Iindaba

UKUHLOLA MINI

Indawo echasene nomhlaza: umhlaza wendalo iphela ngabaphawuli

Chengchen Qian1, Xiaolong Zou2, Wei Li1,3, Yinshan Li4, Wenqiang Yu5

1Shanghai Epiprobe Biotechnology Co., Ltd, Shanghai 200233, China;I-2 iSebe le-General Surgery, iSibhedlele sokuQala esiBambiseneyo seYunivesithi yezoNyango yaseHarbin, iHarbin 150001, eChina;3Shandong Epiprobe Medical Laboratory Co., Ltd, Heze 274108, China;Isibhedlele sabantu esi-4 soMmandla we-Ningxia Hui Autonomous, iYunivesithi yezoNyango yaseNingxia, iYinchuan 750002, eChina;I-5Shanghai yeZiko lezeMpilo yoLuntu lwezeMpilo kunye neSebe lezoNyango Jikelele, iSibhedlele saseHuashan kunye neCancer Metastasis Institute kunye neLabhoratri ye-RNA Epigenetics, amaZiko eSayensi zeBiomedical, iShanghai Medical College, iYunivesithi yaseFudan, iShanghai 200032, eChina.

UMXHOLO

Umhlaza ngoyena nobangela wokusweleka kwabantu kwihlabathi liphela.Ukufunyanwa kwangoko komhlaza kunokwehlisa ukubhubha kwazo zonke iintlobo zomhlaza;nangona kunjalo, ii-biomarkers ezisebenzayo zokubona kwangoko ziyasilela kwiintlobo ezininzi zomhlaza.I-DNA methylation ibisoloko iyinjongo enkulu yomdla kuba i-DNA methylation idla ngokubakho ngaphambi kokuba kubonwe ezinye iinguqu zofuzo.Ngelixa kuphandwa ngeempawu eziqhelekileyo zomhlaza kusetyenziswa isikhokelo senoveli yokubeka ulandelelwano lwe-DNA methylation, uthotho lweempawu zomhlaza wendalo iphela (ii-UCOMs) ziye zavela njengabaviwa abomeleleyo bokubhaqwa komhlaza kwangethuba.Ngelixa ixabiso leklinikhi lee-biomarkers zomhlaza zangoku lincitshiswa bubuntununtunu obuphantsi kunye / okanye ukuchaneka okuphantsi, iimpawu ezizodwa ze-UCOM ziqinisekisa iziphumo ezinentsingiselo yeklinikhi.Ukuqinisekiswa kwamandla eklinikhi e-UCOMs kwimiphunga, umlomo wesibeleko, i-endometrial, kunye nomhlaza we-urothelial kuxhasa ngakumbi ukusetyenziswa kwe-UCOMs kwiintlobo ezininzi zomhlaza kunye neemeko ezahlukeneyo zeklinikhi.Ngapha koko, izicelo ze-UCOMs okwangoku ziphantsi kophando olusebenzayo kunye novavanyo olongezelelweyo ekubhaqweni kwangaphambili komhlaza, ukuxilongwa kokuncedisa, unyango olusebenzayo, kunye nokubeka iliso kwakhona.Iindlela ze-molekyuli apho ii-UCOM zifumanisa umhlaza zizihloko ezilandelayo ezibalulekileyo eziza kuphandwa.Ukusetyenziswa kwee-UCOM kwiimeko zangempela zehlabathi nazo zifuna ukuphunyezwa kunye nokulungiswa.

AMAGAMA ENGQONDO

Ukufunyanwa komhlaza;ukuhlolwa komhlaza;DNA methylation;i-epigenetics yomhlaza;umhlaza biomarkers

Kutheni sifuna entsha ngokungxamisekileyo biomarkers?

Emva kokulwa nomhlaza ngaphezu kwenkulungwane, umhlaza usengowona mngcipheko ubulalayo webhayoloji eluntwini.Umhlaza uhlala uyinkxalabo yezempilo yehlabathi kunye ne-19.3 yezigidi zeemeko ezintsha kwaye phantse i-10 yezigidi zokusweleka kuqikelelwa ngo-20201. Ngo-2020 kuqikelelwa ukuba i-4.6 yezigidi zezehlo zomhlaza zafunyaniswa e-China, zibalelwa kwi-23.7% yezehlo zomhlaza ezitsha kwihlabathi liphela ngokutsho kwe-GLOBOCAN1.Ngaphaya koko, malunga nezigidi ezi-3 zokusweleka okubangelwa ngumhlaza e-China ngo-2020, eyayiyi-30% yokusweleka okunxulumene nomhlaza wehlabathi1.Ezi zibalo zibonise ukuba i-China ikwinqanaba lokuqala kwizehlo kunye nezinga lokufa komhlaza.Ngaphezu koko, izinga lokusinda komhlaza we-5-iminyaka yi-40.5%, engaphantsi kwamaxesha angama-1.5 kunomlinganiselo weminyaka emi-5 e-United States2,3.Amazinga aphantsi okusinda ngokuthelekisa kunye namazinga aphezulu okufa e-China kunakumazwe anezalathisi zophuhliso lwabantu eziphakamileyo acebisa ukuba inkqubo yokuthintela umhlaza esebenzayo nenexabiso eliphantsi kunye nenkqubo yokucupha ifuneka ngokukhawuleza.Ukufunyaniswa komhlaza kwangethuba yenye yezona zinto zibalulekileyo kwinkqubo yokhathalelo lwempilo.Ukufunyaniswa kwangoko komhlaza kunokuphucula ukuxilonga kunye nokuphila kwangethuba phantse kuzo zonke iintlobo zomhlaza4.Izicwangciso zokuhlola eziyimpumelelo zikhokelele ekwehleni okukhulu kwezehlo kunye namazinga okusweleka komhlaza womlomo wesibeleko, webele, we-colorectal kunye nowe-prostate.

Ukufezekisa ukufunyaniswa kwangoko komhlaza, nangona kunjalo, akungomsebenzi olula.Ukuphanda ngebhayoloji kunye nokuxilongwa kwangaphambili komhlaza, ukuchonga kunye nokuqinisekisa iimpawu ezithembekileyo zokufunyanwa kwebhayoloji, kunye nokuphuhlisa ukufikeleleka kunye nobuchwephesha bokubona kwangethuba bekusoloko kuyeyona miqobo enkulu kwinkqubo4.Ukufunyaniswa ngokuchanekileyo komhlaza kunokwahlula i-benign kwizilonda ezinobungozi, ezinceda ukuphepha iinkqubo ezingeyomfuneko kwaye kube lula ukulawula izifo ezingaphezulu.Izicwangciso zangoku zokubona kwangaphambili zibandakanya i-endoscope-based biopsies, imaging yonyango, i-cytology, i-immunoassays, kunye ne-biomarker tests5-7.Ukuba yinto ephazamisayo kunye neendleko, i-biopsies esekwe kwi-endoscope inomthwalo onzima wendalo njengenkqubo enkulu yonyango exhomekeke kubasebenzi abaqeqeshiweyo.Njenge-cytology, zombini iindlela zokuhlola zixhomekeke kwiingcali zonyango kwaye zisekelwe kwisigwebo somntu kunye nokusebenza okude kwi-deal8.Ngokwahlukileyo koko, i-immunoassays ayichanekanga kakhulu, ngenxa yamazinga aphezulu obuxoki.Imifanekiso yezonyango, njengeqhinga lokuhlola, ifuna izixhobo ezibiza kakhulu kunye namagcisa akhethekileyo.Ke ngoko, umfanekiso wezonyango ulinganiselwe kakhulu ngenxa yokufikeleleka okuphantsi.Kuzo zonke ezi zizathu, ii-biomarkers zibonakala ziyindlela engcono yokufunyanwa komhlaza kwangoko.

Imbalelwano: Yinshan Li kunye noWenqiang Yu

Email: liyinshan@nxrmyy.com and wenqiangyu@fudan.edu.cn

I-ID ye-ORCID: https://orcid.org/0009-0005-3340-6802 kwaye

https://orcid.org/0000-0001-9920-1133

Ifunyenwe ngo-Agasti 22, 2023;yamkelwe ngo-Oktobha 12, 2023;

ipapashwe kwi-intanethi ngoNovemba 28, 2023.

Ifumaneka kwi-www.cancerbiomed.org

I-Attribution-Non Commercial 4.0 Ilayisensi yaMazwe ngaMazwe

Amanqaku e-Biomarker okwangoku ahlelwa njengeeprotheyini, iimpawu zokuguqula i-DNA, iimpawu ze-epigenetic, i-chromosomal abnormalities, iimpawu ze-RNA ezithathwe ngokuthe ngqo kumathumba, okanye amaqhekeza ethumba afunyenwe ngokungathanga ngqo kulwelo lomzimba.Iimpawu zeeprotheyini zezona zisetyenziswa ngokubanzi kwii-biomarkers ekuhlolweni komhlaza kunye nokuxilongwa.Iimpawu zeprotein biomarkers, njenge-screening biomarkers, zithintelwe ngumkhwa wokuchatshazelwa zizilonda ezinobungozi, ezikhokelela ekuxilongeni ngokugqithiseleyo kunye nonyango olugqithisiweyo, njengoko kuye kwaxelwa i-α-fetoprotein kunye ne-prostate-specific antigen (PSA)9,10.Iimpawu ze-RNA zibandakanya iipateni zokuchazwa kofuzo kunye nezinye iimpawu ze-RNA ezingakhowudiyo.Indibaniselwano yembonakalo yemfuza yeempawu ze-RNA zinokubonwa kusetyenziswa iisampulu zomchamo, ubuntununtunu bebukude ngokwanelisayo (60%) kumathumba aphambili, kunye nokufunyanwa kwawo ukuchatshazelwa kukuthotywa lula kwe-RNA kwimeko-bume yesiqhelo11.Iimpawu ze-Genetic kunye ne-epigenetic zombini zijongene nengxaki yokuxhaphaka kwamathumba kunye nokulinganiselwa kwiintlobo zomhlaza.

I-DNA methylation ibe ngumgqatswa owomeleleyo njenge-biomarker yokubhaqwa kwangethuba oko yathi yadityaniswa nomhlaza nguFeinberg ngo-198312.I-Aberrant DNA hypermethylation ngokuqhelekileyo iyenzeka kwiziqithi zeCpG kubakhuthazi bemfuza ukuchasana ne-tumor suppressors13,14.Uphononongo lukwacebise ukuba i-hypermethylation engaqhelekanga ye-DNA ibandakanyeka kulawulo lwabalawuli bophuhliso15.I-DNA methylation valley, edla ngokudityaniswa nabalawuli bophuhliso kunye ne-hypermethylated cancers, inokutshintsha imo ye-gene expression kwi-DNA ezinzile ye-methylation-dependent mode kunye nokunciphisa ukudibanisa kwi-methylated histone H3K27me3 kunye ne-polycomb proteins16,17.

Phakathi kwenani elikhulu labamakishi be-DNA methylation epapashwe, abaninzi baye baqala ngempumelelo kwiimarike;nangona kunjalo, iimpawu zangoku ze-DNA methylation ezithengiswayo kunye neephaneli zokuxilonga azikawavuleli ngokupheleleyo amandla okufunyanwa kwangoko komhlaza ngenxa yezizathu ezininzi18.Ngelixa ubukhulu becala bebonisa ukusebenza okwamkelekileyo kusetyenziswa ulwazi lwesiseko sedatha, ezi mpawu zebhayoloji zihlala zingasebenzi kakuhle kwihlabathi lokwenyani ngenxa yokuba iisampulu zelizwe lokwenyani zihlala zintsonkothile kwaye azimelanga njengezo zikhethiweyo kuluhlu lwedatha.Isizukulwana esilandelayo-esekwe kwi-multi-cancer methylation ukufunyaniswa kwangoko kuboniswe ukuba kune-16.8% kunye ne-40.4% ye-sensitivity kwinqanaba I kunye ne-II yomhlaza, ngokulandelanayo19.Uvavanyo lokubona kwangoko lufuna uzinzo olukhulu kunye neempawu zebhayoloji ezichanekileyo.

Ukufunyanwa komhlaza wendalo iphela (i-UCOM) kusetyenziswa ulandelelwano lokubeka isikhokelo (GPS)

Nangona amashumi eminyaka yophando lomhlaza, uthintelo olwanelisayo kunye nonyango aluzange lwenziwe.Iindlela ezintsha ezisetyenziswayo ziyafuneka ukwenza ukuba abaphandi bavavanye ngokucokisekileyo umhlaza.Kule minyaka ingama-23 idlulileyo, iimpawu zomhlaza ezi-6, ezifana nokuphepha i-apoptosis, ukuhlasela kwezicubu kunye ne-metastasis, njl.njl., ziye zandiswa zaya kutsho kwi-14 ngokubandakanya iimpawu ezifana ne-nonmutational epigenetic reprogramming kunye ne-polymorphic microbiomes20,21.Njengoko iinkcukacha ezithe chatha ezibandakanya umhlaza zityhilwa, iindlela ezininzi zokujongwa ziyaziswa kuphando lomhlaza.Uphando lomhlaza ngokuthe ngcembe luye lwangena kwi-neera kumacala amabini (okuqhelekileyo kunye nobuntu).Ngophuhliso lwe-onkholoji echanekileyo kwiminyaka yakutshanje, ugqaliselo kuphando lomhlaza luxhomekeke kunyango olujoliswe kumntu ngamnye kunye ne-heterogeneity yomhlaza22.Ke, ii-biomarkers zomhlaza ezichongiweyo zisandula ukuchongwa zijolise ikakhulu kwiintlobo zomhlaza ezithile, ezinje nge-PAX6 yomhlaza wesibeleko23 kunye ne-BMP3 yomhlaza we-colorectal24.Ukusebenza kwezi mpawu zebhayoloji kwiintlobo zomhlaza kuyehluka, kodwa kusenzima ukuba abantu abasesichengeni bavavanyelwe zonke iimhlaza ngaxeshanye ngenxa yokuthintelwa kokufunyanwa kwesampulu yebhayoloji kunye neendleko eziphezulu.Kuya kuba kuhle ukuba sinokuchonga i-biomarker enye, eyomeleleyo esebenzayo kuzo zonke iintlobo zomhlaza kwinqanaba elisondeleyo.

Ukufezekisa loo njongo ifanelekileyo, umviwa ongcono we-biomarker kufuneka akhethwe kuluhlu lweentlobo ze-biomarker ezinokubakho.I-DNA methylation aberrations, phakathi kwazo zonke iiprofayili zofuzo kunye ne-epigenetic, zaziwa zinxulumene nomhlaza kwaye zezinye zokuqala, ukuba azikho okokuqala, izinto ezingaqhelekanga ezinxulumene nomhlaza ukuba zenzeke ngokulandelelana kweziganeko.Uphando lwe-DNA methylation luqale kwangoko, kodwa luthintelwe kukungabikho kweendlela zophando.Phakathi kwe-28 yezigidi zeesayithi ze-methylated ze-CpG kwi-genome, inani elilawulekayo kufuneka lichongwe kwaye lihambelane ne-genome ukuqonda ngcono i-tumorigenesis.I-Whole genome bisulfite sequencing (WGBS), ethathwa njengomgangatho wegolide we-DNA methylation sequencing, inokugubungela kuphela i-50% ye-Cs kwiiseli zomhlaza ngenxa yobume bonyango lwe-bisulfite olwaphula amaqhekeza e-DNA kwaye yehlise ubunzima be-genome ngexesha. ukuguqulwa kwe-Cs-to-Ts25.Ezinye iindlela, ezifana ne-450k chips, zigubungela kuphela i-1.6% ye-genome methylation.Ngokusekwe kwidatha ye-450k, ipaneli yokufumanisa i-DNA methylation ine-35.4% yobuntununtunu kwiintlobo ze-6 zenqanaba I-cancer26.Ukulinganiselwa kweentlobo zomhlaza, ukusebenza kakubi, kunye nengxolo eveliswa ngeendlela zokufumanisa kwinkqubo yokuhlalutya ibe yimiqobo emikhulu yeepaneli zokufumanisa umhlaza we-pan-cancer.

Ukuphanda ngcono iipatheni ze-epigenetic zeeseli ngexesha le-tumorigenesis kunye ne-metastasis, siphuhlise i-GPS ekhethekileyo yokufumanisa i-genome-wide DNA methylation, equka ukuya kwi-96% yeendawo ze-CpG kwi-0.4 yezigidigidi ezifundwayo25.I-GPS yindlela yokulandelelanisa i-bilat eral usebenzisa i-3 'end of DNA fragment ye-methyl-cytosines engaguqukiyo emva kokunyangwa kwe-bisulfite ekhokela ukulungelelaniswa kwe-DNA methylation calculation of the 5' end through pair-end sequencing (Figure 1)25.I-methyl-cytosine strand ekhokelayo, esebenza njenge-template strand, inceda kwi-high-GC yokulungelelaniswa kwengingqi efumana kwakhona idatha yolandelelwano olulahliweyo kwi-WGBS yemveli.Uphawu oluphezulu lweGPS lubonelela ngesixa esikhulu solwazi lwe-DNA methylation, olusivumela ukuba sivavanye iiprofayili ze-methylation yomhlaza ngesisombululo esiphezulu kakhulu kwimimandla ebikade ingaphandwanga.

I-GPS isinika isixhobo esinamandla sokuphanda ubufanasini bomhlaza, esinokwenza lula uphando lomhlaza kwaye sifumane inkcazo jikelele nge-tum-origenesis kunye ne-metastasis.Ngelixa uhlalutya idatha ye-GPS yemigca yeeseli zomhlaza, into ekhethekileyo yayihlala idibana.Kwakukho inani lemimandla ebonakala ngathi ine-hypermethylated engaqhelekanga kwiintlobo ezininzi zeesampulu zomhlaza.Oku kufunyanisiweyo bekungalindelekanga kwaqinisekiswa emva koko ukuba kusebenze njenge-UCOMs.Iisampulu ezingaphezulu kwe-7,000 ezivela kwiintlobo ze-17 zomhlaza kwi-Cancer Genome Atlas (TCGA) i-database ihlalutyiweyo, phakathi kwayo ichonge i-UCOM yokuqala, i-HIST1H4F, i-gene ehlobene ne-histone ene-hypermethylated kuzo zonke iintlobo zomhlaza27.Uluhlu lwee-UCOM zaye zafunyanwa kwaye zaqinisekiswa kwi-database ye-TCGA, i-Gene Expression Omnibus (GEO) database, kunye neesampuli zeklinikhi zangempela.Ukuza kuthi ga ngoku, i-HIST1H4F, PCDHGB7, kunye ne-SIX6 zifunyenwe kwaye zaqinisekiswa njenge-UCOMs.Ukufunyaniswa okungalindelekanga kwe-UCOMs kunika impendulo enamandla kwimfuno yokufunyanwa kwangoko komhlaza.Ii-UCOM zibonelela ngesisombululo sokubhaqwa kophawu olulodwa lwee-cancer ezininzi.

Iimpawu zeUCOMs

Emva kokuqinisekiswa, ii-UCOMs zibonakaliswe ukuba zibonise iimpawu ezine eziphambili ezenza ukuba i-UCOM ikwazi ukudlula ukusebenza kwee-biomarkers zangoku (Umfanekiso 2).

Yodwa kwinkohlakalo

Ii-UCOM zihlukile kwizilonda ezinomhlaza okanye ezingaphambi komhlaza kwaye azichatshazelwa lutshintsho oluqhelekileyo lwe-physiologic.Ezinye zeziphawuli zangoku ezinxulumene nomhlaza eziye zasetyenziswa ngokubanzi ekubhaqweni kwangaphambili kunye/okanye ukujongwa kuye kwakhokelela kuxilongo olugqithisileyo.Amanqanaba e-PSA aphakanyisiweyo, isixhobo sokuhlola esivunyiweyo seklinikhi, aphinde abonwe kwiimeko ezinobungozi, ezifana ne-prostate hyperplasia kunye ne-prostatitis10.Uxilongo olugqithisileyo kunye nesiphumo sonyango olugqithisileyo lukhokelela kumgangatho ophantsi wobomi ngenxa yamathumbu, umchamo, kunye neengxaki zesini28.Ezinye ii-biomarkers ezisekwe kwiprotheyini kunye nezisetyenziswa ngokubanzi kwisimo seklinikhi, njenge-CA-125, azizange zivelise nzuzo zibalulekileyo ngelixa zibangela ukuxilongwa ngokugqithisileyo kunye nonyango olugqithisileyo29.Ukuchaneka okuphezulu kwe-UCOM's kwizifo ezinobungozi kuthintela ezi ntsilelo.I-UCOM, i-PCDHGB7, yohlula kakuhle izilonda ezikwinqanaba eliphezulu le-squamous intraepithelial (HSILs) kunye nomhlaza womlomo wesibeleko kwiisampulu eziqhelekileyo kunye nezilonda ezisezantsi ze-squamous intraepithelial (LSILs), ngelixa uninzi lwezinye ii-biomarkers zinokwahlula kuphela umhlaza womlomo wesibeleko kwiisampuli eziqhelekileyo30.Nangona i-PCDHGB7 ingawuboni umahluko omkhulu phakathi kwe-endometrium eqhelekileyo kunye ne-endometrial hyperplasia, umahluko obonakalayo ufunyenwe phakathi kwe-endometrium eqhelekileyo kunye ne-atypical hyperplasia, kwaye umahluko omkhulu ngakumbi ufunyenwe phakathi kwe-endometrium eqhelekileyo kunye nomhlaza we-endometrial (EC) esekwe kwi-PCDHGB731.Ii-UCOM zahlukile kwizilonda ezinobungozi kugcino-lwazi kunye neesampulu zeklinikhi.Ngokwembono yesigulana, ii-UCOM ezizodwa zinciphisa umda wokuqonda izibonakaliso ezintsonkothileyo zeempawu ezahlukeneyo zebhayoloji ezingazinzanga kunye nexhala elihambelanayo ngexesha lenkqubo yovavanyo.Ngokombono weklinikhi, ii-UCOM ezizodwa zihlukanisa izifo ezinobungozi ezivela kwizilonda ezinobungozi, ezinceda ekuhlolweni kwezigulane kunye nokunciphisa iinkqubo zonyango ezingadingekile kunye nokunyangwa ngokugqithisileyo.Ke ngoko, ii-UCOM ezizodwa zinciphisa ukuncitshiswa kwenkqubo yezonyango, zithomalalisa unxunguphalo lwenkqubo, kwaye zenze ukuba kufumaneke izixhobo zonyango ngakumbi kwabo basweleyo.

Umzobo we-1 Schematic of GPS workflow for DNA methylation discovery25.Umgca ompunga: ukulandelelana kwe-DNA yegalelo;umgca obomvu: I-DNA iphathwa nge-T4 DNA polymerase, ithatha indawo ye-cytosine kunye ne-5'-methylcytosine ekupheleni kwe-3 yegalelo;blue C kunye nam: methylated cytosine;blue C: unmethylated cytosine;yellow T: thymine25.

Konke okanye akukho nto

Ii-UCOM zikho kuphela kwiiseli zomhlaza kwaye zibonwa ngokuzinzileyo phantse kuzo zonke iiseli zomhlaza.I-HIST1H4F yaqinisekiswa ukuba i-hypermethylated phantse kuzo zonke iintlobo zethumba kodwa hayi kwiisampuli eziqhelekileyo27.Ngokufanayo, i-PCDHGB7 kunye ne-SIX6 nazo zibonakaliswe njenge-hypermethylated kuzo zonke iisampuli ze-tumor kodwa kungekhona kwiisampuli eziqhelekileyo30-32.Olu phawu lukhethekileyo luphucula kakhulu ukusebenza kwe-UCOM ngokubhekiselele kumda wokubona kunye novelwano.Zimbalwa njenge-2% yeeseli zomhlaza ezinokwahlulwa kwiisampulu, nto leyo eyenza ukuba ii-UCOM zibe yi-biomarker enovakalelo ngakumbi kuneyona nto ikhoyo ye-biomarker30. Njenge-biomarker esetyenziselwa ukufunyaniswa komhlaza we-colorectal, utshintsho lwe-KRAS lukhona kuphela malunga ne-36% yeemeko zomhlaza we-colorectal. ukucebisa ukubanakho ukuxilonga okulambathayo33.Ukuxhaphaka okuphantsi kotshintsho lwe-KRAS kumhlaza we-colorectal umda we-KRAS ngokudityaniswa nezinye iimpawu zebhayoloji.Ngapha koko, indibaniselwano yee-biomarkers zinokubonakala zithembisa ekuqaleni, kodwa ayisoloko ivelisa iziphumo ezanelisayo ngelixa ibonisa ingxolo enkulu kuhlalutyo lobhaqo kwaye ihlala ibandakanya iinkqubo zovavanyo ezintsonkothileyo.Ngokwahlukileyo, i-PCDHGB7 kunye nezinye ii-UCOM zikhona kuzo zonke ii-cancer.Ii-UCOMs zibhaqa amacandelo anomhlaza kwiindidi ezahlukeneyo zeesampulu zomhlaza ngokuchaneka okuphezulu ngelixa ziphelisa iinkqubo ezintsonkothileyo zohlalutyo lokurhoxisa ingxolo.Akunzima ukufumana umhlaza kwisampulu eninzi, kodwa kulucelomngeni olukhulu ukubona umhlaza kwisampulu encinci.Ii-UCOM ziyakwazi ukubona inani elincinci lomhlaza.

Umzobo we-2 Iimpawu ze-UCOMs.

Ukufunyanwa komhlaza ngaphambi kotshintsho lwe-pathological

Ii-UCOM ziyakwazi ukufunyanwa kwisigaba sangaphambili somhlaza ngaphambi kotshintsho lwe-pathological.Njengama-biomarkers e-epigenetic, ukungaqhelekanga kwe-UCOM kwenzeka kwisigaba sangaphambili kune-phenotypic abnormalities kwaye kubonakala kuyo yonke i-tumorigenesis, ukuqhubela phambili, kunye ne-metastasis34,35.Uvakalelo lwe-UCOM ngokuhamba kwexesha luphucula ukusebenza kwe-UCOM ekufumaneni umhlaza wenqanaba lokuqala kunye nezilonda zangaphambi komhlaza.Ukufunyaniswa komhlaza wokuqala ngokusekwe kwi-biopsies kunye ne-cytology kunokuba nzima nakwi-pathologists enamava.I-biopsy enye efunyenwe nge-colposcopy ichazwe njengelungileyo kwi-60.6% yeesampulu ze-HSIL+.Ii-biopsies ezongezelelweyo ziyafuneka kwizilonda ezininzi zokwandisa uvakalelo36.Ngokwahlukileyo, i-UCOM, i-PCDHGB7, inovakalelo lwe-82% yeesampuli ze-HSIL +, idlula uvakalelo lwe-biopsies kunye ne-biomarkers ezininzi30.I-methylation marker, i-FAM19A4, ine-sensitivity ye-69% ye-CIN2 +, efana ne-cytology, kodwa ayikwazi ukwahlula i-CIN1 kwiisampuli eziqhelekileyo37.Ii-UCOMs zibonakaliswe njengeyona nto inovelwano ngakumbi kwangethuba.Xa kuthelekiswa nee-pathologists ezisekwe kumava, ii-UCOMs zinovakalelo oluphezulu lokubona umhlaza wesigaba sokuqala, nto leyo enegalelo ekuphuculeni ukuchazwa komhlaza kunye nokusinda30.Ukongeza, ii-UCOMs zibonelela ngeqonga lokubona elifikelelekayo kwiindawo ezingenazo iingcali ze-pathologists ezinamava kwaye ziphucula kakhulu ukusebenza kakuhle.Ngokuthathwa kwesampulu efanayo kunye neenkqubo zokubona, ubhaqo lwe-UCOM luvelisa iziphumo ezizinzileyo nezilula ukuzitolika ezihambelana bhetele neprothokholi yokuhlola efuna abasebenzi abambalwa abaziingcali kunye nezibonelelo zonyango.

Kulula ukubhaqa

Iindlela zangoku zokufumanisa i-DNA methylation zinzima kwaye zidla ixesha.Uninzi lweendlela zifuna ukuguqulwa kwe-bisulfite, okubangela ilahleko kumgangatho wesampuli kwaye mhlawumbi ivelise iziphumo ezingazinzanga nezingachanekanga.Ukuveliswa kakubi okubangelwa unyango lwe-bisulfite kunokukhokelela ekudidekeni koogqirha kunye nezigulane kwaye kuphazamise ngakumbi ukulandelelana kunye / okanye izicwangciso zonyango.Ke ngoko, siye saphinda sayilungisa indlela yokufunyanwa kwe-UCOM ukunqanda unyango oluyingxaki lwe-bisulfite kwiisampulu, ukulungiselela iimfuno zesicelo sekliniki, kunye nokuphucula ukufikeleleka.Siphuhlise indlela yenoveli sisebenzisa i-methylation-sensitive restriction enzymes edityaniswe ne-real-time fluorescent quantitative PCR (Me-qPCR) ukulinganisa ubume be-methylation ye-UCOM ngaphakathi kwe-3 h usebenzisa iinkqubo zokuphatha lula (Umfanekiso 3).I-Me-qPCR inokwamkela iindidi ezininzi zeesampulu, ezinje ngoqokelelo lwezonyango lomkhuhlane womzimba kunye neesampulu zomchamo oziqokeleleyo.Iisampulu zeklinikhi eziqokelelweyo zinokucutshungulwa, zigcinwe, kwaye ziqhubele phambili ngokulula ekubhaqweni kusetyenziswa i-DNA esemgangathweni kunye ne-automated extraction.I-DNA ekhutshiweyo inokuthi isetyenziswe ngokuthe ngqo kwi-platform ye-Me-qPCR ye-reaction ye-pot kunye neziphumo ze-quantification.Emva kohlalutyo olulula lweziphumo kusetyenziswa iimodeli zokuxilonga ezifakelwe kwaye ziqinisekisiwe kwiintlobo ezithile zomhlaza, ukumiselwa kokugqibela kweziphumo zokufumanisa i-UCOM kuchazwa kwaye kuboniswe njengexabiso lesiqingatha sobungakanani.Iqonga le-Me-qPCR ligqwesa i-bisulfite-pyrosequencing yendabuko ekubhaqweni kwe-UCOM ngelixa igcina i-3 h yokuguqulwa kwe-bisulfite, ngokwe-EZ DNA Methylation-Gold kit protocol.Iqonga lokufumanisa i-methylation entsha lenza ukuba ubhaqo lwe-UCOM luzinze, luchaneke ngakumbi, kwaye lufikeleleke30.

Umzobo 3 Inkqubo yokufunyanwa kwee-UCOMs.Iindidi zesampulu ziquka i-BALF eyenziwe iisampulu yobungcali, ibrashi yePap, kunye/okanye nomchamo oziqokelele wona.Inkqubo yokukhutshwa kwe-DNA inokuthi ifakwe kwi-extractor ngokuzenzekelayo, imveliso enokuthi ibonwe ngokuthe ngqo yi-qPCR.

Ukusetyenziswa kwee-UCOMs

Umhlaza wemiphunga

Umhlaza wemiphunga ungowesibini ufunyaniswa rhoqo kwaye ungowona mhlaza ubulalayo kwihlabathi jikelele, ubalelwa kwi-11.4% yamatyala amatsha kunye ne-18.0% yokusweleka okutsha1.Kuzo zonke izifo, i-85% ngumhlaza wemiphunga we-cell (NSCLC) kunye ne-15% ngumhlaza omncinci we-cell lung (SCLC), enezinga eliphezulu le-malignancy38.Idosi ephantsi ye-computed tomography (LDCT) yokuskena yindlela esetyenziswayo ngoku yokuhlola umhlaza wemiphunga kwaye ibonakaliswe ukuphucula ukubhaqwa kwangethuba kunye nokunciphisa ukufa6;nangona kunjalo, ngenxa yokucaciswa okuphantsi kunye nokungafikeleli kakuhle, i-LDCT kusafuneka isebenze njengendlela yokuhlola eyonelisayo, njengezinye iimpawu eziqhelekileyo zomhlaza, ezifana ne-CEA39.Iindleko kunye nokubakho koxilongo oluphosiweyo kunye noxilongo olungalunganga lwesicwangciso sokuhlola i-LDCT kuthintela inkqubela phambili yokuhlolwa komhlaza wemiphunga40.I-HIST1H4F, i-UCOM, inamandla amakhulu njenge-biomarker yokufumanisa kwangaphambili kwiisampuli ze-bronchoalveolar fluid (BALF)27.I-HIST1H4F i-hypermethylated kwi-lung adenocarcinoma kunye ne-lung squamous cell carcinoma, kunye ne-squamous cell carcinoma, kunye ne-96.7% kunye nobuntununtunu be-87.0% (Figure 4A), kunye nokusebenza okungaqhelekanga kwi-cancer yesigaba I27.I-HIST1H4F ine-specicity ye-96.5% kunye novakalelo lwe-85.4% ye-NSCLC, kunye ne-96.5% kunye ne-95.7%, ngokulandelanayo, kwi-SCLC27.Ukongeza, iisampulu zezinye iintlobo ezisibhozo zomhlaza, kubandakanya i-pancreatic kunye ne-colorectal cancers, ziye zaqinisekisa ukuba i-HIST1H4F ine-hypermethylated kuzo zonke ezisibhozo iintlobo ezingama-27.

Umhlaza womlomo wesibeleko

Umhlaza womlomo wesibeleko wawungowesine unobangela wokusweleka komhlaza kwabasetyhini ngo-2020, ubalelwa kwi-3.1% yamatyala amatsha kunye ne-3.4% yokusweleka okunxulumene nomhlaza kwihlabathi liphela.Ukuphelisa umhlaza womlomo wesibeleko ngo-2030, njengoko kucetywe yi-WHO, ukufunyaniswa kwangoko komhlaza womlomo wesibeleko kuyimfuneko.Ukuba kufunyaniswe kwangethuba, izinga lokusinda leminyaka emi-5 lifikelela kuma-92% ngomhlaza womlomo wesibeleko ohlaselayo41.Izikhokelo ze-American Cancer Society (ACS) zibonisa iimvavanyo ze-cytology yomlomo wesibeleko, iimvavanyo eziphambili ze-HPV, okanye iimvavanyo zokuhlola42.I-cytology yomlomo wesibeleko i-invasive kwaye inokubona kuphela i-63.5% ye-CIN2 + iimeko37.

I-PCDHGB7, ngokuchaseneyo, yenze ngcono kakhulu isebenzisa ii-Pap smears kunye nokukhutshwa kwelungu lobufazi, kwaye inokwahlula ngokufanelekileyo i-HSIL kwi-LSIL kwinqanaba lakwangoko.I-PCDHGB7 iyodwa inovakalelo lwe-100.0% kunye ne-specicity ye-88.7% yomhlaza womlomo wesibeleko (Figure 4B), kunye ne-82.1% yobuntununtunu kunye ne-88.7% ekhethekileyo kwiisampuli ze-HSIL+30.I-PCDHGB7 nayo inobuntununtunu obungama-90.9% kunye ne-90.4% ethile kwiisampulu zokuphuma kwilungu lobufazi zomhlaza womlomo wesibeleko, ekulula kakhulu ukuziqokelela30.Xa idityaniswe novavanyo lwe-HPV olunobungozi obuphezulu (hr) okanye uvavanyo lwe-Thinprep Cytology (TCT), i-PCDHGB7 inovakalelo olwandisiweyo lwe-95.7% kunye ne-specific ye-96.2%, idlula kakhulu uvavanyo lwe-hrHPV (20.3%), i-TCT (51.2%) ), kwaye ezi zimbini zidibene (57.8%) zomhlaza womlomo wesibeleko30.I-PCDHGB7 nayo ibonakaliswe ukuba i-hypermethylated kwiintlobo ze-17 zomhlaza kwi-database ye-TCGA, ebonisa ukufaneleka kwayo kwi-UCOM family30.

Umzobo we-4 UCOM uqinisekisiwe kwiintlobo ezine zomhlaza kwizifundo ezinkulu zeklinikhi.A. Ukusebenza kwe-HIST1H4F, i-UCOM, ekufumaneni umhlaza wemiphunga kwiisampuli ze-508.B. Ukusebenza kwe-PCDHGB7, i-UCOM, ekufumaneni umhlaza womlomo wesibeleko kwiisampuli ze-844.C. Ukusebenza kwe-PCDHGB7, i-UCOM, ekubonweni komhlaza we-endometrial ye-577 ye-endometrial Pap kunye ne-Tao brush samples.D. Ukusebenza kwe-SIX6, i-UCOM, ekufumaneni umhlaza we-urothelial kwiisampuli ze-177.

I-EC yenye yezona ndlela zixhaphakileyo zomhlaza wenkqubo yokuzala yabasetyhini kwihlabathi jikelele, kuqikelelwa kwi-4.2 yezigidi zezehlo ezintsha kunye ne-1% yokusweleka okunxulumene nomhlaza ngonyaka1.Ngoxilongo oluyimpumelelo kwibakala elikhawulezileyo, i-EC iyanyangeka kwaye inezinga lokusinda leminyaka emi-5 lama-95% kwisigaba I somhlaza.Izigulane ezineempawu, ezinjengokopha okungaqhelekanga kwesibeleko, zifumana uvavanyo lweklinikhi ngamaxesha athile kwaye zingena kwiinkqubo ezihlaselayo nezibuhlungu ze-biopsy, nangona kuphela i-5% -10% ekugqibeleni iphuhlisa i-EC43.I-Transvaginal ultra-sound, njengendlela yokufumanisa eqhelekileyo, ayithembeki kakhulu ngenxa yokungakwazi ukuhlukanisa i-benign ukusuka kwiinguqu ezinobungozi ze-endometrial kunye nezinga eliphezulu lobuxoki44.

Uthelekiso olunxuseneyo lweserum CA-125, i-EC biomarker ephunyezwe ngokubanzi, kunye nePCDHGB7 yenziwa.I-Serum CA-125 yayinovakalelo lwe-24.8%, ebonisa ukuba i-CA-125 yinto engafanelekanga umakishi we-EC nangona i-specificty ye-92.3%31.Ukufunyaniswa kwe-PCDHGB7 kusetyenziswa iisampulu zebrashi ye-Pap kuvelise uvakalelo lwe-80.65% kunye ne-82.81% yezigaba ze-ECatall, ngelixa ibrashi ye-Tao inovakalelo lwe-61.29% kunye ne-95.31% ye-31.Imodeli ye-PCDHGB7 yokuxilonga, esekelwe kwi-Me-qPCR, ivelise uvakalelo lwe-98.61%, i-specific 60.5%, kunye nokuchaneka okupheleleyo kwe-85.5%, usebenzisa i-Pap kunye ne-Tao isampuli ze-brush (Figure 4C)31.

Umhlaza weUrothelial

Umhlaza we-Urothelial, oquka isinyi, i-renal pelvis, kunye nomhlaza womchamo, ibiyeyesixhenxe idla ngokufunyaniswa ngumhlaza ngo-2020 kwihlabathi liphela, ibangele i-5.2% yamatyala amatsha kunye ne-3.9% yokusweleka1.Umhlaza we-Urothelial, ngaphezulu kwe-50% yawo ingumhlaza wesinyi, yayiyeyesine eyona mhlaza ufunyaniswa rhoqo e-United States ngo-2022, ibalwa kwi-11.6% yamatyala asanda kufunyaniswa3.Malunga nama-75% omhlaza wesinyi achazwa njengomhlaza wesinyi ongeyo-zihlunu othintelwe kuphela kwi-mucosa okanye i-submucosa45.I-cystoscopy biopsy ngumgangatho wegolide wokuxilonga umhlaza we-urothelial ophunyezwe yi-fluorescence in situ hybridization (FISH) kunye novavanyo lwe-cytology.I-FISH kunye ne-cytology inokusebenza kakubi kokuxilonga, kwaye i-cystoscopy i-intrusive kwaye inomngcipheko ongaphantsi kwee-microlesions ezilahlekileyo, izilonda zokutolika ngendlela engafanelekanga, kunye nokubangela ukusasazeka okanye ukuphindaphinda komhlaza46.I-UCOM eqinisekisiweyo yangaphambili, i-PCDHGB7, nayo yaboniswa njenge-hypermethylated kumhlaza we-urothelial, kunye nommandla ophantsi kwe-curve ye-0.86, ebonisa ukukwazi ukuxilonga okunokwenzeka30.Ukuqinisekisa ngakumbi ii-UCOM ezininzi kunye nokwamkela ngcono iintlobo zesampulu ezininzi, i-SIX6, inoveli ye-UCOM, yavavanywa kwaye yabonisa amandla abalaseleyo okuxilongwa ekubhaqweni kwangaphambili komhlaza we-urothelial kusetyenziswa iisampulu zomchamo kwiqonga le-Me-qPCR.Ukufunyaniswa kwe-SIX6 kusetyenziswa iisampulu zomchamo kubonise ubuzaza obukhuphisanayo be-86.7% kunye ne-90.8% ethile (i-Figure 4D), ngelixa i-non-invasive kwaye kulula ukuyifumana32.Ukubanakho kwe-SIX6 kuhlolo lwe-metastasis kunye novavanyo olusebenzayo lonyango luphantsi kophando.

Ikamva kunye nemingeni

Ii-UCOMs zinentsebenzo eyomeleleyo kuxilongo olunokubakho lwemihlaza emininzi, kodwa mninzi umsebenzi oseleyo wokuba wenziwe.Siye sandisa uluhlu lwee-UCOM kwaye siye saqinisekisa ngokusebenzayo ii-UCOM kwiintlobo ezininzi zomhlaza, kubandakanywa nezo ngokuqhelekileyo kunzima ukuzibona.Iziphumo zokuqinisekisa ezisuka koovimba beenkcukacha ze-TCGA ziye zaqinisekisa ngakumbi ukusetyenziswa kwe-UCOMs kwiindidi ezininzi zomhlaza kunye neemeko ezininzi.Kuphando lokuqala, ii-UCOM zibonakaliswe ukuba zinamandla okuxilonga i-cholangiocarcinomas kunye ne-pancreatic adenocarcinomas, ephantse ibe yinto engenakwenzeka ukuxilonga kwinqanaba elingaphambili kunye neendlela zokuhlola zangoku32,47.Ukukwazi ukubona ii-cancer ezinqabileyo ngee-UCOMs zinokusetyenziswa kunye ne-tumor ejikelezayo ye-DNA (ctDNA) ngeqonga eliphuculweyo le-biopsy yolwelo48.Uphononongo olubandakanya iphaneli yokufumanisa umhlaza we-plasma DNA-based pan-cancer ivelise ubuntununtunu be-57.9%49.Ngaphandle kokucaciswa okuphezulu, ukusebenza ngokubanzi kubonisa ukuba kusekho indawo yokuphucula.

Iimpawu ezizodwa ze-UCOM ziye zaxhasa uphando lwe-UCOM enokubakho ekuvavanyeni ukusebenza konyango kunye nokubeka iliso kwakhona.NgokweNqobo yoVavanyo lweMpendulo kumathumba aqinileyo (RECIST), umfanekiso wonyango yindlela ecetyiswayo yokuhlola kwakhona kunye novavanyo olusebenzayo lonyango, ngelixa iziphawuli zethumba zisetyenziswa zodwa kuvavanyo50.Ngokwenyani, nangona kunjalo, iindlela zokucinga zichatshazelwa kakhulu kukuxhaphaka kunye nexesha, kwaye ke ngoko zibeka esichengeni izigulane kumngcipheko ophezulu kunye neendleko51,52.I-SIX6 iye yaqinisekiswa ukuba isebenze njenge-predictor kumhlaza wamabele we-metastasis32.Ukujongwa kwe-ctDNA esekwe kwi-biopsy kuvumela uphononongo lwexesha lokwenyani kwiinyanga ezincinci ezishiyekileyo zesifo phambi kokubhaqwa kwe-radiologic, ngokufanelekileyo ukulibazisa kunye nokuthintela ukuqhubekeka komhlaza onxulumene nokuphinda53.Iziphumo zokuqala zibonisa ukuba i-UCOMs ibonisa inqanaba le-hypermethylation yomhlaza ngexesha langempela emva kokuhlinzwa kunye nonyango32.Uvakalelo oluphezulu olubonakaliswe zii-UCOMs kunye nokusebenza kwiisampulu ezininzi ezingaphazamisiyo zivumela ii-UCOM ukuba zisebenze njenge-biomarker echanekileyo yokuphindaphinda i-biomarker ngelixa igcina ukuthotyelwa kwesigulane.

Ngelo xesha, ukufikeleleka koluntu kuvavanyo ngomnye umba omkhulu ofuna inzame eyongezelelweyo.Ngelixa intsebenziswano yokufumanisa i-UCOM yamkelwe kwizibhedlele ezininzi ngethemba lokuzuza izigulane ezininzi, ukufunyanwa kwepro bono kunye nokuhlolwa kuye kwenziwa ngokukhutheleyo kwiindawo ezisemaphandleni zaseChina.Ii-UCOM zifuna ukufikeleleka okuphuculweyo ukuze zifaneleke njengesixhobo sokuhlola esinokwenzeka, ngakumbi kwiindawo ezingaphuhliswanga kakuhle.

Ngelixa iziphumo zesicelo se-UCOM ekubhaqweni kwangaphambili zithembisa, uninzi olungaziwayo malunga ne-UCOM lukhona.Ngokuphononongwa okusebenzayo, uphando olongezelelweyo luqinisekisiwe malunga nokuba kutheni ii-UCOM zikhona kwihlabathi liphela kwi-cancer.Iindlela ezisisiseko zolawulo lwe-epigenetic eziphantsi kwe-UCOM zifanelekile ukuba ziphandwe ngakumbi, ezinokuthethelela isikhokelo esitsha sonyango lomhlaza.Ukubuyela kunxibelelwano phakathi kwe-tumor homogeneity kunye ne-heterogeneity, sinomdla wokuba kutheni ii-UCOMs zinokuba ngumqobo kuninzi lwee-biomarkers zomhlaza ezidityaniswe ngokuqinileyo kwiintlobo ezithile zomhlaza.Indima ye-UCOM echongiweyo ye-DNA methylation aberrations kwi-tumorigenesis, ukuqhubela phambili kwe-tumor, kunye ne-metastasis ayizange imiselwe kwinkqubo yokulahlekelwa kunye nokubuyisela isazisi seseli kwaye ifuna ukuhlolwa ngokucokisekileyo.Omnye umdla omkhulu ulele kumda wokudityaniswa kwe-homogeneity trait ye-UCOMs ezineempawu ezikhethekileyo zethishu ngethemba lokusondela ngokuthe ngqo ekubhaqweni kwemikhondo yomhlaza kunye nokuchongwa kwemvelaphi yezicubu zethumba ngendlela ebuyayo.Ii-UCOM zinokuba sisixhobo esifanelekileyo sokuthintela umhlaza, ukubona umhlaza, kunye nokukhusela nokuphelisa umhlaza.

Inkxaso yenkxaso

Lo msebenzi uxhaswe yiNkqubo yeSizwe yeR&D engundoqo yaseTshayina (iSibonelelo esinguNombolo 2022BEG01003), iSiseko seSizwe seSayensi yeNdalo yaseChina (iSibonelelo esinguNombolo 32270645 kunye ne-32000505), iSibonelelo esivela kwiKomishoni yezeMpilo yePhondo laseHeilongjiang (iSibonelelo esinguNombolo 2020-111) , kunye neSibonelelo esivela kwiHeze Science and Technology Institute (iSibonelelo esinguNombolo 2021KJPT07).

Ukungqubana kwengxelo yomdla

U-Wei Li nguMlawuli we-R & D we-Shanghai Epiprobe Biotechnology Co., Ltd. U-Wenqiang Yu usebenza kwiBhodi yeeNgcebiso zeNzululwazi ye-Epiprobe.W. Yu kunye ne-Epiprobe baye bavuma amalungelo awodwa omenzi wechiza anxulumene nalo msebenzi.Bonke abanye ababhali babhengeza ukuba akukho mdla ukhuphisanayo.

Iminikelo yombhali

Uyilwe kwaye wayila iprojekthi: Chengchen Qian kunye neWenqiang Yu.

Ubhale iphepha: Chengchen Qian.

Wenze imizekeliso: Chengchen Qian.

Uphonononge kwaye uhlele umbhalo wesandla: Xiaolong Zou, Wei Li, Yinshan Li kunye noWenqiang Yu.

Iimbekiselo

1. Sung H, Ferlay J, Siegel RL, LaversanneM, Soerjomataram I, Jemal A, et al.IGlobal Cancer Statistics 2020: GLOBOCAN uqikelelo lwe

Iziganeko kunye nokufa kwihlabathi jikelele kwii-36 zomhlaza kumazwe angama-185.CA Umhlaza J Clin.2021;71: 209-49.

2. Xia C, Dong X, Li H, Cao M, Sun D, He S, et al.Amanani omhlaza e-China nase-United States, ngo-2022: iiprofayili, iintsingiselo, kunye nezikhombisi.Chin MedJ (Engl).2022;135: 584-90.

3. Siegel RL, Miller KD, WagleNS, JemalA.Izibalo zomhlaza, 2023. CA Cancer J Clin.2023;73: 17-48 .

4. Crosby D, BhatiaS, Brindle KM, Coussens LM, Dive C, Emberton M, et al.Ukufunyaniswa kwangoko komhlaza.Inzululwazi.2022;375: eaay9040.

5. Ladabaum U, Dominitz JA, KahiC, Schoen RE.Izicwangciso ze

ukuhlolwa komhlaza wesisu.I-Gastroenterology.2020;158: 418-32.

6. I-Tanoue LT, iTanner NT, iGould MK, iSilvestri GA.Ukuhlolwa komhlaza wemiphunga.Ndingu-J Respir Crit Care Med.2015;191: 19-33 .

7. Bouvard V, WentzensenN, Mackie A, Berkhof J, BrothertonJ, Giorgi-Rossi P, et al.Umbono we-IARC ekuhlolweni komhlaza womlomo wesibeleko.N EnglJ Med.2021;385: 1908-18.

8. Xue P, Ng MTA, QiaoY.Imingeni ye-colposcopy yokuhlolwa komhlaza womlomo wesibeleko kwi-LMICs kunye nezisombululo ngobukrelekrele bokwenziwa.BMC Med.2020;18: 169.

9. Johnson P, Zhou Q, Dao DY, Lo YMD.Ukujikeleza i-biomarkers ekuxilongweni nasekulawuleni i-hepatocellular carcinoma.Nat Rev Gastroenterol Hepatol.2022;19: 670-81.

10. Van PoppelH, Albreht T, Basu P, HogenhoutR, CollenS, Roobol M. I-Serum PSA-isekelwe ukufumanisa kwangaphambili umhlaza we-prostate eYurophu nakwihlabathi jikelele: elidlulileyo, langoku kunye nexesha elizayo.Nat Rev Urol.2022;19:

562-72.

11. HolyoakeA, O'Sullivan P, Pollock R, Best T, Watanabe J, KajitaY,

okqhubekayo.Ukuphuhliswa kovavanyo lomchamo lwe-RNA ye-multiplex ukuze kufunyanwe kunye ne-stratification ye-transitional cell carcinoma yesinyi.I-Clin Cancer Res.2008;14: 742-9.

12. I-Feinberg AP, i-Vogelstein B. I-Hypomethylation iyahlula izakhi zofuzo zezinye ii-cancer zabantu ezivela kubalingane babo abaqhelekileyo.Indalo.1983;301: 89-92.

13. Ng JM, Yu J. Umgqugquzeli we-hypermethylation ye-tumor suppressor genes njengama-biomarkers anokubakho kumhlaza we-colorectal.IntJ Mol Sci.2015;16: 2472-96.

14. I-Esteller M. Cancer epigenomics: I-DNA methylomes kunye neemephu ze-histone-modification.Nat Rev Genet.2007;8: 286-98.

15. UNishiyama A, Nakanishi M. Ukujonga iDNA methylation landscape yomhlaza.Iimpawu zeGenet.2021;37: 1012-27.

16. Xie W, Schultz MD, ListerR, Hou Z, Rajagopal N, Ray P, et al.Uhlalutyo lwe-Epigenomic yolwahlulo lwemigca emininzi yeeseli ze-embryonic stem.Iseli.2013;153: 1134-48.

17. Li Y, Zheng H, Wang Q, Zhou C, WeiL, Liu X, et al.Uhlalutyo lwe-Genome ngokubanzi lubonisa indima yePolycomb ekukhuthazeni i-hypomethylation ye-DNA methylation valleys.IGenome Biol.2018;19:18.

18. Koch A, JoostenSC, Feng Z, de Ruijter TC, DrahtMX, MelotteV,

okqhubekayo.Uhlalutyo lwe-DNA methylation kumhlaza: indawo ihlaziywe kwakhona.Nat Rev Clin Oncol.2018;15: 459-66.

19. KleinEA, Richards D, Cohn A, TummalaM, Lapham R, Cosgrove D, et al.Ukuqinisekiswa kweklinikhi yovavanyo olujoliswe kwi-methylation-based multi-cancer yokufumanisa kwangoko kusetyenziswa iseti yokuqinisekisa ezimeleyo.Ann Oncol.2021;32: 1167-77.

20. Hanahan D, Weinberg RA.Iimpawu zomhlaza.Iseli.2000;100: 57-70.

21. UHanahan D. Iimpawu zomhlaza: imilinganiselo emitsha.Umhlaza Discover.2022;12:31-46 .

22. Schwartzberg L, Kim ES, Liu D, Schrag D. Precision oncology: ngubani, njani, yintoni, nini, kwaye nini?NdinguSoc Clin Oncol Educ Incwadi.2017: 160-9.

23. ULiu H, uMeng X, uWang J. Ixesha lokwenyani le-methylation yobungakanani

ukufunyanwa kwe-PAX1 gene ekuhlolweni komhlaza womlomo wesibeleko.Umhlaza we-IntJ Gynecol.2020;30: 1488-92.

24. Imperiale TF, RansohoffDF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, et al.Uvavanyo lwe-Multitargetstool DNA yovavanyo lomhlaza we-colorectal.N EnglJ Med.2014;370: 1287-97.

25. Li J, Li Y, Li W, Luo H, Xi Y, Dong S, et al.Ukubekwa kwesikhokelo

Ulandelelwano luchonga iipateni ze-DNA methylation ezigwenxa eziguqula isazisi seseli kunye neenethiwekhi zokucupha i-tumor-immune.IGenome

Res.2019;29: 270-80.

26. Gao Q, LinYP, Li BS, Wang GQ, Dong LQ, Shen BY, et al.Ukufumanisa umhlaza wemininzi engabonakaliyo ngokujikeleza i-cell-free DNA methylation sequencing (THUNDER): uphuhliso kunye nezifundo zokuqinisekisa ezizimeleyo.Ann Oncol.2023;34: 486-95.

27. UDong S, uLi W, uWang L, uHu J, iNgoma Y, uZhang B, et al.Iijini ezinxulumene ne-Histone zi-hypermethylated kumhlaza wemiphunga kunye ne-hypermethylated

I-HIST1H4F inokusebenzisa i-pan-cancer biomarker.Umhlaza Res.2019;79: 6101-12.

28. HeijnsdijkEA, Wever EM,AuvinenA, Hugosson J, Ciatto S, Nelen V, et al.Iziphumo zomgangatho wobomi bokuhlolwa kwe-prostate-specific antigen.N EnglJ Med.2012;367: 595-605.

29. LuzakA, Schnell-Inderst P, Bühn S, Mayer-Zitarosa A, Siebert U. Ukusebenza kweklinikhi yokuhlolwa kwe-biomarker yomhlaza weemvavanyo ezinikezelwa njengenkonzo yezempilo yokuhlawula ngokwakho: ukuphononongwa okucwangcisiweyo.Eur J Health Public.2016;26: 498-505.

30. UDong S, uLu Q, uXu P, uChen L, uDuan X, uMao Z, et al.

I-Hypermethylated PCDHGB7 njengomhlaza wendalo iphela umakisha kuphela kunye nokusetyenziswa kwawo ekuhlolweni kwangaphambili komhlaza womlomo wesibeleko.Clin Transl Med.2021;11: e457.

31. Yuan J, Mao Z, Lu Q, Xu P, Wang C, Xu X, et al.I-Hypermethylated PCDHGB7 njenge-biomarker yokufunyaniswa kwangoko komhlaza we-endometrial kwiisampuli zebrashi ye-endometrial kunye ne-scrapings yomlomo wesibeleko.Ngaphambili Mol Biosci.2022;8: 774215.

32. UDong S, uYang Z, uXu P, uZheng W, uZhang B, uFu F, nabanye.Ngokulinganayo

Ukuguqulwa okukodwa kwe-epigenetic kwi-SIX6 ene-hypermethylation yenqanaba le-precancerous kunye ne-metastasis evelayo yokulandela umkhondo.Ukuhanjiswa kweSignali ekuJoliswe kuyo.2022;7: 208.

33. UHuang L, uGuo Z, uWang F, uFu L. KRAS utshintsho: ukusuka kwi-undrugable to druggable kumhlaza.Ukuhanjiswa kweSignali ekuJoliswe kuyo.2021;6: 386.

34. Belinsky SA, Nikula KJ, PalmisanoWA, MichelsR, SaccomannoG, GabrielsonE, et al.I-Aberrant methylation ye-p16(INK4a) sisiganeko esingalindelekanga kumhlaza wemiphunga kunye ne-biomarker enokubakho yokuxilongwa kwangoko.IProc Natl Acad Sci U SA.1998;95: 11891-6.

35. Robertson KD.I-DNA methylation kunye nesifo somntu.Nat Rev Genet.2005;6: 597-610.

36. WentzensenN, Walker JL, Gold MA, Smith KM, ZunaRE,

UMateyu C, nabanye.Ii-biopsies ezininzi kunye nokufunyanwa kwe-precursors yomhlaza womlomo wesibeleko kwi-colposcopy.J Clin Oncol.2015;33: 83-9.

37. De Strooper LM, Meijer CJ, Berkhof J, Hesselink AT, Snijders

PJ, Steenbergen RD, et al.Uhlalutyo lwe-methylation ye-FAM19A4

I-gene kwi-scrapes yomlomo wesibeleko iphumelele kakhulu ekuboneni umlomo wesibeleko

i-carcinomas kunye ne-CIN2 / 3 izilonda eziphambili.Cancer Prev Res (Phila).2014;7: 1251-7.

38. Thai AA, uSolomon BJ, Sequist LV, Gainor JF, Heist RS.Umhlaza wemiphunga.I-Lancet.2021;398: 535-54.

39. Grunnet M, Sorensen JB.I-Carcinoembryonic antigen (CEA) njenge-tumor marker kumhlaza wemiphunga.Umhlaza wemiphunga.2012;76: 138-43.

40. Wood DE, KazerooniEA, Baum SL, EapenGA, EttingerDS, Hou L, et al.Ukuhlolwa koMhlaza weLung, i-3.2018, i-NCCN yeZikhokelo zokuSebenza kwezonyango kwi-Oncology.J Natl Compr Canc Netw.2018;16: 412-41 .

41. I-American Cancer Society.Iinyani zomhlaza kunye namanani.Atlanta, GA, USA: Umbutho womhlaza waseMelika;2023 [uhlaziywe 2023 Matshi 1;kucatshulwe 2023 Agasti 22].

42. FonthamETH, Wolf AMD, Church TR, EtzioniR, Flowers CR,

Herzig A, et al.Uvavanyo lomhlaza womlomo wesibeleko kubantu abasengozini ephakathi: uhlaziyo lwesikhokelo sika-2020 esivela kuMbutho woMhlaza waseMelika.CA Umhlaza J Clin.2020;70: 321-46.

43. I-Clarke MA, i-Long BJ, i-Del Mar MorilloA, i-Arbyn M, i-Bakkum-Gamez JN, i-Wentzensen N. Umbutho womngcipheko womhlaza we-endometrial kunye nokopha kwe-postmenopausal kwabasetyhini: ukuphononongwa ngokuchanekileyo kunye nohlalutyo lwe-meta.JAMA Intern Med.2018;178: 1210-22.

44. UJacobs I, uGentry-MaharajA, uBurnell M, uManchandaR, uSingh N,

Sharma A, kunye nabanye.Uvakalelo lwe-transvaginal ultrasound screening

ngenxa yomhlaza we-endometrial kubasetyhini be-postmenopausal: isifundo sokulawula imeko ngaphakathi kweqela le-UKCTOCS.ILancet Oncol.2011;12:38-48 .

45. BabjukM, Burger M, CompératEM, Gontero P, MostfidAH,

PalouJ, et al.IziKhokelo zeEuropean Association of Urology kuMhlaza weSinyi ongenazihlunu (TaT1 kunye neCarcinoma In Situ) -

2019 Uhlaziyo.I-Eur Urol.2019;76: 639-57.

46. IAragon-Ching JB.Imiceli mngeni kunye nenkqubela phambili kuxilongo, ibhayoloji, kunye nonyango lwe-urothelial upper tract kunye ne-bladder carcinomas.Urol Oncol.2017;35: 462-4.

47. Rizvi S, KhanSA, Hallemeier CL, Kelley RK, Gores GJ.

I-Cholangiocarcinoma - iingcamango eziguqukayo kunye nezicwangciso zonyango.Nat Rev Clin Oncol.2018;15: 95-111 .

48. Ye Q, Ling S, Zheng S, Xu X. I-biopsy yolwelo kwi-hepatocellular

i-carcinoma: ukujikeleza iiseli zethumba kunye ne-DNA ye-tumor ejikelezayo.Mol Cancer.2019;18:114.

49. Zhang Y, Yao Y, Xu Y, Li L, Gong Y, Zhang K, et al.Umhlaza womhlaza

ukujikeleza ithumba DNA ukubhaqwa phezu 10,000 abaguli Chinese.Nat Commun.2021;12:11.

50. Eisenhauer EA, Therasse P, BogaertsJ, Schwartz LH, Sargent D, Ford R, et al.Indlela entsha yokuvavanya impendulo kumathumba aqinileyo: isikhokelo esihlaziyiweyo se-RECIST (uguqulelo 1.1).Eur J Cancer.2009;45: 228-47.

51. LitièreS, Collette S, de Vries EG, Seymour L, BogaertsJ.I-RECIST - ukufunda kwixesha elidlulileyo ukwakha ikamva.Nat Rev Clin Oncol.

2017;14: 187-92 .

52. Seymour L, BogaertsJ, Perrone A, FordR, Schwartz LH, Mandrekar S, et al.iRECIST: izikhokelo zendlela yokuphendula yokusetyenziswa kulingo

uvavanyo lwe-immunotherapeutics.ILancet Oncol.2017;18: e143-52.

53. I-PantelK, i-Alix-Panabières C. I-Liquid biopsy kunye nesifo esincinci sentsalela - inkqubela phambili yamva nje kunye nefuthe lonyango.Nat Rev Clin Oncol.2019;16: 409-24 .

Caphula eli nqaku njenge: Qian C, Zou X, Li W, Li Y, Yu W. I-outpost echasene nomhlaza: umhlaza wendalo yonke kuphela abamakishi.Umhlaza weBiol Med.2023;20: 806-815.

doi: 10.20892/j.issn.2095-3941.2023.0313

Ixesha lokuposa: May-07-2024

Indawo echasene nomhlaza: umhlaza wendalo iphela ngabaphawuli