UKUBUYEKEZWA KWA-MINI
Indawo yokulwa nomdlavuza: izimpawu zomdlavuza wendawo yonke kuphela
Chengchen Qian1, Xiaolong Zou2, Wei Li1,3, Yinshan Li4, Wenqiang Yu5
1Shanghai Epiprobe Biotechnology Co., Ltd, Shanghai 200233, China;2 Umnyango Wokuhlinza Okujwayelekile, Isibhedlela Esihlanganisiwe Sokuqala sase-Harbin Medical University, e-Harbin 150001, e-China;3Shandong Epiprobe Medical Laboratory Co., Ltd, Heze 274108, China;4 Isibhedlela Sabantu saseNingxia Hui Autonomous Region, Ningxia Medical University, Yinchuan 750002, China;5Shanghai Public Health Clinical Centre & Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
ABSTRACT
Umdlavuza uyimbangela yokufa ehamba phambili emhlabeni wonke.Ukutholwa komdlavuza kusenesikhathi kunganciphisa ukufa kwazo zonke izinhlobo zomdlavuza;kodwa-ke, ama-biomarker asebenzayo okuthola kusenesikhathi ayashoda ezinhlotsheni eziningi zomdlavuza.I-DNA methylation ibilokhu iyinhloso enkulu yentshisekelo ngoba i-DNA methylation ivamise ukwenzeka ngaphambi kwezinye izinguquko zofuzo ezibonakalayo.Ngenkathi kuphenywa izici ezijwayelekile zomdlavuza kusetshenziswa umhlahlandlela wenoveli wokulandelana kwe-DNA methylation, uchungechunge lwezimpawu zomdlavuza wendawo yonke kuphela (ama-UCOM) ziqhamuke njengamakhandidethi aqinile okutholwa komdlavuza okusebenzayo nokunembe kusenesikhathi.Ngenkathi inani lomtholampilo lama-biomarker omdlavuza wamanje lincishiswa ukuzwela okuphansi kanye/noma ukucaciswa okuphansi, izici ezihlukile zama-UCOM ziqinisekisa imiphumela enengqondo yomtholampilo.Ukuqinisekiswa kwamandla omtholampilo we-UCOM emdlavuza wamaphaphu, womlomo wesibeletho, we-endometrial, kanye ne-urothelial kusekela futhi ukusetshenziswa kwama-UCOM ezinhlotsheni zomdlavuza eziningi kanye nezimo ezihlukahlukene zomtholampilo.Eqinisweni, izinhlelo zokusebenza ze-UCOM okwamanje zingaphansi kophenyo olusebenzayo nokuhlolwa okwengeziwe ekutholweni komdlavuza kusenesikhathi, ukuxilonga okuyisizayo, ukusebenza ngempumelelo kokwelashwa, nokuqapha ukuphindeka.Izindlela zamangqamuzana ama-UCOM athola ngazo umdlavuza ziyizihloko ezilandelayo ezibalulekile okufanele ziphenywe.Ukusetshenziswa kwama-UCOM ezimeni zomhlaba wangempela nakho kudinga ukuqaliswa kanye nokucwengwa.
AMAZWI angukhiye
Ukutholwa komdlavuza;ukuhlolwa komdlavuza;i-DNA methylation;i-epigenetics yomdlavuza;umdlavuza biomarkers
Kungani sidinga okusha ngokuphuthumayo ama-biomarker?
Ngemva kokulwa nomdlavuza iminyaka engaphezu kwekhulu, umdlavuza usewusongo oluyingozi kakhulu lwebhayoloji esintwini.Umdlavuza usalokhu uyinkinga yezempilo emhlabeni wonke njengoba kunamacala amasha ayizigidi eziyi-19.3 kanye nokufa okulinganiselwa ezigidini eziyi-10 ngo-20201. Ngo-2020 balinganiselwa ezigidini ezingu-4.6 abantu abasha abatholakala benesifo somdlavuza eChina, okubalelwa ku-23.7% wabantu abasha abanomdlavuza emhlabeni wonke ngokusho kwe-GLOBOCAN1.Ngaphezu kwalokho, cishe abantu abayizigidi ezi-3 babulawa umdlavuza eChina ngo-2020, okwakungama-30% okufa okuhlobene nomdlavuza emhlabeni wonke.Lezi zibalo ziveze ukuthi iChina ikleliswe kuqala ngezinga lokushona kwabantu abanomdlavuza.Ngaphezu kwalokho, izinga lokusinda komdlavuza weminyaka engu-5 lingama-40.5%, elingaphansi izikhathi ezingu-1.5 kunezinga lokusinda leminyaka engu-5 e-United States2,3.Izinga lokusinda eliphansi uma kuqhathaniswa namazinga aphezulu okufa e-China kunasemazweni anezinkomba eziphakeme zokuthuthuka kwabantu aphakamisa ukuthi uhlelo lokuvikela umdlavuza olusebenzayo nolungabizi ludingeka ngokushesha.Ukutholwa komdlavuza kusenesikhathi kungenye yezinto ezibaluleke kakhulu ohlelweni lokunakekelwa kwezempilo.Ukutholwa komdlavuza kusenesikhathi kungathuthukisa ukubikezela kanye nokuphila kusenesikhathi cishe kuzo zonke izinhlobo zomdlavuza4.Amasu okuhlola aphumelele aholele ekwehleni okukhulu kwezehlakalo kanye namazinga okufa komdlavuza womlomo wesibeletho, webele, we-colorectal, nowe-prostate.
Ukuthola umdlavuza ngokushesha, akuwona umsebenzi olula.Ukuphenya ngebhayoloji kanye nokubikezelwa komdlavuza wangaphambi kwesikhathi, ukuhlonza kanye nokuqinisekisa izimpawu ze-biomark ezitholakala kusenesikhathi, kanye nokuthuthukisa ubuchwepheshe bokutholwa kusenesikhathi obufinyelelekayo nobunembile bekulokhu kuyizithiyo ezinkulu kakhulu kule nqubo4.Ukutholwa okunembile komdlavuza kungahlukanisa izilonda ezimbi, okusiza ukugwema izinqubo ezingadingekile futhi kusize ekulawuleni izifo ezengeziwe.Amasu amanje okuthola kusenesikhathi ahlanganisa ama-biopsies asekelwe ku-endoscope, imaging yezokwelapha, i-cytology, ama-immunoassays, kanye nokuhlolwa kwe-biomarker5-7.Njengoba iyaxaka futhi iyabiza, ama-biopsies asuselwa ku-endoscope athwala umthwalo osindayo ngokwemvelo njengenqubo yezokwelapha enkulu encike kubasebenzi abaqeqeshiwe.Njenge-cytology, zombili izindlela zokuhlola zincike kochwepheshe bezokwelapha futhi zisekelwe ekwahluleleni komuntu siqu ngokusebenza okukude kakhulu nokuhle8.Ngokuphambene, ukuhlolwa kwe-immunoassay akunembile kakhulu, uma kubhekwa amazinga aphezulu angamanga.Imifanekiso yezokwelashwa, njengendlela yokuhlola, idinga imishini ebizayo kanye nochwepheshe abakhethekile.Ngakho-ke, izithombe zezokwelapha zilinganiselwe kakhulu ngenxa yokufinyeleleka okuphansi.Kuzo zonke lezi zizathu, ama-biomarker abonakala eyinketho engcono yokutholwa komdlavuza kusenesikhathi.
Ukuxhumana no-: Yinshan Li no-Wenqiang Yu
Email: liyinshan@nxrmyy.com and wenqiangyu@fudan.edu.cn
I-ID ye-ORCID: https://orcid.org/0009-0005-3340-6802 futhi
https://orcid.org/0000-0001-9920-1133
Kutholwe ngo-Agasti 22, 2023;yamukelwe ngo-Okthoba 12, 2023;
ishicilelwe ku-inthanethi ngoNovemba 28, 2023.
Itholakala ku-www.cancerbiomed.org
©2023 Cancer Biology & Medicine.I-Creative Commons
I-Attribution-NonCommerce 4.0 International License
Ama-Biomarker njengamanje ahlukaniswa njengamaprotheni, izimpawu zokuguqulwa kwe-DNA, omaka be-epigenetic, ukungahambi kahle kwe-chromosomal, omaka be-RNA abatholakala ngokuqondile kumathumba, noma izingcezu zesimila ezitholwe ngokungaqondile oketshezini lomzimba.Omaka bamaprotheni ama-biomarker asetshenziswa kakhulu ekuhlolweni nasekuxilongweni komdlavuza.Ama-protein biomarker, njengezimpawu zokuhlola i-biomarker, anqunyelwe ukuthambekela kokuthinteka yizilonda ezinobungozi, okuholela ekuxilongweni nasekuphathweni ngokweqile, njengoba kuye kwabikwa nge-α-fetoprotein ne-prostate-specific antigen (PSA)9,10.Omaka be-RNA bahlanganisa amaphethini wokuvezwa kofuzo kanye nezinye izimpawu ze-RNA ezingafaki amakhodi. Inhlanganisela yezimpawu zofuzo ze-RNA zingatholwa kusetshenziswa amasampula omchamo, ukuzwela obekukade kungagculisi (60%) kumathumba okuqala, kanye nokutholwa kwawo ukuthintwa ukuwohloka kalula kwe-RNA endaweni evamile11.Izimpawu zofuzo kanye ne-epigenetic zombili zibhekene nenkinga yokusabalala kwamathumba kanye nomkhawulo ezinhlotsheni zomdlavuza.
I-DNA methylation ibe yikhandidethi eliqinile njenge-biomarker yokutholwa kusenesikhathi kusukela yaxhunyaniswa nomdlavuza ngu-Feinberg ngo-198312. Ukuphazamiseka kwe-DNA methylation kubonakala kuzo zonke izigaba zomdlavuza, ekuqaleni kwesigaba sokuqala somdlavuza.I-Aberrant DNA hypermethylation ivame ukwenzeka eziqhingini ze-CpG kubagqugquzeli bezakhi zofuzo ukuze kulwisane nabacindezeli besimila13,14.Ucwaningo luye lwaphakamisa ukuthi i-DNA hypermethylation engavamile ihilela ukulawulwa kwezilawuli zentuthuko15.I-DNA methylation valley, evame ukuhlotshaniswa nezilawuli zentuthuko kanye nomdlavuza we-hypermethylated, ingase ishintshe imodi yokubonisa izakhi zofuzo kumodi encike kakhulu ye-DNA methylation futhi yehlise ukuxhuma ku-methylated histone H3K27me3 kanye namaprotheni e-polycomb ahlobene16,17.
Phakathi kwenani elikhulu lezimpawu ze-DNA methylation ezishicilelwe, abambalwa baye baqala ngempumelelo emakethe;noma kunjalo, izimpawu zamanje ze-DNA methylation ezithengiswayo kanye namaphaneli okuxilonga awakawavuli ngokugcwele amandla okutholwa komdlavuza kusenesikhathi ngenxa yezizathu eziningi18.Nakuba ngokuvamile ebonisa ukusebenza okwamukelekayo kusetshenziswa ulwazi lwesizindalwazi, lawa ma-biomarker ngokuvamile asebenza kahle kancane emhlabeni wangempela ngenxa yokuthi amasampula omhlaba wangempela avame ukuba yinkimbinkimbi futhi awameleli njengalawo akhethiwe kuzigcinalwazi.Ukutholwa kusenesikhathi kwe-multi-cancer methylation esekelwe esizukulwaneni esilandelayo kuboniswe ukuthi kunokuzwela nje okungama-16.8% no-40.4% esigabeni sokuqala somdlavuza wesigaba I no-II, ngokulandelana19.Ukuhlolwa kokutholwa kusenesikhathi kudinga ukuzinza okukhulu nama-biomarker anembe kakhudlwana.
Ukutholwa kophawu lomdlavuza wendawo yonke (UCOM) kusetshenziswa ukulandelana kokubeka umhlahlandlela (GPS)
Naphezu kwamashumi eminyaka ocwaningo lomdlavuza, ukuvinjelwa nokwelashwa okwanelisayo akukenzeki.Kudingeka izindlela ezintsha zokwenza abacwaningi bakwazi ukuhlola kahle umdlavuza.Kule minyaka engama-23 edlule, izimpawu zomdlavuza eziyisi-6, njengokugwema i-apoptosis, ukuhlasela kwezicubu kanye ne-metastasis, njll., zinwetshwe zaba yi-14 ngokufaka izici ezifana ne-non-mutational epigenetic reprogramming kanye ne-polymorphic microbiomes20,21.Njengoba imininingwane eyengeziwe ehilela umdlavuza yembulwa, izindlela zokubheka ezengeziwe zethulwa ocwaningweni lomdlavuza.Ucwaningo lomdlavuza kancane kancane selungena esimweni esisha ngezindlela ezimbili (okujwayelekile kanye nobuntu).Ngokuthuthuka kwe-oncolology enembile eminyakeni yamuva nje, okugxilwe kukho ocwaningweni lomdlavuza kuncike ekwelashweni okuhloswe ngakunye kanye ne-heterogeneity yomdlavuza22.Ngakho-ke, ama-biomarker omdlavuza asanda kukhonjwa agxile kakhulu ezinhlotsheni ezithile zomdlavuza, njenge-PAX6 umdlavuza we-forcervical23 kanye ne-BMP3 yomdlavuza we-colorectal24.Ukusebenza kwalezi zimpawu ze-biomarker eziqondene nezinhlobo zomdlavuza kuyehluka, kodwa kusengenzeka ukuthi abantu abasengozini bahlolelwe wonke umdlavuza ngesikhathi esisodwa ngenxa yomkhawulo wokuthola amasampula egazi kanye nezindleko eziphezulu.Kungaba kuhle uma singakhomba i-biomarker eyodwa, eqinile esebenza kuzo zonke izinhlobo zomdlavuza ngokushesha.
Ukuze kuzuzwe umgomo onjalo omuhle, ikhandidethi elingcono le-biomarker kufanele likhethwe ohlwini lwezinhlobo zama-biomarker ezingaba khona.I-DNA methylation aberrations, phakathi kwawo wonke amaphrofayili wofuzo kanye ne-epigenetic, kwaziwa ukuthi ihlobene nomdlavuza futhi ngezinye zezinto ezingavamile, uma kungenjalo, okokuqala, okuhlobene nomdlavuza okwenzeka ngokulandelana kwesikhathi.Uphenyo lwe-DNA methylation luqale kusenesikhathi, kodwa luye lwaphazanyiswa ukuntuleka kwezindlela zocwaningo.Phakathi kwezindawo ezingaba izigidi ezingu-28 ze-methylated CpG ku-genome, inombolo elawulekayo kufanele ibonwe futhi iqondaniswe ne-genome ukuze kuqondwe kangcono i-tumorigenesis.I-Whole genome bisulfite sequencing (WGBS), ethathwa njengezinga legolide lokulandelana kwe-DNA methylation, ingamboza kuphela u-50% wama-Cs kumaseli omdlavuza ngenxa yemvelo yokwelashwa kwe-bisulfite ephula izingcezu ze-DNA futhi yehlise ubunzima be-genome ngesikhathi. ukuguqulwa kwe-Cs-to-Ts25.Ezinye izindlela, ezifana nama-chips angu-450k, zimboza kuphela u-1.6% we-genome methylation.Ngokusekelwe kudatha ye-450k, iphaneli yokutholwa kwe-DNA methylation inokuzwela okungama-35.4% ezinhlotsheni eziyisi-6 zesigaba sokuqala somdlavuza26.Imikhawulo yezinhlobo zomdlavuza, ukusebenza kabi, nomsindo odalwa izindlela zokutholwa enqubweni yokuhlaziya kube yizithiyo ezinkulu kakhulu zamaphaneli okuthola umdlavuza.
Ukuze siphenye kangcono amaphethini e-epigenetic wamaseli ngesikhathi se-tumorigenesis kanye ne-metastasis, sithuthukise i-GPS eyingqayizivele yokutholwa kwe-genome-wide DNA methylation, ehlanganisa kufika ku-96% wamasayithi e-CpG ku-0.4 billion reads25.I-GPS iyindlela yokulandelana kwe-bilatral esebenzisa isiphetho esingu-3′ se-DNA fragment ye-methyl-cytosine engaguquki ngemva kokwelashwa kwe-bisulfite eqondisa ukuqondanisa kokubala kwe-DNA methylation yesiphetho se-5' ngokulandelana kokuphela ngakubili (Umfanekiso 1)25.Umucu oqondisayo we-methyl-cytosine, osebenza njengomucu wesifanekiso, usiza ekuqondaneni kwesifunda se-GC esiphezulu esibuyisela idatha yokulandelana eshiywe kakhulu ku-WGBS yendabuko.Isici esiphezulu se-GPS sihlinzeka ngenani elikhulu lolwazi lwe-DNA methylation, olusivumela ukuthi sihlole amaphrofayili e-methylation yomdlavuza ngokuxazulula okuphezulu kakhulu ezindaweni ebezingaphenywanga ngaphambilini.
I-GPS isinikeza ithuluzi elinamandla lokuphenya ukufana komdlavuza, elingenza lula ucwaningo lomdlavuza futhi lithole incazelo yendawo yonke ye-tum- genesis kanye ne-metastasis.Ngenkathi kuhlaziywa idatha ye-GPS yemigqa yamaseli omdlavuza, into eyingqayizivele yayivame ukuhlangana nayo.Kube nenani lezifunda ezibonakale zine-hypermethylated ngendlela engavamile ezinhlotsheni eziningi zamasampula omdlavuza.Lokhu kutholwa okungalindelekile kwaqinisekiswa kamuva ukuze kusebenze njengama-UCOM.Amasampula angaphezu kuka-7,000 avela ezinhlotsheni eziyi-17 zomdlavuza kusizindalwazi seCancer Genome Atlas (TCGA) ahlaziywe, phakathi kwawo sahlonza i-UCOM, HIST1H4F yokuqala, isakhi sofuzo esihlobene ne-histone esine-hypermethylated kuzo zonke izinhlobo zomdlavuza27.Kwabe sekutholwa uchungechunge lwama-UCOM futhi lwaqinisekiswa kusizindalwazi se-TCGA, isizindalwazi se-Gene Expression Omnibus (GEO), kanye namasampula omtholampilo omhlaba wangempela.Kusukela manje, i-HIST1H4F, PCDHGB7, kanye ne-SIX6 zitholwe futhi zaqinisekiswa njengama-UCOM.Ukutholakala okungalindelekile kwama-UCOM kunikeza impendulo enamandla esidingweni sokutholwa komdlavuza kusenesikhathi.Ama-UCOM ahlinzeka ngesixazululo sokuthola umaka owodwa wamakhensa amaningi.
Izici ze-UCOMs
Ngemva kokuqinisekiswa, ama-UCOM akhonjiswe ukuthi abonise izici ezine ezinkulu ezenza ama-UCOM akwazi ukudlula ukusebenza kahle kwama-biomarker amanje (Umfanekiso 2).
Ihlukile ku-malignancy
Ama-UCOM ahlukile ezilonda ezinomdlavuza noma zangaphambi komdlavuza futhi azithintwa izinguquko ezivamile ze-physiologic.Ezinye zezimpawu zamanje ezihlobene nomdlavuza ezisetshenziswe kabanzi ekubonweni kusenesikhathi kanye/noma ekuhlolweni ziholele ekuxilongeni ngokweqile.Amazinga e-PSA aphakeme, ithuluzi lokuhlola eligunyazwe ngokomtholampilo, aphinde atholakale ezimeni ezingezinhle, njenge-prostate hyperplasia kanye ne-prostatitis10.Ukuxilonga ngokweqile kanye nokwelashwa ngokweqile okuwumphumela kuholela ekwehliseni izinga lempilo ngenxa yamathumbu, umchamo, kanye nezinkinga zocansi28.Amanye ama-biomarker asekelwe kumaprotheni futhi asetshenziswa kabanzi esimweni somtholampilo, njenge-CA-125, awazange alethe izinzuzo ezibalulekile ngenkathi enza ukuxilonga ngokweqile kanye nokwelashwa ngokweqile29.Ukucaciswa okuphezulu kwama-UCOM ngezifo ezimbi kugwema lokhu kushiyeka.I-UCOM, i-PCDHGB7, ihlukanisa kahle izilonda ze-squamous intraepithelial (HSILs) zebanga eliphezulu kanye nomdlavuza womlomo wesibeletho kumasampula avamile kanye nezilonda ze-squamous intraepithelial (LSILs) zezinga eliphansi, kuyilapho iningi lezinye izimpawu ze-bio-marker zingahlukanisa kuphela umdlavuza womlomo wesibeletho kumasampuli avamile30.Nakuba i-PCDHGB7 ingawuboni umehluko omkhulu phakathi kwe-endometrium evamile ne-endometrial hyperplasia, umehluko omkhulu uyatholakala phakathi kwe-endometrium evamile ne-atypical hyperplasia, futhi umehluko omkhulu nakakhulu uyatholakala phakathi kwe-endometrium evamile kanye nomdlavuza we-endometrial (EC) ngokusekelwe ku-PCDHGB731.Ama-UCOM ahlukile ezingozini eziyingozi ezinqolobaneni zolwazi namasampula omtholampilo.Ngokombono wesiguli, ama-UCOM ahlukile anciphisa umkhawulo wokuqonda izinkomba eziyinkimbinkimbi zama-biomarker ahlukahlukene angasebenzi kahle kanye nokukhathazeka okuhambisanayo phakathi nenqubo yokuhlola.Ngokombono wodokotela, ama-UCOM ahlukile ahlukanisa izifo ezibulalayo nezilonda eziyingozi, ezisiza ekuhloleni iziguli futhi zehlise izinqubo zokwelapha ezingadingekile kanye nokwelashwa ngokweqile.Ngakho-ke, ama-UCOM ahlukile anciphisa ukuncishiswa kwesistimu yezokwelapha, akhulula ukucindezeleka kwesistimu, futhi enze kutholakale izinsiza zokwelapha ezengeziwe kulabo abadinga usizo.
Umfanekiso 1 Isikimu sokuhamba komsebenzi we-GPS sokutholwa kwe-DNA methylation25.Umugqa ompunga: ukulandelana kwe-DNA okokufaka;umugqa obomvu: I-DNA iphathwa nge-T4 DNA polymerase, esikhundleni se-cytosine nge-5'-methylcytosine ekupheleni kwe-3' yokufaka;blue C with Me: methylated cytosine;blue C: cytosine unmethylated;ophuzi T: thymine25.
Konke noma lutho
Ama-UCOM atholakala kuphela kumaseli omdlavuza futhi atholwa cishe kuwo wonke amangqamuzana omdlavuza.I-HIST1H4F yaqinisekiswa ukuthi ine-hypermethylated cishe kuzo zonke izinhlobo zesimila kodwa hhayi kumasampula ajwayelekile27.Ngokufanayo, i-PCDHGB7 ne-SIX6 nazo ziboniswe ukuthi zine-hypermethylated kuwo wonke amasampula e-tumor kodwa hhayi kumasampuli ajwayelekile30-32.Lesi sici esiyingqayizivele sithuthukisa kakhulu ukusebenza kwama-UCOM ngokuphathelene nomkhawulo wokutholwa nokuzwela.Ambalwa amaphesenti angu-2 amangqamuzana omdlavuza angahlukaniswa ngamasampula, okwenza ama-UCOM abe i-biomarker ezwela kakhulu kunezimpawu eziningi ezikhona ze-biomarker30. Njenge-biomarker esetshenziselwa ukutholwa komdlavuza wamathumbu, ukuguqulwa kwe-KRAS kwenzeka kuphela cishe ku-36% wezimo zomdlavuza we-colorectal. ukuphakamisa amandla okuxilonga ampofu33.Ukuvama okuphansi kokuguqulwa kwe-KRAS kumdlavuza we-colorectal kunciphisa i-KRAS ngokuhlanganiswa nezinye izimpawu ze-biomarker.Eqinisweni, inhlanganisela yama-biomarker ingase ibonakale ithembisa ekuqaleni, kodwa ayihlali ikhiqiza umphumela owanelisayo kuyilapho ibonisa umsindo omkhulu ekuhlaziyeni kokutholwa futhi ngokuvamile ihilela izinqubo zokuhlola eziyinkimbinkimbi.Ngokuphambene, i-PCDHGB7 namanye ama-UCOM akhona kuwo wonke umdlavuza.Ama-UCOM athola izingxenye ezinomdlavuza ezinhlotsheni ezihlukene zamasampula omdlavuza ngokunemba okukhulu ngenkathi eqeda izinqubo zokuhlaziya eziyinkimbinkimbi zokukhansela umsindo.Akunzima ukuthola umdlavuza ngesampula eningi, kodwa kuyinselele enkulu ukuthola umdlavuza ngesampula encane.Ama-UCOM ayakwazi ukubona amanani amancane omdlavuza.
Umfanekiso 2 Izimpawu zama-UCOM.
Ukutholwa komdlavuza ngaphambi kwezinguquko ze-pathological
Ama-UCOM angatholwa esigabeni sangaphambi komdlavuza ngaphambi kwezinguquko ze-pathological.Njengama-biomarker e-epigenetic, izinto ezingavamile ze-UCOM zenzeka esigabeni sangaphambili kune-phenotypic abnormalities futhi ziyabonakala kulo lonke i-tumorigenesis, ukuqhubeka, kanye ne-metastasis34,35.Ukuzwela kwe-UCOM ngokuhamba kwesikhathi kuthuthukisa ukusebenza kwe-UCOM ekutholeni umdlavuza wesigaba sokuqala kanye nezilonda zangaphambi komdlavuza.Ukutholwa komdlavuza wakuqala okusekelwe kuma-biopsies kanye ne-cytology kungaba nzima ngisho nakudokotela abanolwazi kakhulu.I-biopsy eyodwa etholwe nge-colposcopy kubikwe ukuthi ine-positive kumasampuli angu-60.6% we-HSIL+.Ama-biopsies engeziwe ayadingeka ukuze kube nezilonda eziningi ukwandisa ukuzwela36.Ngokuphambene, i-UCOM, i-PCDHGB7, inokuzwela okungama-82% kumasampuli e-HSIL+, idlula ukuzwela kwama-biopsies kanye nama-biomarker amaningi30.Umaka we-methylation, i-FAM19A4, unokuzwela okungu-69% ku-CIN2+, okufana ne-cytology, kodwa ayikwazi ukuhlukanisa i-CIN1 kumasampuli avamile37.Ama-UCOM aboniswe njengesibonakaliso esibucayi kakhulu sokutholwa kusenesikhathi.Uma kuqhathaniswa nama-pathologists asekelwe ekuhlangenwe nakho, ama-UCOM anokuzwela okuphezulu kokutholwa komdlavuza wesigaba sokuqala, okubuye kube nomthelela ekuthuthukisweni kokuqanjwa komdlavuza kanye nokusinda30.Ukwengeza, ama-UCOM anikeza inkundla yokuthola efinyeleleka ezindaweni ezingenazo odokotela abanolwazi lwezifo futhi ithuthukisa kakhulu ukusebenza kahle kokutholwa.Ngezinqubo ezifanayo zokusampula nezindlela zokubona, ukutholwa kwe-UCOM kuveza imiphumela ezinzile futhi okulula ukuyichaza evumelana kangcono nephrothokholi yokuhlola edinga abasebenzi abambalwa abangochwepheshe nezinsiza zezokwelapha.
Kulula ukubona
Izindlela zamanje zokutholwa kwe-DNA methylation ziyinkimbinkimbi futhi zidla isikhathi.Iningi lezindlela zidinga ukuguqulwa kwe-bisulfite, okubangela ukulahlekelwa kwekhwalithi yesampula futhi ngokunokwenzeka kukhiqize imiphumela engazinzile nengalungile.Ukukhiqiza kabusha okungalungile okubangelwa ukwelashwa kwe-bisulfite kungase kubangele ukudideka kodokotela neziguli futhi kuphazamise nakakhulu amasu okulandelela kanye / noma okwelapha.Ngakho-ke, siphinde salungisa indlela yokutholwa kwe-UCOM ukuze sigweme ukwelashwa okunezinkinga kwe-bisulfite kwamasampula, kuhlangatshezwane nezidingo zohlelo lomtholampilo, futhi kuthuthukise ukufinyeleleka.Sakhe indlela yenoveli sisebenzisa ama-enzyme e-methylation-sensitive restriction ahlanganiswe ne-real-time fluorescent quantitative PCR (Me-qPCR) ukuze silinganise isimo se-methylation sama-UCOM phakathi kwamahora angu-3 sisebenzisa izinqubo zokuphatha kalula (Umfanekiso 3).I-Me-qPCR ingakwazi ukwamukela izinhlobo eziningi zamasampula, njengokuqoqwa komtholampilo kwemikhuhlane yomzimba kanye namasampula omchamo aziqongele wona.Amasampula omtholampilo aqoqiwe angacutshungulwa, agcinwe, futhi aqhubeke kalula ekutholweni kusetshenziswa ukukhishwa kwe-DNA okujwayelekile nokuzenzakalelayo.I-DNA ekhishiwe ingase isetshenziswe ngokuqondile endaweni yesikhulumi se-Me-qPCR ukuze kutholakale impendulo yebhodwe elilodwa kanye nemiphumela yokulinganisa kokuphumayo.Ngemuva kokuhlaziywa kwemiphumela elula kusetshenziswa amamodeli okuxilonga afakwe futhi aqinisekiswa ezinhlotsheni ezithile zomdlavuza, ukuzimisela kokugcina kwemiphumela yokutholwa kwe-UCOM kuhunyushwa futhi kwethulwe njengenani le-semi-quantitative.Inkundla ye-Me-qPCR idlula i-bisulfite-pyrosequencing evamile ekutholweni kwe-UCOM kuyilapho ilondoloza amahora angu-3 wokuguqulwa kwe-bisulfite, ngokuvumelana ne-EZ DNA Methylation-Gold kit protocol.Inkundla yokutholwa kwe-methylation emisha yenza ukutholwa kwe-UCOM kuzinze, kunembe kakhudlwana, futhi kufinyeleleke kakhudlwana30.
Umfanekiso 3 Inqubo yokutholwa kwama-UCOM.Izinhlobo zamasampuli zihlanganisa i-BALF eyenziwe isampula yobungcweti, ibhulashi le-Pap, kanye/noma umchamo oziqoqele wona.Inqubo yokukhipha i-DNA ingafakwa kusikhiphi esizenzakalelayo, umkhiqizo wawo ongatholwa ngokuqondile yi-qPCR.
Ukusetshenziswa kwe-UCOMs
Umdlavuza wamaphaphu
Umdlavuza wamaphaphu ungowesibili umdlavuza ovame ukutholakala futhi obulala kakhulu emhlabeni wonke, ubala u-11.4% wabantu abasha kanye no-18.0% wokufa okusha1.Phakathi kwakho konke okuxilongwayo, ama-85% umdlavuza wamaphaphu ongewona omncane (NSCLC) kanti u-15% umdlavuza wamaphaphu omncane wamangqamuzana (SCLC), onezinga eliphezulu le-malignancy38.Ukuskena kwe-low-dose computed tomography (LDCT) kuyindlela enconywayo njengamanje yokuhlola umdlavuza wamaphaphu futhi kuboniswe ukuthuthukisa ukutholwa kusenesikhathi nokunciphisa ukufa6;nokho, ngenxa yokucaciswa okuphansi nokungafinyeleleki kahle, i-LDCT kusamele isebenze njengendlela yokuhlola egculisayo, njengoba kwenza ezinye izimpawu zomdlavuza ezivamile, njenge-CEA39.Izindleko namandla okuxilonga okugejiwe kanye nokungaxilongwa kahle kwesu lokuhlola i-LDCT kuphazamisa inqubekelaphambili yokuhlolwa komdlavuza wamaphaphu40.I-HIST1H4F, i-UCOM, inamandla amakhulu njenge-biomarker yokutholwa kusenesikhathi kumasampula oketshezi lwe-bronchoalveolar (BALF)27.I-HIST1H4F i-hypermethylated ku-lung adenocarcinoma kanye ne-lung squamous cell carcinoma, enemininingwane yokuhlonza engu-96.7% kanye nokuzwela okungama-87.0% (Umfanekiso 4A), kanye nokusebenza okukhethekile kwesigaba I somdlavuza27.I-HIST1H4F inokucaciswa okungu-96.5% kanye nokuzwela okungu-85.4% ku-NSCLC, kanye no-96.5% no-95.7%, ngokulandelana, ku-SCLC27.Ukwengeza, amasampula ezinye izinhlobo eziyisishiyagalombili zomdlavuza, okuhlanganisa umdlavuza we-pancreatic kanye nomdlavuza we-colorectal, aqinisekisile ukuthi i-HIST1H4F ine-hypermethylated kuzo zonke izinhlobo eziyisishiyagalombili27.
Umdlavuza womlomo wesibeletho
Umdlavuza womlomo wesibeletho ubungowesine ovame ukutholakala umdlavuza futhi uyimbangela yesine ehamba phambili yokufa komdlavuza kwabesifazane ngo-2020, ubala u-3.1% wabantu abasha kanye no-3.4% wokufa okuhlobene nomdlavuza emhlabeni jikelele1.Ukuqeda umdlavuza womlomo wesibeletho ngo-2030, njengoba kwahlongozwa yi-WHO, ukuhlonzwa komdlavuza womlomo wesibeletho kusenesikhathi kuyisidingo.Uma kutholwa kusenesikhathi, izinga lokusinda leminyaka engu-5 lifinyelela ku-92% nomdlavuza womlomo wesibeletho ohlaselayo41.Imihlahlandlela ye-American Cancer Society (ACS) iphakamisa ukuhlolwa kwe-cytology yomlomo wesibeletho, ukuhlolwa kwe-HPV okuyinhloko, noma ukuhlolwa kokuhlolwa42.I-cytology yomlomo wesibeletho iyahlasela futhi ingathola kuphela u-63.5% we-CIN2+ amacala37.
I-PCDHGB7, ngokuphambene, yenze kangcono kakhulu isebenzisa i-Pap smear nokuphuma kwesitho sangasese sowesifazane, futhi ingahlukanisa ngempumelelo i-HSIL ne-LSIL esigabeni sokuqala kakhulu.I-PCDHGB7 iyodwa inokuzwela okungu-100.0% kanye nokucaciswa okungu-88.7% kumdlavuza womlomo wesibeletho (Umfanekiso 4B), kanye nokuzwela okungama-82.1% kanye nokucaciswa okungu-88.7% kwamasampuli e-HSIL+30.I-PCDHGB7 iphinde ibe nokuzwela okungu-90.9% kanye nokucaciswa okungu-90.4% kumasampuli okuphuma kwesitho sangasese sowesifazane somdlavuza womlomo wesibeletho, okulula kakhulu ukuwaqoqa30.Uma kuhlanganiswe nokuhlolwa kwe-HPV okunobungozi obukhulu (hr) noma i-Thinprep Cytology Test (TCT), i-PCDHGB7 inokuzwela okukhuphukile okungu-95.7% nokucaciswa okungu-96.2%, okudlula kakhulu lokho kokuhlolwa kwe-hrHPV (20.3%), i-TCT (51.2%) ), kanye nokubili kuhlangene (57.8%) umdlavuza womlomo wesibeletho30.I-PCDHGB7 nayo iboniswe njenge-hypermethylated ezinhlotsheni ze-17 zomdlavuza kusukela ku-database ye-TCGA, okubonisa ukufaneleka kwayo emndenini we-UCOM30.
Umfanekiso we-4 UCOMs uqinisekisiwe ezinhlotsheni ezine zomdlavuza ezifundweni zomtholampilo ezinkulu.A. Ukusebenza kwe-HIST1H4F, i-UCOM, ekutholweni komdlavuza wamaphaphu kwamasampuli angu-508.B. Ukusebenza kwe-PCDHGB7, i-UCOM, ekutholweni komdlavuza womlomo wesibeletho wamasampuli angu-844.C. Ukusebenza kwe-PCDHGB7, i-UCOM, ekutholweni komdlavuza we-endometrial wamasampuli angu-577 e-endometrial Pap kanye ne-Tao brush.D. Ukusebenza kwe-SIX6, i-UCOM, ekutholeni umdlavuza we-urothelial wamasampuli angu-177.
EC
I-EC ingenye yezifo zomdlavuza ezitholakala kakhulu emhlabeni wonke, cishe izigidi ezi-4.2 zezifo ezintsha kanye ne-1% yokufa okuhlobene nomdlavuza minyaka yonke1.Ngokuxilonga okuyimpumelelo ngokushesha, i-EC iyelapheka futhi inezinga lokusinda leminyaka emi-5 lama-95% kumdlavuza wesigaba I.Iziguli ezinezimpawu, ezifana nokopha okungavamile kwesibeletho, zithola ukuhlolwa komtholampilo ngezikhathi ezithile futhi zenza izinqubo ezihlaselayo nezibuhlungu ze-biopsy, naphezu kokuthi kuphela u-5% -10% ekugcineni uthuthukisa i-EC43.I-Transvaginal ultra- sound, njengendlela yokuthola evamile, ayithembeki kakhulu ngenxa yokungakwazi kwayo ukuhlukanisa okungenabungozi kusukela ekushintsheni kwe-endometrial embi kanye nezinga eliphezulu lamanga-positive44.
Ukuqhathanisa okufanayo kwe-serum CA-125, i-EC biomarker esetshenziswa kabanzi, kanye ne-PCDHGB7.I-Serum CA-125 ibe nokuzwela okungu-24.8%, okuphakamisa ukuthi i-CA-125 iwuphawu olunganele lwe-EC naphezu kokucaciswa okungu-92.3%31.Ukutholwa kwe-PCDHGB7 kusetshenziswa amasampula ebhulashi le-Pap kuveze ukuzwela okungama-80.65% kanye nokucaciswa okungu-82.81% kwezigaba ze-ECatall, kuyilapho ibhulashi le-Tao libe nokuzwela okungama-61.29% kanye nokucaciswa okungu-95.31%31.Imodeli yokuxilonga ye-PCDHGB7, esekelwe ku-Me-qPCR, iveze ukuzwela okungu-98.61%, ukucaciswa okungu-60.5%, nokunemba sekukonke okungu-85.5%, kusetshenziswa amasampula e-Pap ne-Tao brush (Umfanekiso 4C)31.
Umdlavuza we-Urothelial
Umdlavuza we-urothelial, ohlanganisa isinye, i-renal pelvis, kanye nomdlavuza womchamo, ubungowesikhombisa ovame ukutholakala umdlavuza ngo-2020 emhlabeni jikelele, udale u-5.2% wabantu abasha kanye no-3.9% wokufa1.Umdlavuza we-urothelial, ongaphezu kwama-50% wawo okuwumdlavuza wesinye, bekungowesine ovame ukutholakala umdlavuza e-United States ngo-2022, ubalwa ku-11.6% wabantu abasanda kutholakala3.Cishe ama-75% omdlavuza wesinye ahlukaniswa njengomdlavuza wesinye ongahlaseli imisipha kuphela ku-mucosa noma i-submucosa45.I-cystoscopy biopsy iyindinganiso yegolide yokuhlonza umdlavuza we-urothelial esetshenziswa yi-fluorescence in situ hybridization (FISH) nokuhlolwa kwe-cytology.IZINHLANZI kanye ne-cytology azikwazi kahle ukuxilonga, futhi i-cystoscopy iyaxaka futhi inengozi ecashile yokushoda kwama-microlesions, izilonda ezingachazwa kahle, futhi ezingase zibangele ukusabalala noma ukuphindeka komdlavuza46.I-UCOM eqinisekisiwe ngaphambilini, i-PCDHGB7, nayo yaboniswa njenge-hypermethylated kumdlavuza we-urothelial, nendawo engaphansi kwejika le-0.86, okuphakamisa amandla okuxilongwa okungenzeka30.Ukuze kuqhutshekwe kuqinisekiswe ama-UCOM engeziwe futhi kwamukeleke kangcono izinhlobo eziningi zesampula, i-SIX6, inoveli i-UCOM, yahlolwa futhi yabonisa amandla amahle kakhulu okuxilonga ekutholweni kokuqala komdlavuza we-urothelial kusetshenziswa amasampula omchamo endaweni yesikhulumi se-Me-qPCR.Ukutholwa kwe-SIX6 kusetshenziswa amasampula omchamo kubonise ukuzwela kokuncintisana okungama-86.7% nokucaciswa okungu-90.8% (Umfanekiso 4D), kuyilapho kungahlanyisi futhi kulula ukukuthola32.Amandla e-SIX6 ekuqaphelweni kwe-metastasis nokuhlolwa kokuphumelela kokwelashwa okwamanje ayaphenywa.
Ikusasa nezinselele
Ama-UCOM asebenza ngokuqinile emathubeni okuxilonga ama-cancer amaningi, kodwa muningi umsebenzi osele okufanele wenziwe.Besinweba uhlu lwama-UCOM futhi besiqinisekisa ngenkuthalo ama-UCOM ezinhlotsheni eziningi zomdlavuza, okuhlanganisa nalezo okunzima ukuzibona ngokwesiko.Imiphumela yokuqinisekisa evela kusizindalwazi se-TCGA iphinde yaqinisekisa ukusetshenziswa kwama-UCOM ezinhlotsheni eziningi zomdlavuza nezinye izimo.Ophenyweni lokuqala, ama-UCOM aboniswe ukuthi anamandla okuxilonga aqinile e-cholangiocarcinomas kanye ne-pancreatic adenocarcinomas, cishe okungenakwenzeka ukuxilonga ngokushesha ngezindlela zokuhlola zamanje32,47.Amandla okuthola umdlavuza ongavamile ngama-UCOM angasetshenziswa ne-circulating tumor DNA (ctDNA) nge-platform ye-biopsy ye-liquid ethuthukisiwe48.Ucwaningo oluhilela iphaneli yokuthola umdlavuza we-pan-cancer ku-plasma DNA luveze ukuzwela okungu-57.9%49.Ngaphandle kokucaciswa okuphezulu, ukusebenza kukonke kuveza ukuthi sisekhona isikhala sokuthuthukiswa.
Izici eziyingqayizivele ze-UCOMs futhi ziye zasekela uphenyo lwamandla e-UCOM ekuhlolweni kokuphumelela kokwelashwa nokuqapha ukuphindeka.Ngokwe-Response Evaluation Criteria in Solid Tumors (RECIST), imaging yezokwelapha iyindlela enconyiwe yokuqapha ukuphindeka kanye nokuhlolwa kokuphumelela kokwelashwa, kuyilapho izimpawu zesimila zisetshenziswa zodwa ekuhlolweni50.Eqinisweni, nokho, izindlela zokucabanga zithinteka kakhulu yimvamisa nesikhathi, ngakho-ke zibeka iziguli engcupheni ephakeme kanye nezindleko51,52.I-SIX6 iqinisekisiwe ukuthi isebenze njengesibikezelo se-metastasis yomdlavuza webele32.Ukuqapha kwe-ctDNA okusekelwe ku-Liquid biopsy kunika amandla ukubhekwa kwesikhathi sangempela ezinyangeni ezimbalwa ezisele ngaphambi kokutholwa kwe-radiologic, kubambezeleka kahle futhi kuvimbele ukuqhubeka komdlavuza ohlobene nokubuyela emuva53.Imiphumela yokuqala iphakamisa ukuthi ama-UCOM abonisa izinga le-hypermethylation yomdlavuza ngesikhathi sangempela ngemva kokuhlinzwa nokwelashwa32.Ukuzwela okuphezulu okuvezwa ama-UCOM kanye nokusebenziseka ezinhlotsheni eziningi zamasampuli angaphazamisi kuvumela ama-UCOM ukuthi asebenze njenge-biomarker enembile yokuqapha ukuphindaphinda ngenkathi egcina ukuthotshelwa kwesiguli okuphezulu.
Ngesikhathi esifanayo, ukufinyeleleka komphakathi ekuhlolweni kungenye inkinga enkulu edinga umzamo owengeziwe.Nakuba ukusebenzisana kokutholwa kwe-UCOM kuye kwamukelwa ezibhedlela eziningi ngethemba lokuzuzisa iziguli eziningi, ukutholwa kwe-pro bono nokuhlolwa kuye kwenziwa ngenkuthalo emaphandleni aseChina.Ama-UCOM adinga ukufinyeleleka okuthuthukisiwe ukuze afaneleke njengethuluzi lokuhlola elinokwenzeka, ikakhulukazi ezindaweni ezingathuthukile.
Ngenkathi imiphumela yesicelo se-UCOM ekutholakaleni kusenesikhathi iyathembisa, kuningi okungaziwa mayelana ne-UCOM.Ngokuhlola okusebenzayo, ucwaningo olwengeziwe luyaqinisekiswa ngokuthi kungani ama-UCOM ekhona emhlabeni wonke kumdlavuza.Izindlela zokulawula i-epigenetic ezingaphansi kwe-UCOM zikufanele ukuphenywa okwengeziwe, okungase kuthethelele indlela entsha yokwelapha umdlavuza.Uma sibuyela ekusebenzisaneni phakathi kwe-tumor homogeneity kanye ne-heterogeneity, sinentshisekelo yokuthi kungani ama-UCOM engaba ngaphandle kweningi lama-biomarker omdlavuza axhumene ngokuqinile nezinhlobo ezithile zomdlavuza.Indima ye-DNA methylation aberrations ehlonzwe i-UCOM ku-tumorigenesis, ukuqhubeka kwesimila, kanye ne-metastasis ayikanqunywa ngesikhathi sokulahlekelwa kanye nokuthola ubunjalo beseli futhi kudinga ukuhlolwa okuphelele.Enye intshisekelo enkulu ilele kububanzi bokufakwa kophawu lwe-homogeneity lwama-UCOM anezimpawu ezihlukile kwezicubu ngethemba lokusondela ekutholweni okunembile kweminonjana yomdlavuza kanye nokuhlonzwa kwemvelaphi yezicubu zesimila ngendlela ehlehlayo.Ama-UCOM angaba ithuluzi elikahle lokuvikela umdlavuza, ukubona umdlavuza, futhi akwazi ukuvikela nokuqeda umdlavuza.
Nikeza ukwesekwa
Lo msebenzi usekelwe Uhlelo Lukazwelonke Olubalulekile Lwe-R&D yase-China (Isibonelelo No. 2022BEG01003), Isisekelo Sikazwelonke Sesayensi Yezemvelo yase-China (Umnikelo Nombolo 32270645 kanye no-32000505), Uxhaso oluvela kuKhomishana Yezempilo Yesifundazwe sase-Heilongjiang (Isibonelelo No. 2020-111) , kanye noxhaso oluvela ku-Heze Science and Technology Institute (Isibonelelo No. 2021KJPT07).
Ukungqubuzana kwesitatimende sentshisekelo
U-Wei Li unguMqondisi we-R&D we-Shanghai Epiprobe Biotechnology Co., Ltd. U-Wenqiang Yu usebenza kubhodi Lokweluleka Ngesayensi le-Epiprobe.U-W. Yu kanye ne-Epiprobe bagunyaze amalungelo obunikazi alindile ahlobene nalo msebenzi.Bonke abanye ababhali bamemezela ukuthi akukho okuthakaselayo okuqhudelanayo.
Iminikelo yombhali
Iqanjwe futhi yaklama iphrojekthi: u-Chengchen Qian no-Wenqiang Yu.
Ubhale iphepha: Chengchen Qian.
Wenze imifanekiso: Chengchen Qian.
Ubuyekeze futhi wahlela umbhalo wesandla: Xiaolong Zou, Wei Li, Yinshan Li kanye no-Wenqiang Yu.
Izikhombo
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doi: 10.20892/j.issn.2095-3941.2023.0313
Isikhathi sokuthumela: May-07-2024