PCR chikamu chakakwirira mu 125/171 (73%) varwere vane AFP level <20 ng / mL nekunzwa kwe72.5% uye a chaiyo ye95.0%, ichienzaniswa ne57.0% uye 90.0% yeAFP pane cutoff 20 ng / mL.66 Kusanganiswa kweAFP neCTCs kunogona kuvandudza HCC kuonekwa.45 Zvinotendwa kuti CTCs ine mukana pane AFP mukutanga kuongororwa kwemapoka. panjodzi huru yeHCC. Zvisineyi, zvicherechedzo zvakasanganiswa-based CTC kuonekwa zvinogona kuwedzera positivity rate.54 Musanganiswa wemasoja ekudzivirira chirwere anorwisa ASGPR neCPS1 akawana CTC yekuona chiyero che91% muvarwere veHCC.63 Zhang et al akashandisa CTC-Chip ine masoja ekudzivirira chirwere anorwisa ASGPR, P. -CK neCPS1, uye vakasiyanisa varwere veHCC kubva kune avo vane chirwere chechirwere chechiropa kana kuti isiri-HCC kenza pamwero we100%.64 Ongororo yakaitwa naWang yakaona EpCAM + CTCs mu60% yevarwere ve42 HCC uye yakawana kuwirirana kwakakosha pakati pezvose zviri positivity. chiyero uye nhamba yeCTCs neTNM stage.65 Guo et al vakawana kuti CTC-yakatorwa PCR chikamu chakakwirira mu 125/171 (73%) varwere vane AFP level <20 ng / mL nekunzwa kwe72.5% uye a chaiyo ye95.0%, ichienzaniswa ne57.0% uye 90.0% yeAFP pane cutoff 20 ng / mL.66 Kusanganiswa kweAFP neCTCs kunogona kuvandudza HCC kuonekwa.45 Zvinotendwa kuti CTCs ine mukana pane AFP mukutanga kuongororwa kwemapoka. panjodzi huru yeHCC.Zvisinei, kucherechedzwa kwakabatanidzwa kunowanikwa kweCTCs kunogona kuwedzera chikamu chemigumisiro yakanaka.54 Musanganiswa weASGPR uye CPS1 antibodies akawana CTC yekuona chiyero che91% kune varwere vane HCC.63 Zhang et al.akashandisa CTC-Chip ine masoja ekudzivirira chirwere anorwisa ASGPR, P-CK neCPS1, uyewo akasiyanisa varwere vane HCC kubva kune avo vane chirwere chepachiropa chisina kunaka kana kuti vasiri HCC pamwero we100%.частота и количество ЦОК со стадией TNM.65 Guo и соавторы обнаружили, что показатель ПЦР, полученный из ЦОК, был повышен у 125/171 (73%) пациентов, у которых уровень АФП был <20 нг/мл с чувствительностью 72,5% и специфичность 95,0% по сравнению с 57,0% и 90,0% для АФП при пороговом уровне 20 нг/мл.66 Комбинация АФП и ЦОК может улучшить обнаружение ГЦК.45 Считается, что ЦОК имеют преимущество перед АФП при раннем скрининге групп. kuwanda uye nhamba yeCTCs neTNM stage.65 Guo et al akawana kuti PCR yakabva kuCTCs yakasimudzwa mu 125/171 (73%) varwere vaiva neAFP mazinga <20 ng / mL nekunzwa kwe72.5% uye zvakananga zve 95.0% kana ichienzaniswa ne57.0% uye 90.0% yeAFP pachikamu chekucheka che20 ng / mL.66 Kusanganiswa kweAFP neCTCs kunogona kuvandudza kuonekwa kweHCC.45 CTCs inoonekwa seine mukana pane AFP mukutanga kuongorora. mapoka.ine njodzi yakakura yeHCC.Zvakadaro, kucherechedzwa-kwakavakirwa kwakasanganiswa kucherechedzwa kweCTCs kunogona kuwedzera chikamu chemhedzisiro yakanaka.54 Musanganiswa weanorwisa ASGPR neCPS1 masoja ekudzivirira chirwere akawana 91% CTC yekuonekwa mwero muvarwere vane HCC.63 Zhang et al.akashandisa CTC machipi ane masoja ekudzivirira chirwere anorwisa ASGPR, P-CK neCPS1 uye akasiyanisa varwere vane HCC kubva kuchirwere chechiropa chisingaiti uye vasiri HCC vane 100%.64 Ongororo yaWang yakaratidza 60% yeEpCAM+ CTCs muvarwere makumi mana nevaviri HCC uye yakawana kuwirirana kwakakosha pakati pezviitiko nehuwandu hweCTCs padanho reTNM. 65 Guo 等人发现,在AFP 水平<20 ng/mL 的125/171 (73%) 名患者中,CTC 衍生的PCR 评分升高,敏感性在A7感漧,敏感性,敂感性,敏感性,敏感性,敏感性,敏感性,敏感性,敏感性,敏感性,敏感性,敏感性,敏感性。值為20 ng/mL 时的特异性為57.0% 和90.0%. 65 Guo 等 人 发现 发现 在 在 在 在 水平截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 截止 W 865 Guo et al.обнаружили, что у 125/171 (73%) пациентов с уровнем АФП <20 нг/мл показатели ПЦР, полученные с помощью ЦОК, были повышены с чувствительностью 72,5% и специфичностью 95,0%, в то время как АФП на уровне отсечки Специфичность составляла 20 нг/мл. vakawana kuti mu125/171 (73%) varwere vane AFP mazinga <20 ng/mL, CTC-yakatorwa PCR tsika dzakasimudzwa nekunzwa kwe72.5% uye chaiyo ye95. yaiva 20 ng/mL.ml yaive 57.0% uye 90.0%.66 Kusanganiswa kweORP neCTC kunovandudza kuonekwa kweHCC.45 CTCs dzinofungidzirwa kuti dzakapfuura AFP mukutanga kuongororwa kwehuwandu hwehCC ine njodzi.Saka, kumapoka eCTC-positive uye ane njodzi huru yeHCC, kuongororwa kweCTC kunofanirwa kusanganiswa nguva dzose ne ultrasound uye AFP yekuona.Nekudaro, maCTC anoonekwa akakosha ekufanotaura kwebundu metastasis uye kudzokorora, uye kuongororwa kweCTCs hakukurudzirwe zvakazvimiririra sechinhu chekuongorora.62 Naizvozvo, CTC inogona kushanda senge iri nani inofanotaura biomarker pane mamwe anoshandiswa mamaki. Zhou et al vakawana kuti varwere vane nhamba dzakakwirira dzeEpCAM + CTCs uye masero eT anodzora vakaratidza njodzi yakakura yekuvandudza HCC kudzokorora, kupfuura avo vane nhamba shoma yeCTCs, ine chiyero chekudzoka kwe66.7% vs 10.3% (P <0.001) .67 . Chidzidzo chakafanana chakataurwa naZhong et al.68 Uyezve, Qi yakawana kuti 101 yevarwere ve112 (90.81%) neHCC, kusanganisira avo vane chirwere chepakutanga, vaiva neCTCs uye kuti zviduku zvishoma zveHCC zvakaonekwa mushure me3. kusvika kumwedzi ye5 yekutevera. Zhou et al vakawana kuti varwere vane nhamba dzakakwirira dzeEpCAM + CTCs uye masero eT anodzora vakaratidza njodzi yakakura yekuvandudza HCC kudzoka kune avo vane nhamba shoma yeCTCs, ine chiyero chekudzoka kwe66.7% vs 10.3% (P <0.001) .67 A. Kuongorora kwakafanana kwakashumwa naZhong et al.68 Mukuwedzera, Qi akawana kuti 101 yevarwere ve112 (90.81%) neHCC, kusanganisira avo vane chirwere chepakutanga, vaiva neCTCs uye kuti zviduku zvishoma zveHCC zvakaonekwa mushure me3 kusvika. 5 mwedzi yekutevera. Чжоу и др.обнаружили, что у пациентов с повышенным количеством ЦОК EpCAM+ и регуляторных Т-клеток риск развития рецидива ГЦК был выше, чем у пациентов с низким количеством ЦОК, с коэффициентом рецидивов 66,7% против 10,3% (P <0,001)67. Zhou et al akawana kuti varwere vane EpCAM + CTCs yakakwirira uye masero eT anodzora aiva nengozi yakawanda yeHCC yekudzoka kune avo vane CTCs yakaderera, ine chiyero chekudzoka kwe66.7% vs 10.3% (P <0.001) 67.Chidzidzo chakafanana chakaitwa naZhong et al.68. Mukuwedzera, Qi yakaona kuti 101 kubva kune 112 varwere (90.81%) neHCC, kusanganisira avo vane chirwere chepakutanga, vaiva neCTCs, uye kuti maduku maduku eHCC akaonekwa mushure me3 kusvika kumwedzi ye5 yekutevera. Zhou 的 发现, 与 ctc 数量 少 的 的 患者 相比, Epcam + ctc 和 患者 发生 数量 数量 发生 更, 复发率 更 高, Zhou 等 发现 与 与 与 与 与 与 与 患者, Epcam + ctc 和 数量 数量 数量 的 的, 复发率 分别 为 为 为 为 为 为 为 为p <0.001)........... Чжоу и др.обнаружили, что пациенты с повышенным количеством ЦОК EpCAM+ и регуляторных Т-клеток имели более высокий риск рецидива ГЦК по сравнению с пациентами с меньшим количеством ЦОК, с частотой рецидивов 66,7% и 10,3% соответственно (P <0,001). Zhou et al.vakawana kuti varwere vane EpCAM + CTCs yakakwirira uye masero eT anodzora aiva nengozi yakawanda yeHCC kudzokorora kana ichienzaniswa nevarwere vane CTCs shoma, nekudzoka kwehuwandu hwe66.7% uye 10.3%, maererano (P <0.001).Chidzidzo chakafanana chakataurwa naZhong et al.68 Mukuwedzera, Qi yakaona kuti 101 ye112 HCC varwere (90.81%), kusanganisira varwere vane chirwere chepakutanga, vaiva nemigumisiro yakanaka yeCTC uye vakawana zviduku zvishoma zveHCC mushure mekushanyira katatu.Kutarisa kusvika kumwedzi mishanu.Vakawanawo maCTC muvarwere gumi nevaviri vane chirwere chisingaperi cheHBV uye vakawana mamota madiki eHCC mukati memwedzi mishanu mune 2 CTC-positive varwere.69 Saka, maCTC anogona kushandiswa kufanotaura HCC, 70 asi anogona kushandiswa zvakanyanya semazuva ese ekufungidzira biomarkers.
Kufanana necfDNA, cfRNA inoburitswa muropa kuburikidza nehurongwa hwakasiyana.Aya mamorekuru ari muropa rekutenderera anomiririra ganda regomarara rekwakabva.Kuenzaniswa nemakakisi akaonekwa nenzira dzisiri-dzinopinda, cfRNAs dzinodzorwa zvine simba, tishu-chaiyo, uye dzakawanda munzvimbo yekunze.Kukosha uye kuongororwa kukosha kwe71 miRNAs (miRNAs) muHCC zvakataurwa mune zvakawanda zvidzidzo.miRNAs ndeye endogenous isiri-coding RNAs (ncRNAs) inodzora akasiyana mamolecular biological zviitiko nekudzivisa kududzirwa kwechinangwa chenhume maRNAs (mRNAs).miRNAs iri mumitumbi yeapoptotic yakavharidzirwa mune exosomes, asi inogonawo kusunga zvakasimba kune serum mapuroteni uye lipids muropa reperipheral uye inogona kushandiswa kuongorora HCC.microRNAs inobatanidzwa mukuvandudzwa kwechiropa, lipid metabolism, apoptosis, kuzvimba, uye kukura kweHCC.72 Oncogenic miRNAs yakadai semiR-21, miR-155 uye miR-221 inozivikanwa muHCC.Kunyanya, miR-21 inoita basa rakakosha mu collagen synthesis mune extracellular matrix uye fibrosis uye inosimudzira hepatocarcinogenesis ne activating hematopoietic stem masero.72,73 Tumor suppressor miRNAs muHCC inosanganisira miRNA-122, miRNA-29, mhuri yeLet-7, uye miRNA-15 mhuri.Mhuri yeLet-7 ine akawanda bundu suppressor miRNAs anonangana nemhuri yeRAS.Mhuri ye miR-15 inosanganisira miR-15a, miR-15b, miR-16, miR-195, uye miR-497, ine mitsetse inopindirana yemamwe mRNAs.Pamusoro pezvo, maRNA akareba asina kukodha (lncRNAs) uye denderedzwa RNAs (cirRNAs) akakoshawo pakuongorora kwekutanga kweHCC.lncRNAs inomiririra kirasi yakakura kwazvo yencRNAs, kusanganisira mRNA-senge ncRNAs, uye inobatanidzwa muhutachiona hwezvirwere zvakawanda zvevanhu.LncRNAs inotora basa rekutonga mune chiropa microenvironment uye chisingaperi chirwere chechiropa.74 CircRNAs zvakare kirasi yencRNAs ine akawanda mabasa mukutonga kwemajini ekutaura.Munguva pfupi yapfuura, circRNAs zvakaonekwa sematurusi ekuongorora eHCC.
Kutenderera kwemahara RNA kune kugadzikana kunoshamisa, kusanganisira kuramba tembiricha, pH, uye RNase, izvo zvinoita kuti kuparadzaniswa kwefnRNA kubva kuropa repamhepo kusanetesa uchishandisa yakajairwa RNA nzira dzekuchenesa.Nzira dzinonyanya kushandiswa dzinosanganisira NGS, microarray uye RT-qPCR.NGS inobvumira microRNAs kuyerwa mukati megenome yese.Zvisinei, nzira iyi inodhura uye kuongorora hakuna kumira.Kusiyana neizvi, RT-qPCR haidhure, inokurumidza kukudza nucleic acids, uye inopa akawanda mabhenefiti akadai sekunzwa kwepamusoro, kurongeka kwepamusoro, hupamhi hwesimba, uye inoda mashoma mashoma.Microarrays ndiyo imwe nzira inoshandiswa pakuona miRNA yakavakirwa pahwirirano uye chaiyo hybridization yezvinangwa zvemiRNAs ine anopindirana maDNA probes, 75 asi kuongororwa kweiyo microarray data inotora nguva.
Inotenderera miR-122 uye Let-7 yakanzi inogona kubatsira mukuongorora nhanho yekutanga HCC mumapoka ane njodzi huru, mamaki muvarwere vane HBV-yakabatana premalignant nodules uye yekutanga-nhanho HCC.76 Cai et al.vakawana kuti nhengo dzemhuri yeLet-7 (miR-92, miR-122, miR-125b, miR-143, miR-192, miR-16, miR-126, uye miR-199a/b) vari panjodzi yekurwara kwenguva refu. HCC mune varwere vane hepatitis.Mhuri yeLet-7 inogona kushanda semubatsiri wehupenyu hunobudirira hwekufanotaura kukura kweHCC mumapoka ane ngozi yakawanda anosangana nechirwere chisingaperi chehepatitis C. 77 miR-122 ine ruzivo rwakanyanya rwekuongorora kuongorora kwekutanga kweHCC kune varwere vane chiropa chechiropa.78 Serum inotenderera MiR-107 yakaongororwawo mumatanho ekutanga eHCC, 79 uye yakaratidza kukwanisa kwakanaka muhuwandu hwevanhu vane ngozi.Zhou et al vakashuma kuti boka remiRNAs (miR-122, miR-192, miR-21, miR-223, miR-26a, miR-27a uye miR-801) inogona kusiyanisa HCC kubva kune chisingaperi hepatitis B (CHB) uye cirrhosis. sensitivity yaive 79.1% uye 75%, uye chaiyo 76.4% uye 91.1%, zvichiteerana.80 MuHBV-inoenderana neHCC, takaona kuti miR150 mazinga akaderedzwa zvakanyanya kana achienzaniswa neaya mune vasingaperi HBV varwere vasina HCC (sensitivity 79.1%, chaiyo 76.5%).-224 yakasimudzwa muHCC ichienzaniswa nekutonga kwakanaka, uye kuongororwa kweboka kwakaratidza mazinga akakwirira kune varwere vane HCC yakabatana neHBV.hepatitis B-inobatanidza cirrhosis uye varwere veHCC vakacherechedza siRNA classifier ine zvinomwe zvakasiyana-siyana zvakaratidzwa siRNAs zvinogona kuona HCC mukutonga kwakasiyana;AUC renji pakuongororwa kwekutanga kuri nani pane vanozvipira veAFP.Vakaona kuti mamiRNA mana (miR-1972, miR-193a-5p, miR-214-3p, uye miR-365a-3p) aigona kusiyanisa varwere vane HCC nevarwere vasina HCC.MiRNA mashanu akawandisa (miR-122-5p, miR-125b-5p, miR-885-5p, miR-100-5p, uye miR-148a-3p) anoonekwa seanogona kutapukirwa neHBV muHCC, cirrhosis, uye CHB biomarkers, kunyanya. miR-34a-5p inogona kunge iri ma biomarkers echiropa cirrhosis,85 uye inogona kunge iri ma biomarkers ekutanga kuongororwa kweHCC muvanhu vane njodzi huru.Iyo yakanyanya kudzidzwa lncRNA muHCC inoshandiswa zvakanyanya mukenza yechiropa (HULC).Zvimwe zvidzidzo zvakaratidza kuti HULC inotenderera muvarwere veHCC inogona kushandiswa sechiratidzo chekuongorora nokuti lncRNA iyi yakanyatsogadziriswa muvarwere veHCC kana ichienzaniswa nevanhu vane hutano.71,86 Pakati pemamwe lnRNAs, LINC00152 inoonekwa seyakanakisa diagnostic lncRNA nekuda kweiyo AUC yakakwirira, sensitivity uye chaiyo.86 Mune imwe ongororo, peripheral blood expression of LINC00152 zvishoma nezvishoma yakawedzera kubva kune yakajairika hutano kutonga kune varwere vane CHB uye cirrhosis, uye pakupedzisira yaive yepamusoro muHCC.Zvidzidzo zvekutaura kwe circSMARCA5 muplasma yevarwere vane HCC zvakaratidza kuderera kunofambira mberi kwekutaura muHCC kubva kuhepatitis kusvika ku cirrhosis uye precancerous maronda.87 Ongororo yeROC curves yakasimbisa kugona kweiyi circRNAs mukusiyanisa varwere vane hepatitis kana chiropa chechiropa kubva kune avo vane HCC, kunyanya avo vane AFP mazinga ari pasi pe200 ng/mL.Mukuwedzera, Zhu akaongorora 13,617 cyclic RNAs mumasampuli eplasma kubva kuHBV-yakabatana neHCC varwere uye akasimbisa kuti 6 cyclic RNAs yakaratidzwa zvakasiyana muHCC uye HBV-yakabatana cirrhosis, zvichiratidza kuti cRNAs inogona kubatsira.zvicherechedzo zvekutanga kuongororwa kwemapoka ane njodzi zvakanyanya seaya ane chekuita nechirwere chechiropa, varwere vesclerosis.88
Exosomes ndiwo membrane vesicles 40-160 nm mudhayamita;akawanda intracellular vesicles anosanganiswa nesero membrane uye anoburitswa mu extracellular matrix.Iwo ane akawanda anoshanda zvikamu, zvinosanganisira lipids, mapuroteni, RNA neDNA, uye anoita basa rakakosha mukutaurirana pakati pemasero, ese HCC uye asiri-HCC masero.89,90 Exosomes inodzora kufambira mberi kweHCC nekuita hepatocyte fibroblasts uye masero estellate, masero ekudzivirira muviri, hepatocytes, uye masero eHCC.91 Mune bundu microenvironment, masero ebundu anoburitsa huwandu hukuru hwemaexosomes anotakurwa kubva kumaseru ekenza kuenda kumaseru asina kukura, ayo anozobatanidzwa mune oncogenesis, degradation, uye cellular signing.[92] Zvidzidzo zvakaratidza kuti exosomes inogona kuendesa oncogenes kune akajairwa maseru panguva ye pathological process, inogona kunge iri imwe yenzira dzekupinda nebundu uye metastasis.93 Basa remaexosomes mukufambira mberi kwegomarara rinogona kunge rine simba uye rakanangana nerudzi rwegomarara, 89 Exosomes inogona kuiswa mukati nemasero ari padyo kana ari kure kuti atonge akawanda anotarirwa majini mumasero anogamuchira anogona kunge ari kubatanidzwa mu intercellular communication ions uye cellular microenvironment interactions, vanogona. mediate cellular signing uye metabolism.94 Hunhu uye shanduko ine simba ye exosome cargo molecules inoratidzira zvakananga maitiro uye shanduko ine simba yevabereki bundu masero,95 inovawo hwaro hwekushandisa exosomes mukuongororwa uye kufungidzira kwegomarara, pamwe nekufanotaura mhinduro yemunhu kune anticancer therapy. ..96
Nzira dzechinyakare dzerabhoritari dzekuparadzanisa uye kuongorora exosomes dzakaoma, dzakawanda-nhanho, uye dzinotora nguva, kusanganisira ultracentrifugation, filtration, size exclusion chromatography, immunoaffinity purification, Western blotting, enzyme-linked immunosorbent assay (ELISA), PCR, uye kuongorora kuyerera.miniaturized masisitimu uye lab-on-a-chip mapuratifomu anoshandisa micro/nanotechnology ari kugadzirwa zvakanyanya kukurumidza, nyore mune situ kuparadzaniswa kwe exosomes.Nanoparticle tracking analysis (NTA) inzira inoshandiswa nevakawanda yekutarisa saizi uye kusungirirwa kwe exosomes, kusanganisira nzira dzakadai semagineti nanoparticles uye polyhydroxyalkanoates.Microfluidic uye electrochemical nzira dzinogona zvakare kuona nekukurumidza exosomes mugoho rakakura.
Exosomal mapuroteni akakosha mamaki ekuongororwa kweHCC.Muchidzidzo cheArbelaiz, mwero we98 RasGAP SH3 inosunga mapuroteni (G3BP) uye polymeric immunoglobulin receptor (PIGR) yakanyanya kukwidziridzwa muHCC-yakatorwa exosomes, uye iyo putative yakasanganiswa efficacy yemapuroteni maviri yaive yepamusoro kune yeAFP.Iron overload chinhu chakakosha chinobatsira mukuvandudzwa kweHCC.Tseng akataura kuti hepcidin inogona kuita basa rakakosha mukupokana neHCC.99 Exosomes yakabva kusera yevarwere veHCC yaive nenhamba yakakwira zvakanyanya yehepcidin mRNA akasiyana pane avo vane hutano, zvichiratidza kuti hepcidin inogona kunge iri novel diagnostic biomarker yeHCC.Iyo 14-3-3ζ protein mu exosomes inogadzirwa ne100 HCC inogona kuderedza T cell activation, kupararira, uye kusiyanisa uye inogona kuita kuti T cell shanduko iite masero eT anodzora, zvichiita kuti T cell ipere.101 Izvi zvinotsigirwa nezvidzidzo zvakati wandei zvinoferefeta kunzvenga bundu kubva mukutariswa kwemuviri, 102 izvo zvinogona kubatsira kuHCC tumorigenesis.
Pamusoro pekuvapo kwe ecRNA muplasma kana serum, RNA-yakapfuma exosomes inogona kushandiswa isingapindiki-chaiyo-nguva nhanho mukutanga kuongorora bundu uye kuona kushanduka kwebundu uye kupindura kurapwa.Nhamba ye exosomal miRNA-21 mu serum yeropa muboka reHCC yakanga iri 2.21 nguva yakakwirira kudarika muboka reCHB, uye muboka reHCC raiva 5.57 nguva dzakakwirira kudarika muhuwandu hwevanhu vane hutano.Muchidzidzo cheWang, exosomes yakawedzera zvakanyanya HCC kana ichienzaniswa nevarwere vane cirrhotic vane AUC kukosha kwe0.83 (95% CI 0.74-0.93) uye 0.94 (95% CI 0.88-1.00).104 Iyo data yakawanikwa yakajekesa kubatanidzwa kweakananga exosomal cargo molecules mukutonga kwe oncogenesis uye HCC kufambira mberi.105 Serum kutaura kwe miR-221, miR-103, miR-181c, miR-181a, miR-93 uye miR-26a inowirirana.uye metastasis, uye miR21 mazinga akanga akakwirira zvikuru muvarwere veHCC kupfuura mukutonga kwehutano uyewo muvarwere veCHB.102 LncRNA yakanga ine ruzivo rwakakosha rwekuongorora muHCC.Zvidzidzo zvakaratidza kuti exosomes yakabva kusera yevarwere veHCC vane mazinga akakwirira zvikuru eLINC00161, LINC000635, uye lncRNA inoshandiswa nekushandura kukura factor-β pane varwere vasina HCC, uye idzi lncRNAs dzakanyatsobatanidzwa neTNM nhanho uye bundu volume.110 Conigliaro et al.CD90 + exosomes yakawanikwa ichiratidza huwandu hwepamusoro hwelncRNAH19, iyo yakawedzera zvakanyanya vascular endothelial growth factor (VEGF) kusunungurwa uye VEGF-R1 receptor kugadzirwa, zvichiita kuti angiogenesis.93 CircRNAs imwe mhando ye exosomal ncRNAs - inoratidzwa pazasi asi yakagadzikana mazinga pamarudzi ese, circRNAs inoratidzawo chaiyo yerudzi rwesero, mhando yetishu, nhanho yekusimudzira, uye basa rekutonga.111 circRNAs idiagnostic biomarkers yekutanga uye ine zvishoma invasive cancer.112 Miedzo yekiriniki ichangoburwa yakaratidza kuti hunhu hwemiRNA yega yega mukufanotaura HCC haina kunaka.Nokudaro, kuongororwa kwakaoma kushandisa maitiro akawanda (eg, miR-122 uye miR-48a pamwe chete neAFP) inogona kuvandudza kuzivikanwa kwekutanga kweHCC uye kusiyanisa kweHCC kubva kune cirrhosis.100
Varwere vane CHB uye chiropa cirrhosis ndivo vanonyanya kuwanda boka rine njodzi yekuvandudza HCC.Kumapoka ane njodzi huru, kana mhinduro yakaramba iripo yehutachiona yave kuwanikwa, chirongwa chekutarisa chinodhura chinoenderana nenjodzi yeHCC chinofanira kugadzirwa, uye kuongororwa kwekutanga ndiyo kiyi yekuvandudza kuongororwa uye kurapwa kweHCC ine mutengo wakakura-unoshanda ratio2. ..Nzira dzekutanga dzekuvheneka gomarara dzine zvipingamupinyi zvakawanda: nzira dzekutanga dzekuongorora dzinoshanda hadzina kugadzirwa kumhando zhinji dzegomarara, uye kutevedzera kunowanzo kuderera.Kuenzaniswa nemaitiro echinyakare ekutanga ekuongorora, yemvura biopsy tekinoroji ine zvakanakira zviri pachena: kusununguka kwesampling, kuona panrac, yakanaka sampuli kuberekana, uye mhinduro inoshanda kune bundu heterogeneity.Tichifunga nezvekudhura-kushanda kwenzira dzine chekuita neiyo liquid biopsy, kushandiswa kwavo muHCC kuongorora hakuna kuongororwa nguva nenguva.Kunyangwe kufambira mberi mukuonekwa kwakaringana pachiyero chemolecular, fluid biopsy inodhura kuona HCC mune varwere vanovavarira, ichidzikamisa kushandiswa kwayo kwakapararira zvichienzaniswa nemaitiro ekufungidzira akadai seultrasound uye magineti resonance imaging.113,114 Zvisinei, chidzidzo chekare chakaratidza kuti mvura inonzi biopsy yakaratidza kubatsirwa kwakakosha maererano nehutano-yakagadziriswa makore ehupenyu (QALYs).115 Zvakanakira zvemvura biopsy mukutanga carcinoma yemudumbu uye nasopharynx zvakaratidzwa zvakare.116,117 Maonero azvino ndeekuti liquid biopsy inogona kuzadzisa serum biomarkers uye radiological screening mukuona uye kuongororwa kwemamota.117 118
Zvinoenderana nezvinyorwa zvazvino, tekinoroji yebiopsy tekinoroji yakaratidza zvakanyanya kunzwisiswa uye hunyanzvi mukutanga kuongororwa kwemapoka ane njodzi yegomarara rechiropa.Pasinei nerudzi rwemvura inonzi biopsy, inogona kusiyanisa HCC kubva kune vanhu vane njodzi huru vasina HCC, zvichiratidza kukosha kwekutanga kuongororwa sezvo mutsauko pakati pevanhu vane njodzi uye vane hutano huri pachena.ctDNA ine hafu yeupenyu hupfupi uye inogona kushandiswa kuona HCC, saka chero shanduko mubundu-inotorwa cDNA inogona kupa chaiyo-nguva chaiyo humbowo hwekufambira mberi kwebundu, kunyanya kumamota madiki.Huwandu hwepamusoro hwectDNA hunoratidza kukura nekupararira kwegomarara uye chiratidzo chekutanga chekufambira mberi uye kudzokazve.Mukuwedzera, zvichienderana nemigumisiro yectDNA, varwere vanogona kugamuchira kurapwa kwega uye kutevera.119 Yakananga methylation nzvimbo inogona kunge iri nani mucherechedzo kupfuura AFP yekutanga kuzivikanwa kweHCC uye cirrhotic nodule.Muzviitiko zvinogadziriswa zveHCC, mazinga akakwirira ecDNA anoratidza microvascular invasion uye postoperative recurrence uye metastasis.Kuchinja kwenhamba yekopi kwakabatana nekupona kwevarwere vane HCC.Zvinogona kufungidzirwa kuti cDNA kuongorora inogona kubatanidzwa mukurapa kwese kweHCC, uye cDNA inogona kushanda sechiratidzo chinoshanda chekurapa modulation.Makaka anobva pane chaiwo genetic mutations mu ctDNA akatorwa nekiriniki nhungamiro yekufanotaura kushanda uye kutarisa kuramba zvinodhaka.ctDNA yekuongorora inogona kunge iri yakanyanya kubatsira mvura biopsy chishandiso chekutanga kuongorora.MaCTC anoitawo basa rakakosha mukutariswa kwekutanga kwemapoka ane njodzi yeHCC.Makaka akasiyana eHCC-akabatana neCTC anonyanya kukosha mukutanga, kusimudzira, uye kudzokorora kweHCC.Se membrane vesicles, exosomes inobatanidzwa mukutaurirana kwepakati, kunyanya mumasero eHCC.Kutenderera microRNAs yakagadzikana muropa uye nekudaro inogona kubatsira zvakanyanya pakutanga kuongororwa kweHCC.Zvishoma nezvishoma, exosomal mapuroteni uye RNA-rich exosomes akawanikwa, uye kufungidzira kwavo kushanda kweHCC kwakasimbiswa.Sezvineiwo, akasiyana etiologies eHCC anogona zvakare kusanganisirwa nekuchinja kwakasiyana, saka isu tinogona kusarudza akasiyana biomarker ekutanga kuongororwa zvichienderana neakasiyana etiologies eHCC.120
Nekudaro, ikozvino fluid biopsy matekiniki anopokana maererano nekugadzikana uye haakwanise akazvimirira kuita yekutanga kuongorora kana kutarisa kweHCC, asi inogona kutsigira kuongororwa kwemunhu uye kuongororwa.121 Semhando yebiopsy yemvura, kucherechedzwa uye kufungidzira kwectDNA, CTC, cfRNA uye exosome-yakabatana AFP kana PIVKA-II zvine maapplication anovimbisa mukutanga kuongororwa uye kufungidzira kweHCC.Nekudaro, iyo chaiyo nzira yekuburitsa ctDNA muropa inoramba ichijekeswa.Kuburitsa zvakakosha biological zvimiro zvectDNA zvinogona kufambisa kushandiswa kwayo sechiratidzo.Huwandu hudiki hwectDNA mukutenderera uye dzakasimba sampuli yekubata zvinodiwa matambudziko ekuitwa kwekiriniki yekuonekwa kwecDNA muHCC.Mukuwedzera, genetic mutations haina chaiwo maficha anobvumira kunyatsozivikanwa kwecarcinogens.Sezvo akawanda genetic uye somatic akasiyana aripowo mune akajairwa matishu, genetic shanduko yakaonekwa neiyo fluid biopsy inogona kunge isingashande mukutanga kuongororwa kweHCC.122 Izvo zvinogumira zvinonyatsotsanangurwa zvinonangwa zvemajini zvinobatsira uye biomarker inobatsira kusiyanisa cDNA kubva kune isiri-bundu DNA ndiyo nyaya dzakanyanya kukosha mukushandiswa kwecDNA.kushaikwa kwekubatsira kweanocherekedza uye chaiwo mamaki ekuonekwa kweCTCs.Maseru anoshanda chete ane metastatic kugona akawanikwa, uye musanganiswa wakakwana weCSC wakafumisa mamaki aive asina kujeka.Kusarudzika kweCTCs kwetsika uye kuongororwa kwemaprofiles avo ekuchinja zvakare ibasa rakaoma.Nekuda kwematambudziko ekuzivikanwa, kuparadzaniswa uye kucheneswa kweiyo exosomes, iyo chaiyo molecular mechanism haisati yanyatsojeka, uye zvidzidzo zvekare pamusoro pemashini exosomes neHCC hazvina kudzika, uye nzira iyo miRNAs, lncRNAs, uye mapuroteni anorongwa kuita exosomes. , uye hazvina kujeka kana exosome uptake imhando chaiyo maitiro.Iko kushandiswa kwe exosomes yekuongororwa uye kurapwa kweHCC kuchiri padanho rekutanga.Kushaikwa kwekumisikidzwa kweiyo liquid biopsy maitiro, senge rudzi rwemachubhu anoshandiswa kuunganidza ropa, huwandu hweropa, sampuli kuchengetwa uye kuona, kuzviparadzanisa nevamwe uye kupfumisa, zvinogona kudzivirira kushandiswa kwavo mumuitiro wekiriniki nekuda kwekusiyana kwemaitiro munzvimbo dzese dzekurapa.Kushanda kwemvura biopsy mukutanga kuongorora, kuongororwa, kuongororwa kwekuita, uye kufanotaura kweHCC kunoramba kuchiongororwa, kunyanya kumapoka ane njodzi.Liquid biopsy tekinoroji ine mukana mukuru uye inotarisirwa kushandiswa zvakanyanya mukiriniki tsika yekenza yechiropa munguva pfupi iri kutevera.
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Nguva yekutumira: Sep-23-2022