Nzvimbo yekupokana negomarara: kenza yepasirese chete mamaki

MINI ONGORORO

Nzvimbo yekupokana negomarara: kenza yepasirese chete mamaki

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

1Shanghai Epiprobe Biotechnology Co., Ltd, Shanghai 200233, China;2 Dhipatimendi reGeneral Surgery, Yekutanga Affiliated Hospital yeHarbin Medical University, Harbin 150001, China;3Shandong Epiprobe Medical Laboratory Co., Ltd, Heze 274108, China;4 People's Hospital yeNingxia Hui Autonomous Region, Ningxia Medical University, Yinchuan 750002, China;5Shanghai Public Health Clinical Center & Dhipatimendi reGeneral Surgery, Huashan Hospital & Cancer Metastasis Institute & Laboratory yeRNA Epigenetics, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China

ABSTRACT

Gomarara ndiro riri kukonzera ndufu munyika yose.Kukurumidza kuonekwa kwegomarara kunogona kuderedza kufa kwemarudzi ose egomarara;zvisinei, anoshanda ekutanga-anoona biomarkers ari kushomeka kune mazhinji marudzi egomarara.DNA methylation yakagara iri chinangwa chikuru chekufarira nekuti DNA methylation inowanzoitika pasati paitika mamwe maitiro anoonekwa ekuchinja.Ndichiri kuferefeta zvakajairika maficha egomarara uchishandisa chinyorwa chinotungamira chekumisikidza kutevedzana kweDNA methylation, nhevedzano yekenza yepasirese chete mamaki (UCOMs) akabuda sevamiriri vakasimba vekuita uye kwakaringana kuonekwa kwegomarara.Nepo kukosha kwekiriniki yeazvino cancer biomarkers ichidzikiswa nekuderera kwekunzwa uye / kana kushomeka kwakadzika, hunhu hwakasiyana hweUCOM hunovimbisa mhedzisiro ine kliniki.Kusimbiswa kwekiriniki inogoneka yeUCOMs mumapapu, cervical, endometrial, uye urothelial cancer inowedzera kutsigira kushandiswa kweUCOMs mumhando dzakawanda dzegomarara uye akasiyana ekiriniki mamiriro.Muchokwadi, mashandisirwo eUCOMs parizvino ari pasi pekuferefeta nekumwe ongororo mukuonekwa kwekutanga kwegomarara, kuongororwa kwekubatsira, kushanda kwekurapa, uye kuongorora kudzokorora.Maitiro emamorekuru ayo maUCOM anoona negomarara ndiwo anotevera akakosha misoro kuti aongororwe.Iko kushandiswa kweUCOMs mumamiriro ezvinhu epasirese kunodawo kuita uye kunatswa.

MASHOKO ANOKOSHA

Kuonekwa kwegomarara;kuongororwa kwegomarara;DNA methylation;cancer epigenetics;cancer biomarkers

Sei tichida zvitsva nekukurumidza biomarkers?

Mushure mekurwisa kenza kweanopfuura zana ramakore, kenza ichiri kuuraya zvakanyanya kurudzi rwevanhu.Chirwere chegomarara chinoramba chiri nyaya yezvehutano pasi rose nekuti vanhu vanosvika miriyoni gumi nepfumbamwe vabatwa nechirwere ichi uye vanosvika miriyoni gumi vakafa vanofungidzirwa kuti muna 20201. Muna 2020 vanhu vanosvika miriyoni 4.6 vakabatwa negomarara muChina, zvichitora 23.7% yekenza itsva pasi rose maererano neGLOBOCAN1.Zvakare, vangangosvika mamirioni matatu vakafa vanonzi negomarara muChina muna 2020, vaive makumi matatu muzana erufu rwepasi rose rwakakonzerwa nekenza1.Huwandu uhu hwakaratidza kuti China iri pekutanga mukuitika uye kufa kwegomarara.Uyezve, huwandu hwemakore mashanu ekupona kwegomarara ndeye 40.5%, inova yakadzikira ka1.5 pane yemakore mashanu ekupona muUnited States2,3.Hupenyu hwakadzikira uye huwandu hwevanhu vanofa muChina kupfuura munyika dzine ma indexes ekusimudzira vanhu anoratidza kuti nzira yekudzivirira gomarara uye yekutarisa inodiwa nekukurumidza uye inodhura.Kuonekwa kwegomarara kwekutanga ndechimwe chezvinhu zvakakosha muhutano hwehutano.Kuonekwa kwegomarara kwekutanga kunogona kuvandudza kufungidzira uye kurarama panguva yekutanga munenge marudzi ese egomarara4.Kubudirira kwekuongorora nzira kwakonzera kudzikira kukuru kwehuwandu uye huwandu hwekufa kwegomarara remuromo wechibereko, rezamu, colorectal, uye prostate.

Kuwana kukasika kuonekwa kwegomarara, zvisinei, harisi basa riri nyore.Kuongorora biology uye fungidziro yegomarara rekutanga, kuona uye kusimbisa akavimbika ekutanga ekuona ma biomarker, uye kugadzira hunyanzvi hwekuziva uye hunogona kuwanikwa hwekutanga hwagara huri zvipingamupinyi zvikuru mukuita4.Kunyatsoonekwa kwegomarara kunogona kusiyanisa hutsinye kubva kumaronda akashata, izvo zvinobatsira kudzivirira nzira dzisina kufanira uye kufambisa humwe hutungamiriri hwechirwere.Azvino maitiro ekutanga ekuona anosanganisira endoscope-based biopsies, yekurapa imaging, cytology, immunoassays, uye biomarker bvunzo5-7.Kuve intrusive uye kudhura, endoscope-based biopsies inotakura mutoro unorema senzira huru yekurapa ichivimba nevashandi vehunyanzvi.Senge cytology, nzira dzese dzekuongorora dzinoenderana nenyanzvi dzekurapa uye dzinobva pakutonga kwemunhu nekuita kuri kure nekwakanaka8.Kusiyana neizvi, ma immunoassays haana kurongeka zvakanyanya, achipihwa yakakwirira yenhema-yakanaka mitengo.Kufungidzira kwekurapa, senzira yekuongorora, inoda michina inodhura uye nyanzvi dzehunyanzvi.Nekudaro, kufungidzira kwekurapa kwakaganhurirwa zvakanyanya nekuda kwekushomeka kwekuwana.Nezvikonzero zvese izvi, ma biomarkers anoita senge iri nani sarudzo yekukurumidza kuona kenza.

Kunyorerana na: Yinshan Li naWenqiang Yu

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

ORCID ID: https://orcid.org/0009-0005-3340-6802 uye

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

Yakagamuchira Nyamavhuvhu 22, 2023;yakagamuchirwa Gumiguru 12, 2023;

yakaburitswa online Mbudzi 28, 2023.

Inowanikwa pa www.cancerbiomed.org

©2023 Cancer Biology & Medicine.Creative Commons

Attribution-NonCommerce 4.0 International License

Biomarkers parizvino akaiswa muchikamu semapuroteni, DNA mutation mamaki, epigenetic mamaki, chromosomal abnormalities, RNA mamaki anotorwa zvakananga kubva kumamota, kana bundu zvidimbu zvakawanikwa zvisina kunanga kubva kumvura yemuviri.Mapuroteni mamaki ndiwo anonyanyo shandiswa biomarker mukuongorora gomarara uye kuongororwa.Maprotein biomarkers, seanoongorora ma biomarker, anoganhurirwa nekatsika kekubatwa nemaronda asina kunaka, izvo zvinotungamira mukuwongorora uye kuwandisa, sezvakashumwa kune α-fetoprotein uye prostate-specific antigen (PSA)9,10.Zvinyorwa zveRNA zvinosanganisira genetic expression mapatani uye mamwe asina-coding RNA mamaki.Mubatanidzwa weiyo genetic kutaura RNA mamaki anogona kuwonekwa pachishandiswa weti samples, kunzwisiswa kwacho kwaive kure nekugutsa (60%) kumapundu ekutanga, uye kuonekwa kweiyo inogona. kukanganiswa nekudzikira kuri nyore kweRNA munharaunda yakajairwa11.Genetic uye epigenetic mamaki ese ari maviri anotarisana nedambudziko rekupararira mumamota uye kudzikisira kumhando dzegomarara.

DNA methylation yanga iri mukwikwidzi akasimba semucherechedzo wekukurumidza kuona kubva pakatanga kubatanidzwa nekenza naFeinberg muna 198312. DNA methylation aberrations inocherechedzwa mumatanho ese egomarara, kutanga padanho rekenza.Aberrant DNA hypermethylation inowanzoitika pazvitsuwa zveCpG mune zvinokurudzira majini kurwisa tumor suppressors13,14.Zvidzidzo zvakaratidzawo kuti isina kujairika DNA hypermethylation inobata mukukwidziridzwa kwedevelopment regulators15.Iyo DNA methylation valley, iyo inowanzobatanidzwa nekuvandudza regulators uye hypermethylated cancers, inogona kushandura iyo gene expression mode kune yakagadzikana DNA methylation-inotsamira modhi uye kuderedza kubatana kune methylated histone H3K27me3 uye yakabatana polycomb mapuroteni16,17.

Pakati pehuwandu hukuru hweakadhindwa eDNA methylation mamaki, akati wandei akabudirira kuita debut mumusika;zvisinei, ikozvino inotengeswa DNA methylation mamaki uye diagnostic mapaneru haasati anyatso vhura mukana wekuonekwa kwekutanga kenza nekuda kwezvikonzero zvakawanda18.Kunyange zvichinyanya kuratidza mashandiro anogamuchirika uchishandisa ruzivo rwedatabase, aya ma biomarker anowanzo kuita zvishoma zvisina kunaka munyika chaiyo nekuda kwekuti masampuli epasirese anowanzo kuoma uye kwete seanomiririra seaya anosarudzwa mumadhatabhesi.Chizvarwa chinotevera-sequencing-based multi-cancer methylation yekukurumidza kuonekwa kwakaratidza kungoita 16.8% uye 40.4% sensitivity muchikamu I uye II kenza, zvakateerana19.Kukurumidza kuona bvunzo kunoda kugadzikana kwakanyanya uye kwakaringana ma biomarker.

Universal cancer chete mamaki (UCOM) kuwanikwa uchishandisa gwara rekumisikidza sequencing (GPS)

Pasinei nemakumi emakore ekutsvagisa kenza, kudzivirira kunogutsa uye kurapwa hakuna kuwanikwa.Nzira itsva dzinodiwa kuitira kuti vatsvakurudzi vakwanise kunyatsoongorora gomarara.Kwemakore makumi maviri nematatu apfuura, zvitanhatu zvegomarara, senge kunzvenga apoptosis, kupindira kwetishu & metastasis, nezvimwewo, zvakawedzerwa kusvika gumi nemana nekubatanidza zvinhu zvakaita senge nonmutational epi-genetic reprogramming uye polymorphic microbiomes20,21.Sezvo zvimwe zvakawanda zvine chekuita negomarara zvichiburitswa, mamwe maonero anounzwa mukutsvagisa cancer.Tsvagiridzo yegomarara zvishoma nezvishoma yapinda mune imwe nzira mumativi maviri (yakajairika uye yega).Nekuvandudzwa kweiyo chaiyo oncoology mumakore achangopfuura, tarisiro yekutsvagisa cancer yakatsamira kune yakasarudzika yakanangana nekurapa uye heterogeneity yegomarara22.Saka, nguva pfupi yadarika yakaonekwa cancer biomarkers yakatarisana zvakanyanya nemhando dzegomarara, senge PAX6 yeforcervical cancer23 uye BMP3 ye colorectal cancer24.Kuita kweaya ma biomarker akanangana nemhando dzegomarara kunosiyana, asi hazvisati zvave kukwanisika kuti vanhu vari panjodzi vavhenekwe magomarara ese panguva imwe chete nekuda kwekudzikiswa kwekutora samples yebiological uye kudhura kwakanyanya.Zvingave zvakanaka kana tikakwanisa kuona imwe chete, yakasimba biomarker inoshanda kune ese marudzi egomarara panguva pfupi.

Kuti uwane chinangwa chakadaro, mumiriri ari nani webiomarker anofanirwa kusarudzwa kubva pane rondedzero yeanogona biomarker marudzi.DNA methylation aberrations, pakati pezvese genetic uye epigenetic profiles, anozivikanwa kuve ane hukama negomarara uye ndemamwe ekutanga, kana asiri ekutanga, abnormalities ane hukama nekenza kuitika maererano nenguva.Kuferefetwa kweDNA methylation kwakatanga kare, asi kwakakanganiswa nekushaikwa kwenzira dzekutsvagisa.Pakati pemamiriyoni makumi maviri nemasere anokwanisa methylated CpG nzvimbo mune genome, nhamba inogoneka inofanirwa kuwonekwa uye yakanangana neiyo genome kuti inzwisise zviri nani tumorigenesis.Whole genome bisulfite sequencing (WGBS), iyo inonzi ndiyo yegoridhe chiyero cheDNA methylation sequencing, inogona kungovhara 50% yeCs mumasero egomarara nekuda kwechimiro chekurapa kwebisulfite inopwanya zvimedu zveDNA uye kuderedza kuoma kwegenome panguva. shanduko yeCs-to-Ts25.Dzimwe nzira, dzakadai se450k chips, dzinongovhara 1.6% yegenome methylation.Kubva pane 450k data, DNA methylation yekuona pani ine 35.4% senitivity ye6 marudzi edanho I cancers26.Kuganhurirwa kwemhando dzegomarara, kusaita zvakanaka, uye ruzha rwunogadzirwa nemaitiro ekuona muchirongwa chekuongorora zvave zvipingamupinyi zvikuru zvepan-cancer yekuona mapaneru.

Kuti tiongorore zvirinani maitiro epigenetic emaseru panguva ye tumorigenesis uye metastasis, takagadzira yakasarudzika GPS yegenome-wide DNA methylation yekuona, iyo inovhara kusvika 96% yenzvimbo dzeCPG mu 0.4 bhiriyoni kuverenga25.GPS inzira yebilat- eral sequencing inoshandisa 3 ′ kuguma kweDNA chidimbu che-non-convertible methyl-cytosines mushure mekurapa kwebisulfite inotungamira kurongeka kweDNA methylation kuverenga kweiyo 5' kuguma kuburikidza neaviri-yekupedzisira sequencing (Mufananidzo 1)25.Iyo methyl-cytosine inotungamira tambo, ichiita seye template tambo, inobatsira mune yakakwirira-GC dunhu kurongeka iyo inodzoreredza iyo yakanyanya kusiiwa yekuteedzera data mune yechinyakare WGBS.Iyo yakakwirira yekuvhara yeGPS inopa huwandu hwakakura hweruzivo rweDNA methylation, iyo inotibvumira kuongorora cancer methylation profiles ine chigadziriso chepamusoro munzvimbo dzaimbove dzisina kuferefetwa.

GPS inotipa chishandiso chine simba chekuongorora homogeneity yegomarara, iyo inogona kurerutsa tsvakiridzo yegomarara uye kuwana tsananguro yepasirese yetum- genesis uye metastasis.Ndichiri kuongorora GPS data yekenza cell mitsara, chiitiko chakasiyana chaigara chichisangana.Paive nenhamba yematunhu airatidza kuve abnormal hypermethylated mumhando dzakawanda dzekenza samples.Izvi zvisingatarisirwi zvakawanikwa zvakazosimbiswa kuti zvishande seUCOMs.Zvinopfuura zviuru zvinomwe zvemasamples kubva kumhando gumi nenomwe dzegomarara muThe Cancer Genome Atlas (TCGA) dhatabhesi yakaongororwa, pakati payo takaona yekutanga UCOM, HIST1H4F, gene rine hukama nehistone iro rine hypermethylated mumarudzi ese egomarara27.Nhevedzano dzeUCOM dzakazowanikwa uye dzakasimbiswa muTCGA dhatabhesi, iyo Gene Expression Omnibus (GEO) dhatabhesi, uye chaiyo-yenyika kliniki samples.Kubva ikozvino, HIST1H4F, PCDHGB7, uye SIX6 zvakawanikwa uye zvakasimbiswa seUCOMs.Kuwanikwa kusingatarisirwe kweUCOMs kunopa mhinduro ine simba kune kudiwa kwekutanga kuoneka kwegomarara.UCOMs inopa mhinduro yekucherechedzwa kwemaki imwe chete kweakawanda cancers.

Hunhu hweUCOMs

Pakusimbiswa, maUCOM akaratidzwa kuratidza maitiro mana makuru anoita kuti maUCOM apfuure kushanda kwezvino biomarkers (Mufananidzo 2).

Yakasiyana kune yakaipa

UCOMs akasiyana nekenza kana pre-gomarara maronda uye haabatike neyakajairwa physiologic shanduko.Zvimwe zvezvino mamakisi zvine chekuita negomarara izvo zvakashandiswa zvakanyanya mukuonekwa kwekutanga uye / kana kuongororwa zvakakonzera kuwandisa.Yakakwira PSA mazinga, kiriniki yakatenderwa yekuongorora chishandiso, inowanikwawo mumamiriro ezvinhu asina kunaka, akadai seprostate hyperplasia uye prostatitis10.The overdiagnosis uye kukonzeresa kuwandisa kunoita kuti hupenyu hudzikire nekuda kwemaura, weti, uye kusangana pabonde28.Mamwe mapuroteni-akavakirwa uye anoshandiswa zvakanyanya biomarker muchirongwa chekiriniki, senge CA-125, haana kuburitsa mabhenefiti akakosha asi achiunza overdiagnosis uye kuwandisa29.Iyo yakanyanya kujeka yeUCOMs yemalignancies inodzivirira izvi zvipfupi.Iyo UCOM, PCDHGB7, inonyatso kusiyanisa epamusoro-giredhi squamous intraepithelial maronda (HSILs) negomarara remuchibereko kubva kune akajairwa samples uye yakaderera-giredhi squamous intraepithelial maronda (LSILs), nepo mamwe akawanda biomarker anogona chete kusiyanisa gomarara rechibereko kubva kune akajairwa samples30.Kunyangwe PCDHGB7 isingaone misiyano yakakura pakati peyakajairika endometrium uye endometrial hyperplasia, misiyano yakakura inoonekwa pakati peyakajairika endometrium uye atypical hyperplasia, uye kunyange misiyano yakakura kwazvo inowanikwa pakati peyakajairika endometrium neendometrial cancer (EC) yakavakirwa paPCDHGB731.UCOMs akasiyana kune akashata maronda mudhatabhesi uye ekiriniki masamples.Kubva pakuona kwemurwere, maUCOM akasarudzika anoderedza chikumbaridzo chekunzwisisa zviratidzo zvemhando dzakasiyana-siyana dzisina kugadzikana dzebiomarker uye kushushikana kunoenderana panguva yekuongorora.Kubva pakuona kwemukiriniki, maUCOM akasiyana anosiyanisa hutsinye kubva kune maronda asina kunaka, ayo anobatsira mukuongororwa kwevarwere uye anoderedza kurapa kusiri madikanwa uye kuwandisa.Naizvozvo, maUCOM akasarudzika anoderedza kuderedzwa kwehurongwa hwekurapa, kudzoreredza kushushikana kwehurongwa, uye kuita kuti kuwanikwe zvimwe zvekurapa kune avo vanoshaya.

Mufananidzo 1 Schematic yeGPS workflow yeDNA methylation yekuona25.Grey line: kupinza DNA kutevedzana;mutsara mutsvuku: DNA inobatwa neT4 DNA polymerase, inotsiva cytosine ne 5'-methylcytosine pamagumo e3;blue C with Me: methylated cytosine;blue C: unmethylated cytosine;yero T: thymine25.

Zvese kana hapana

UCOMs anowanikwa chete mumaseru egomarara uye anoonekwa akasimba munenge ese maseru egomarara.HIST1H4F yakasimbiswa kuti ive hypermethylated munenge marudzi ese emamota asi kwete mumasampuli akajairwa27.Saizvozvo, PCDHGB7 uye SIX6 zvakaratidzwawo kuve hypermethylated mune ese tumor samples asi kwete mune zvakajairika samples30-32.Iyi yakasarudzika hunhu inovandudza zvakanyanya mashandiro eUCOM maererano nemuganho wekuona uye kunzwa.Sezvo vashoma se2% yemaseru egomarara anogona kusiyaniswa mumasamples, zvichiita kuti maUCOM ave akanyanya kunzwisisika biomarker kupfuura akawanda aripo biomarkers30. zvichiratidza kusagona kuongororwa kwechirwere33.Iyo yakaderera kuwanda kweKRAS shanduko mune colorectal cancer inomisa KRAS musanganiswa nemamwe ma biomarker.Muchokwadi, musanganiswa wemabiomarker ungangoita seunovimbisa pakutanga, asi haugaro buritsa mhedzisiro inogutsa apo uchiratidza ruzha rwakanyanya mukuongororwa kwekuongorora uye kazhinji kunosanganisira maitiro akaomarara ekuyedza.Kusiyana neizvi, PCDHGB7 nemamwe maUCOM aripo mumakenza ese.MaUCOM anoona zvinhu zvine kenza mumhando dzakasiyana dzekenza samples zvine humbowo hwakanyanya apo ichibvisa maitiro ekuongorora-ruzha-kudzima.Hazvina kuoma kuona gomarara mumuenzaniso wakawanda, asi zvinonetsa kuona gomarara mune sampuli diki.MaUCOM anokwanisa kuona mashoma egomarara.

Mufananidzo 2 Hunhu hweUCOMs.

Kuonekwa kwegomarara pamberi pekuchinja kwepathological

UCOMs inogona kuwonekwa mune pre-kenza nhanho isati yachinja pathological.Se epigenetic biomarkers, UCOM abnormalities inoitika padanho rekutanga kupfuura phenotypic abnormalities uye inowonekwa mukati me tumorigenesis, kufambira mberi, uye metastasis34,35.Kunzwa kweUCOM nekufamba kwenguva kunowedzera mashandiro eUCOM mukuona kenza yepakutanga-tanga uye maronda e-pre-gomarara.Kuonekwa kwegomarara rekutanga kwakavakirwa pabiopsies uye cytology kunogona kunetsa kunyange kune vane ruzivo rwakanyanya.Imwe biopsy yakawanikwa kuburikidza necolposcopy inonzi yakanaka mu60.6% yemasampuli eHSIL+.Mamwe mabiopsies anodiwa kuti maronda akawanda awedzere kunzwa36.Kusiyana neizvi, iyo UCOM, PCDHGB7, ine sensitivity ye82% yeHSIL+ samples, inodarika kunzwisiswa kwebiopsies uye akawanda biomarkers30.Iyo methylation marker, FAM19A4, ine sensitivity ye69% yeCIN2+, iyo yakafanana necytology, asi haigone kusiyanisa CIN1 kubva kune yakajairika samples37.MaUCOM akaratidzwa kuve akanyanya kutarisisa ekutanga kuona biomarker.Kuenzaniswa nevanoziva-based pathologists, maUCOM ane yepamusoro yekuona senitivity kune ekutanga-danho kenza, izvo zvinozoita kuti kuvandudzwa kwechirwere chegomarara uye kupona30.Pamusoro pezvo, maUCOMs anopa chikuva chekuona chinosvikika kunzvimbo dzisina ruzivo rwenyanzvi dzezvirwere uye inovandudza zvakanyanya kugona kwekuona.Nemasampling mayunifomu uye maitiro ekuona, kuona kweUCOM kunoburitsa mibairo yakagadzikana uye iri nyore kududzira inoenderana neprotocol yekuongorora inoda vashoma vashandi vane hunyanzvi uye zviwanikwa zvekurapa.

Zviri nyore kuona

Nzira dzazvino dzekuona DNA methylation dzakaoma uye dzinotora nguva.Mazhinji enzira dzinoda bisulfite shanduko, izvo zvinokonzeresa kurasikirwa mumhando yemuenzaniso uye pamwe kuburitsa isina kugadzikana uye isina kururama mhedzisiro.Urombo husina kunaka hunokonzerwa nekurapa kwebisulfite hunogona kukonzera kuvhiringidzika kune vanachiremba nevarwere uye kunowedzera kukanganisa maitiro ekutevera uye / kana kurapa.Naizvozvo, takagadziridza zvakare nzira yekuonekwa kweUCOM kuti tidzivise dambudziko rekurapa bisulfite yemasampuli, kuenderana nezvinodiwa zvekiriniki yekushandisa, uye kuwedzera kuwanikwa.Isu takagadzira nzira itsva tichishandisa methylation-sensitive restriction enzymes yakasanganiswa neiyo chaiyo-nguva fluorescent quantitative PCR (Me-qPCR) kuyera iyo methylation mamiriro eUCOM mukati me3 h tichishandisa nyore kubata maitiro (Mufananidzo 3).Me-qPCR inogona kugarisa akati wandei emhando dzemhando, senge kiriniki yekuunganidza yemvura yemuviri uye wakazviunganidza wega weti masampuli.Akaunganidzwa ekiriniki samples anogona kugadziriswa, kuchengetwa, uye nyore kuenda kunoonekwa uchishandisa yakamisikidzwa uye otomatiki DNA kutorwa.Iyo yakabviswa DNA inogona kuiswa yakananga kuMe-qPCR papuratifomu kune imwe-poto reaction uye inobuda quantification mhinduro.Mushure mekuongorora kwakapfava kwemhedzisiro uchishandisa ma diagnostic modhi akaiswa uye akasimbiswa kune chaiwo marudzi egomarara, iyo yekupedzisira kutsunga kweiyo UCOM yekuona mhinduro inodudzirwa uye inoratidzwa semi-quantitative kukosha.Iyo Me-qPCR papuratifomu inokunda yechinyakare bisulfite-pyrosequencing mukuonekwa kweUCOM uku ichichengetedza maawa matatu ekushandurwa kwebisulfite, maererano neEZ DNA Methylation-Gold kit protocol.Iyo itsva methylation yekuona chikuva inoita kuti kuona kweUCOM kugadzike, kuve kwakanyatsojeka, uye kuwanika nyore30.

Mufananidzo 3 Kuonekwa maitiro eUCOMs.Mhando dzemienzaniso dzinosanganisira ine hunyanzvi sampled BALF, Pap brashi, uye/kana weti yakazviunganidza.Iyo DNA yekubvisa maitiro inogona kugariswa kune otomatiki extractor, chigadzirwa chayo chinogona kunyatsoonekwa neqPCR.

Kushandiswa kweUCOMs

Kenza yemapapu

Kenza yemapapu ndiyo yechipiri inowanzo zivikanwa uye inouraya kenza pasi rese, ichiverengera 11.4% yezviitiko zvitsva uye 18.0% yevakafa vatsva1.Pakati pekuongororwa kwese, makumi masere neshanu muzana asiri diki kenza yemapapu (NSCLC) uye 15% idiki kenza yemapapu yemapapu (SCLC), iyo ine mwero wepamusoro wemalignancy38.Low-dose computed tomography (LDCT) scanning ndiyo yazvino inokurudzirwa nzira yekuongorora kenza yemapapu uye yakaratidzwa kuvandudza kukurumidza kuonekwa uye kuderedza kufa6;zvisinei, nekuda kwekushomeka uye kusasvikwa zvakanaka, LDCT haisati yashanda senzira inogutsa yekuongorora, sezvinoita zvimwe zvinocheresa gomarara, seECA39.Mutengo uye mukana wekurasikirwa kwekuongororwa uye kusaziva kweiyo LDCT yekuongorora nzira inotadzisa kufambira mberi kwekenza yemapapu yekusimudzira40.HIST1H4F, UCOM, ine mukana wakakura seyekutanga kuona biomarker mubronchoalveolar fluid (BALF) samples27.HIST1H4F inonzi hypermethylated mu lung adenocarcinoma uye lung squamous cell carcinoma, ine 96.7% yekuonekwa uye kunzwa kwe87.0% (Mufananidzo 4A), uye kushanda kwakasiyana-siyana kwechikamu chekutanga chekenza27.HIST1H4F ine hunhu hwe96.5% uye sensitivity ye85.4% yeNSCLC, uye 96.5% uye 95.7%, zvichiteerana, yeSCLC27.Pamusoro pezvo, masampuli emamwe marudzi masere egomarara, anosanganisira pancreatic uye colorectal cancers, akasimbisa kuti HIST1H4F is hypermethylated mumhando sere dzese27.

Gomarara rechibereko

Chirwere chegomarara remuchibereko chaive chechina chinowanzo batwa gomarara uye chechina chiri kukonzera kufa kwegomarara muvakadzi muna 2020, ichiverengera 3.1% yezviitiko zvitsva uye 3.4% yenzufu dzine chekuita negomarara pasi rose.Kuti gomarara remuchibereko ripere panosvika gore ra2030, sezvakarongwa neWHO, zvinotoda kuti vanhu vaone gomarara remuchibereko nekukasika.Kana zvikaonekwa padanho rekutanga, huwandu hwemakore mashanu hwekupona hunosvika 92% negomarara remuromo wechibereko41.Nhungamiro yeAmerican Cancer Society (ACS) inopa cervical cytology bvunzo, yekutanga HPV bvunzo, kana cotes yekuongorora42.Cervical cytology invasive uye inogona kungoona 63.5% yeCIN2+ kesi37.

PCDHGB7, mukupesana, yakaita zvirinani kushandisa Pap smears uye kuvharirwa kwemukadzi, uye inogona kunyatsosiyanisa HSIL kubva kuLSIL munguva yekupedzisira-yekutanga.PCDHGB7 chete ine sensitivity ye100.0% uye chaiyo ye88.7% yegomarara rechibereko (Mufananidzo 4B), uye 82.1% senitivity uye 88.7% chaiyo yeHSIL+ samples30.PCDHGB7 zvakare ine 90.9% senitivity uye 90.4% yakanangana muvaginal secretion samples yegomarara remuchibereko, izvo zviri nyore kuunganidza30.Kana yasanganiswa neyepamusoro-ngozi (hr) HPV bvunzo kana Thinprep Cytology Test (TCT), PCDHGB7 ine yakawedzera senitivity ye95.7% uye chaiyo ye96.2%, zvakanyanya kupfuura iyo yehrHPV bvunzo (20.3%),TCT (51.2% ), uye maviri akasanganiswa (57.8%) egomarara remuromo wechibereko30.PCDHGB7 yakaratidzawo kuve hypermethylated mumhando gumi nenomwe dzegomarara kubva kuTCGA dhatabhesi, zvichiratidza kukodzera kwayo mumhuri yeUCOM30.

Mufananidzo 4 UCOMs dzakasimbiswa mumhando ina dzegomarara muzvidzidzo zvakakura zvekiriniki.A. Kuita kweHIST1H4F, UCOM, mukuonekwa kwegomarara remapapu 508 samples.B. Kuita kwePCDHGB7, UCOM, mukuonekwa kwekenza yekervical ye844 samples.C. Kuita kwePCDHGB7, UCOM, mukuonekwa kwegomarara reendometrial 577 endometrial Pap uye Tao brush samples.D. Performance yeSIX6, UCOM, mukuonekwa kwekenza yeurothelial ye177 samples.

EC

EC nderimwe rechirwere chegomarara revanhukadzi pasi rose, rine vanhu vatsva vanosvika miriyoni 4.2 uye 1% yendufu dzine chekuita negomarara pagore.Nekuongororwa kwakabudirira padanho rekutanga, EC inorapika uye ine makore mashanu ekupona kwe95% yegomarara redanho rekutanga.Varwere vane zviratidzo, zvakadai sekubuda ropa kusingawanzoitiki, vanogamuchira kuongororwa kwekliniki nguva nenguva uye vanopinda maitiro anorwadza uye anorwadza ebiopsy, pasinei ne5% -10% pakupedzisira inovandudza EC43.Transvaginal ultra-sound, seyakajairika nzira yekuona, haina kuvimbika zvakanyanya nekuda kwekusakwanisa kusiyanisa benign kubva kune yakaipa endo-metrial shanduko uye yakakwirira yenhema-positive rate44.

Kuenzanisa kwakafanana kweserum CA-125, yakashandiswa zvakanyanya EC biomarker, uye PCDHGB7 yakaitwa.Serum CA-125 yaive nekunzwa kwe24.8%, izvo zvinoratidza kuti CA-125 haina kukwana mucherechedzo weEC kunyangwe paine chaiyo ye92.3%31.Kuonekwa kwePCDHGB7 uchishandisa Pap bhurashi samples kwakaburitsa kunzwisiswa kwe80.65% uye chaiyo ye82.81% yeECatall nhanho, nepo bhurashi reTao raive nekunzwa kwe61.29% uye chaiyo ye95.31% 31.Iyo PCDHGB7 yekuongororwa modhi, yakavakirwa paMe-qPCR, yakapa kunzwisiswa kwe98.61%, chaiyo ye60.5%, uye yakazara ye85.5%, vachishandisa Pap uye Tao brashi samples (Mufananidzo 4C)31.

Urothelial cancer

Gomarara reUrothelial, rinosanganisira dundira, renal pelvis, uye ureter cancers, yaive yechinomwe yaiwanzoonekwa kenza muna 2020 pasi rose, zvichikonzera 5.2% yezviitiko zvitsva uye 3.9% yerufu1.Urothelial cancers, inodarika makumi mashanu muzana yegomarara redundiro, yaive yechina yaiwanzo onekwa kenza muUnited States muna 2022, ichiverengera 11.6% yevachangobva kuwanikwa3.Inosvika makumi manomwe neshanu muzana egomarara redundiro anorondedzerwa segomarara redundira risingapindi mhasuru rinongowanikwa mucosa kana submucosa45.Iyo cystoscopy biopsy ndiyo chiyero chegoridhe chekuongorora gomarara reurothelial rinoitwa nefluorescence in situ hybridization (FISH) uye cytology bvunzo.HOVE uye cytology zvine hurombo hwekuongororwa kwekuita, uye cystoscopy intrusive uye ine njodzi inokonzeresa yekushaikwa ma microlesions, kusadudzira maronda, uye zvinogona kukonzera kupararira kana kudzoka kwegomarara46.Iyo yakambosimbiswa UCOM, PCDHGB7, yakaratidzwawo kuve hypermethylated mugomarara reurothelial, ine nzvimbo iri pasi pe 0.86 curve, zvichiratidza kugona kuongororwa30.Kuenderera mberi nekusimbisa mamwe maUCOM uye kugarisa zvirinani mamwe masampuli emhando, SIX6, inoveli UCOM, yakaongororwa uye yakaratidza yakanakisa diagnostic kugona mukuonekwa kwekutanga kwegomarara reurothelial uchishandisa weti samples paMe-qPCR papuratifomu.Kuonekwa kweSIX6 uchishandisa weti samples kwakaratidza makwikwi ekunzwa kwe86.7% uye chaiyo ye90.8% (Mufananidzo 4D), asi isiri-invasive uye iri nyore kuwana32.Iko kugona kweSIX6 mukutarisisa metastasis uye kuongororwa kwehutano hwekurapa ikozvino iri kuferefetwa.

Ramangwana nematambudziko

MaUCOM ane kuita kwakasimba mukuongororwa kwegomarara rakawanda, asi pane basa rakawanda rasara kuita.Isu tanga tichiwedzera rondedzero yeUCOMs uye tanga tichishingairira maUCOM mune mamwe marudzi egomarara, kusanganisira ayo ane tsika yakaoma kuona.Mhedzisiro yemhedzisiro kubva kuTCGA dhatabhesi yakawedzera kusimbisa kushandiswa kweUCOMs mune mamwe marudzi egomarara uye mamwe mamiriro.Mukuferefeta kwekutanga, maUCOM akaratidzwa kuva ane simba rekuongorora chirwere checholangiocarcinomas uye pancreatic adenocarcinomas, izvo zvinenge zvisingabviri kuongororwa munguva pfupi nenzira dzemazuva ano dzekuongorora32,47.Iko kugona kuona isingawanzo cancer neUCOMs inogona kushandiswa neinotenderera bundu DNA (ctDNA) neyakagadziridzwa mvura biopsy platform48.Chidzidzo chinosanganisira plasma DNA-based pan-cancer yekuona pani yakaburitsa kunzwa kwe57.9%49.Pasinei nehukuru hwepamusoro, kuita kwese kunoratidza kuti pachine nzvimbo yekuvandudza.

Iwo akasarudzika maitiro eUCOM akatsigirawo kuferefetwa kweUCOM mukana mukuongororwa kwehutano hwekurapa uye kuongorora kwekudzokorora.Zvinoenderana neResponse Evaluation Criteria muSolid Tumors (RECIST), kufungidzira kwekurapa ndiyo nzira inokurudzirwa yekuongorora kudzokorora uye kuongororwa kwehutano hwekurapa, nepo mabundu mamaki achishandiswa ega pakuongorora50.Muchokwadi, zvisinei, nzira dzekufungidzira dzinokanganiswa zvakanyanya nekuwanda uye nguva, uye saka inoisa varwere kunjodzi huru uye mutengo51,52.SIX6 yakasimbiswa kuti ishande sechinofanotaura nezvekenza yemazamu metastasis32.Liquid biopsy-based ctDNA yekutarisa inogonesa-chaiyo-nguva yekutarisa pamusoro peiyo shoma yasara chirwere mwedzi pamberi pekuonekwa kweradiologic, kunonoka uye kudzivirira kudzoka-inoenderana nekenza kufambira mberi53.Mhedzisiro yekutanga inoratidza kuti maUCOM anoratidza huwandu hwekenza hypermethylation munguva chaiyo mushure mekuvhiyiwa uye kurapwa32.Kunzwa kwepamusoro kunoratidzwa neUCOMs uye kushanda mumhando dzakasiyana-siyana dzesamera dzinobvumira maUCOM kuti ashande seanonyatso kudzokorora kuongorora biomarker uku uchiramba uchiteerera murwere.

Panguva imwecheteyo, kuwanikwa kweveruzhinji kubvunzo ndiyo imwe nyaya hombe inoda kuwedzera simba.Nepo kubatana kwekuona kweUCOM kwakagamuchirwa mune zvimwe zvipatara netarisiro yekubatsira varwere vazhinji, kuongororwa kwepro bono uye kuongororwa kwave kuchiitwa mumaruwa eChina.MaUCOM anoda kuvandudzwa kuwanikwa kuti akwanise kuita sechinhu chinogoneka chekuongorora, kunyanya kunzvimbo dzisina budiriro.

Nepo chikumbiro cheUCOM chichiguma nekuonekwa kwekutanga kuri kuvimbisa, zvakawanda zvisingazivikanwe nezve UCOM zviripo.Nekutsvagisa kwakasimba, tsvakiridzo yekuwedzera inotenderwa kuti nei maUCOM aripo pasi rose mumakenza.Iwo ari pasi pe epigenetic regulation masisitimu ari pasi peUCOMs akakodzera kuongororwa, izvo zvinogona kururamisa gwara idzva rekurapa cancer.Kudzokera kukubatana pakati pebundu homogeneity uye heterogeneity, isu tiri kufarira kuti sei maUCOMs achigona kusarudzika kune mazhinji egomarara biomarkers akabatana zvakanyanya kune chaiwo marudzi egomarara.Basa reUCOM-inozivikanwa DNA methylation aberations mu tumorigenesis, tumor progression, uye metastasis harina kurongerwa mukurasikirwa nekuwanazve kuzivikanwa kwesero uye zvinoda kunyatsoongororwa.Kumwe kufarira kukuru kuri muchikamu chekubatanidzwa kweiyo homogeneity hunhu hweUCOM nemamatishu-akasarudzika mamaki mutariro yekusvika chaiyo yekuonekwa kwegomarara uye kuzivikanwa kwebundu matishu mabviro nenzira inodzosera kumashure.UCOMs inogona bhinzi chishandiso chakanakira kudzivirira cancer, kuona cancer, uye inogona kudzivirira nekubvisa cancer.

Ipa rubatsiro

Iri basa rakatsigirwa neNational Key R&D Chirongwa cheChina (Grant No. 2022BEG01003), National Natural Science Foundation yeChina (Grant Nos. 32270645 uye 32000505), Grant kubva kuHeilongjiang Provincial Health Commission (Grant No. 2020-111) , uye Grant kubva kuHeze Science and Technology Institute (Grant No. 2021KJPT07).

Kupokana kwechido chekufarira

Wei Li ndiye R&D Director weShanghai Epiprobe Biotechnology Co., Ltd. Wenqiang Yu anoshanda paScientific Advisory Board yeEpiprobe.W. Yu neEpiprobe vakatendera ma patent akamirira ane chekuita nebasa iri.Vamwe vese vanyori vanotaura kuti hapana zvinokwikwidza.

Mipiro yemunyori

Akatora uye akagadzira chirongwa ichi: Chengchen Qian uye Wenqiang Yu.

Akanyora pepa: Chengchen Qian.

Akagadzira mifananidzo: Chengchen Qian.

Akaongorora uye akagadzirisa zvinyorwa: Xiaolong Zou, Wei Li, Yinshan Li uye Wenqiang Yu.

References

1. Akaimba H, Ferlay J, Siegel RL, LaversanneM, Soerjomataram I, Jemal A, et al.Global Cancer Statistics 2020: GLOBOCAN fungidziro dze

chiitiko uye kufa pasi rose kwe36 cancers munyika 185.CA Cancer J Clin.2021;71:209-49.

2. Xia C, Dong X, Li H, Cao M, Sun D, ​​He S, et al.Nhamba dzeCancer muChina neUnited States, 2022: profiles, maitiro, uye zvinotaridza.Chin MedJ (Engl).2022;135: 584-90.

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

4. Crosby D, BhatiaS, Brindle KM, Coussens LM, Dive C, Emberton M, et al.Kukurumidza kuonekwa kwegomarara.Sayenzi.2022;375: eaay9040.

5. Ladabaum U, Dominitz JA, KahiC, Schoen RE.Strategies for

kuongorora cancer ye colorectal.Gastroenterology.2020;158:418-32.

6. Tanoue LT, Tanner NT, Gould MK, Silvestri GA.Kuongororwa kenza yemapapu.Ndiri J Respir Crit Care Med.2015;191:19-33.

7. Bouvard V, WentzensenN, Mackie A, Berkhof J, BrothertonJ, Giorgi-Rossi P, et al.Iyo IARC maonero ekuongororwa kenza yekervical.N EnglJ Med.2021;385: 1908-18.

8. Xue P, Ng MTA, QiaoY.Matambudziko ecolposcopy ekuongororwa kenza yekervical muLMICs uye mhinduro nehungwaru hwekugadzira.BMC Med.2020;18:169.

9. Johnson P, Zhou Q, Dao DY, Lo YMD.Kutenderera biomarkers mukuongororwa uye manejimendi ehepatocellular carcinoma.Nat Rev Gastroenterol Hepatol.2022;19: 670-81.

10. Van PoppelH, Albreht T, Basu P, HogenhoutR, CollenS, Roobol M. Serum PSA-yakavakirwa pakukurumidza kuona kenza yeprostate muEurope uye pasi rose: kare, ikozvino uye ramangwana.Nat Rev Urol.2022;19:

562-72.

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

et al.Kuvandudzwa kwe multiplex RNA weti bvunzo yekuona uye stratification ye transitional cell carcinoma yedundira.Clin Cancer Res.2008;14:742-9.

12. Feinberg AP, Vogelstein B. Hypomethylation inosiyanisa majini emamwe kenza evanhu kubva kune avo akajairika.Nature.1983;301: 89-92.

13. Ng JM, Yu J. Promoter hypermethylation ye tumor suppressor genes sezvingangoita biomarkers mu colorectal cancer.IntJ Mol Sci.2015;16:2472-96.

14. Esteller M. Cancer epigenomics: DNA methylomes uye histone-modification mepu.Nat Rev Genet.2007;8:286-98.

15. Nishiyama A, Nakanishi M. Kufambisa DNA methylation mamiriro egomarara.Trends Genet.2021;37:1012-27.

16. Xie W, Schultz MD, ListerR, Hou Z, Rajagopal N, Ray P, et al.Epigenomic ongororo yekusiyanisa mitsara yakawanda yemunhu embryonic stem masero.Sero.2013;153: 1134-48.

17. Li Y, Zheng H, Wang Q, Zhou C, WeiL, Liu X, et al.Genome-wide ongororo inoratidza basa rePolycomb mukusimudzira hypomethylation yeDNA methylation valleys.Genome Biol.2018;19:18.

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

et al.Kuongororwa kweDNA methylation mukenza: nzvimbo yakadzokororwa.Nat Rev Clin Oncol.2018;15:459-66.

19. KleinEA, Richards D, Cohn A, TummalaM, Lapham R, Cosgrove D, et al.Kusimbiswa kwekiriniki kweyakanangwa methylation-yakavakirwa yakawanda-gomarara yekutanga kuongororwa bvunzo uchishandisa yakazvimirira yekusimbisa seti.Ann Oncol.2021;32: 1167-77.

20. Hanahan D, Weinberg RA.Zviratidzo zvegomarara.Sero.2000;100: 57-70.

21. Hanahan D. Zviratidzo zvegomarara: mipimo mitsva.Cancer Discover.2022;12:31-46.

22. Schwartzberg L, Kim ES, Liu D, Schrag D. Precision oncology: ndiani, sei, chii, rini, uye rini?Am Soc Clin Oncol Educ Book.2017: 160-9.

23. Liu H, Meng X, Wang J. Realtime quantitative methylation

kuonekwa kwePAX1 gene mukuongorora kenza yechibereko.IntJ Gynecol Cancer.2020;30: 1488-92.

24. Imperiale TF, RansohoffDF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, et al.Multitargestool DNA yekuongorora ye colorectal- cancer yekuongorora.N EnglJ Med.2014;370: 1287-97.

25. Li J, Li Y, Li W, Luo H, Xi Y, Dong S, nevamwe.Guide positioning

kutevedzana kunozivisa aberrant DNA methylation mapatani anoshandura sero kuzivikanwa uye tumor-immune surveillance network.Genome

Res.2019;29:270-80.

26. Gao Q, LinYP, Li BS, Wang GQ, Dong LQ, Shen BY, et al.Unintrusive yakawanda-kenza yekuona nekutenderedza sero-isina DNA methylation sequencing (THUNDER): kusimudzira uye yakazvimirira yekusimbisa zvidzidzo.Ann Oncol.2023;34: 486-95.

27. Dong S, Li W, Wang L, Hu J, Song Y, Zhang B, nevamwe.Majini ane hukama neHistone ane hypermethylated mukenza yemapapu uye hypermethylated

HIST1H4F inogona kushanda asa pan-cancer biomarker.Cancer Res.2019;79: 6101-12.

28. HeijnsdijkEA, Wever EM,AuvinenA, Hugosson J, Ciatto S, Nelen V, et al.Hunhu-hwe-hupenyu mhedzisiro yeprostate-specific antigen kuongorora.N EnglJ Med.2012;367: 595-605.

29. LuzakA, Schnell-Inderst P, Bühn S, Mayer-Zitarosa A, Siebert U. Kubudirira kwekliniki yekenza yekuongorora biomarker miedzo inopiwa sehutano hwekubhadhara iwe pachako: kuongorora kwakarongeka.Eur J Hutano Hwevanhu.2016;26: 498-505.

30. Dong S, Lu Q,Xu P, Chen L, Duan X, Mao Z, et al.

Hypermethylated PCDHGB7 sekenza yepasirese chete mucherechedzo uye kushandiswa kwayo mukutanga kuongororwa kenza yechibereko.Clin Transl Med.2021;11: e457.

31. Yuan J, Mao Z, Lu Q,Xu P, Wang C, Xu X, nevamwe.Hypermethylated PCDHGB7 sechinhu chinonzi biomarker chekuonekwa kwekutanga kwekenza ye endometrial mu endometrial brush samples uye cervical scrapings.Mberi Mol Biosci.2022;8: 774215.

32. Dong S, Yang Z,Xu P, Zheng W, Zhang B, Fu F, nevamwe.Mutually

exclusive epigenetic modification paSIX6 ine hypermethylation ye precancerous stage uye metastasis kubuda kwekutsvaga.Signal Transduct Target Ther.2022;7:208.

33. Huang L, Guo Z, Wang F, Fu L. KRAS mutation: kubva pakusagadziriswa kusvika kune druggable mugomarara.Signal Transduct Target Ther.2021;6:386.

34. Belinsky SA, Nikula KJ, PalmisanoWA, MichelsR, SaccomannoG, GabrielsonE, et al.Aberrant methylation yep16(INK4a) chiitiko chichangobva kuitika mukenza yemapapu uye inogona biomarker yekuongororwa kwekutanga.Proc Natl Acad Sci U SA.1998;95: 11891-6.

35. Robertson KD.DNA methylation uye chirwere chevanhu.Nat Rev Genet.2005;6: 597-610.

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

Matthew C, nevamwe.Multiple biopsies uye kuongororwa kwekenza yekervical precursors pa colposcopy.J Clin Oncol.2015;33:83-9.

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

PJ, Steenbergen RD, nevamwe.Methylation kuongororwa kweFAM19A4

gene mucervical scrapes inoshanda zvakanyanya pakuona cervical

carcinomas uye advanced CIN2/3 maronda.Cancer Prev Res (Phila).2014;7: 1251-7.

38. Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS.Kenza yemapapu.Lancet.2021;398: 535-54.

39. Grunnet M, Sorensen JB.Carcinoembryonic antigen (CEA) semucherechedzo webundu mukenza yemapapu.Kenza yemapapu.2012;76:138-43.

40. Wood DE, KazerooniEA, Baum SL, EapenGA, EttingerDS, Hou L, et al.Kuongororwa Kwekenza Yemapapu, Shanduro 3.2018, NCCN Clinical Practice Guidelines muOncology.J Natl Compr Canc Netw.2018;16:412-41.

41. American Cancer Society.Cancer chokwadi & manhamba.Atlanta, GA, USA: American Cancer Society;2023 [yakagadziridzwa 2023 Kurume 1;yakataurwa 2023 Nyamavhuvhu 22].

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

Herzig A, nevamwe.Kuongororwa kwegomarara remuchibereko kune vanhu vari paavhareji njodzi: 2020 nhungamiro yekuvandudza kubva kuAmerican Cancer Society.CA Cancer J Clin.2020;70: 321-46.

43. Clarke MA, Long BJ, Del Mar MorilloA, Arbyn M, Bakkum-Gamez JN, Wentzensen N. Association of endometrial cancer risk ne postmenopausal kubuda ropa muvakadzi: kuongorora kwakarongeka uye meta-kuongorora.JAMA Intern Med.2018;178: 1210-22.

44. Jacobs I, Gentry-MaharajA, Burnell M, ManchandaR, Singh N,

Sharma A, nevamwe.Sensitivity ye transvaginal ultrasound kuongorora

ye endometrial cancer mu postmenopausal vakadzi: a case-control study mukati meUKCTOCS cohort.Lancet Oncol.2011;12:38-48.

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

PalouJ, nevamwe.European Association of Urology Guidelines pamusoro peCancer isina tsandanyama-inoparadza Dundira (TaT1 uye Carcinoma In Situ) -

2019 Update.Eur Urol.2019;76: 639-57.

46. ​​Aragon-Ching JB.Matambudziko uye kufambira mberi mukuongororwa, biology, uye kurapwa kweurothelial repamusoro turakiti uye bladder carcinomas.Urol Oncol.2017;35:462-4.

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

Cholangiocarcinoma - inoshanduka pfungwa uye nzira dzekurapa.Nat Rev Clin Oncol.2018;15:95-111.

48. Ye Q, Ling S, Zheng S, Xu X. Liquid biopsy muhepatocellular

carcinoma: kutenderera bundu masero uye kutenderera bundu DNA.Mol Cancer.2019;18:114.

49. Zhang Y, Yao Y, Xu Y, Li L, Gong Y, Zhang K, et al.Pan-cancer

kutenderera bundu DNA kuwanikwa mune vanopfuura zviuru gumi vevarwere veChinese.Nat Commun.2021;12:11.

50. Eisenhauer EA, Therasse P, BogaertsJ, Schwartz LH, Sargent D, Ford R, et al.Mitsva yekuongorora nzira yekuongorora mumatumbu akasimba: yakagadziridzwa RECIST nhungamiro (vhezheni 1.1).Eur J Cancer.2009;45:228-47.

51. LitièreS, Collette S, de Vries EG, Seymour L, BogaertsJ.RECIST - kudzidza kubva kare kuvaka ramangwana.Nat Rev Clin Oncol.

2017;14:187-92.

52. Seymour L, BogaertsJ, Perrone A, FordR, Schwartz LH, Mandrekar S, et al.iRECIST: nhungamiro yekupindura maitiro ekushandiswa mumiedzo

kuongorora immunotherapeutics.Lancet Oncol.2017;18: e143-52.

53. PantelK, Alix-Panabières C. Liquid biopsy uye zvishoma zvakasara chirwere - kufambira mberi kwezvino uye zvinorehwa pakurapa.Nat Rev Clin Oncol.2019;16:409-24.

Taura chinyorwa ichi se: Qian C, Zou X, Li W, Li Y, Yu W. The outpost against cancer: universal cancer only markers.Cancer Biol Med.2023;20: 806-815.

doi: 10.20892/j.issn.2095-3941.2023.0313