Ucwaningo oluzayo: I-PCR-based blood ctDNA methylation technology ivula inkathi entsha yokubhekwa kwe-MRD yomdlavuza we-colorectal.

Muva nje, i-JAMA Oncology (IF 33.012) ishicilele umphumela obalulekile wocwaningo [1] yithimba likaProf. Cai Guo-ring waseCancer Hospital yaseFudan University kanye noProf. Wang Jing waseRenji Hospital yaseShanghai Jiao Tong University School of Medicine, e ukusebenzisana ne-KUNYUAN BIOLOGY: “Ukutholwa Kwangaphambi Kwesifo Se-Molecular Residual and Risk Stratification for Stage I to III Colorectal Cancer ngokusebenzisa I-Circulating Tumor DNA Methylation kanye ne-Risk Stratification) ”. Lolu cwaningo luwucwaningo lokuqala lwe-multicenter emhlabeni ukusebenzisa ubuchwepheshe begazi be-PCR-based ctDNA multigene methylation ukubikezela ukuphindaphinda komdlavuza we-colorectal kanye nokuqapha ukuphindaphinda, okuhlinzeka ngendlela yobuchwepheshe engabizi kakhulu nesixazululo uma kuqhathaniswa nezindlela zobuchwepheshe zokuthola i-MRD ezikhona, okulindelekile. ukuthuthukisa kakhulu ukusetshenziswa komtholampilo kokubikezela nokuqapha ukuvela komdlavuza we-colorectal, kanye nokuthuthukisa kakhulu ukusinda kwesiguli kanye nekhwalithi yokuphila . Lolu cwaningo luphinde lwahlaziywa kakhulu yiphephabhuku nabahleli balo, lwafakwa ohlwini njengephepha lokuncoma elibalulekile kulolu daba, kwathi uSolwazi Juan Ruiz-Bañobre waseSpain kanye noSolwazi u-Ajay Goel wase-United States bamenywa ukuba balubuyekeze. Ucwaningo luphinde lwabikwa yiGenomeWeb, imidiya ehamba phambili ye-biomedical e-United States.

Umdlavuza we-Colorectal (CRC) yisimila esiyingozi esivamile sepheshana lamathumbu e-China. Idatha ye-2020 ye-International Agency for Research on Cancer (IARC) ibonisa ukuthi amacala amasha angu-555,000 e-China athatha cishe i-1/3 yomhlaba, izinga lezehlakalo ligxumela endaweni yesibili yomdlavuza ovamile e-China; Ukufa okungu-286,000 kubala cishe i-1/3 yomhlaba, kukleliswe njengembangela yesihlanu evame kakhulu yokufa komdlavuza eChina. Imbangela yesihlanu yokufa eChina. Kuyaphawuleka ukuthi phakathi kweziguli ezixilongwayo, izigaba ze-TNM I, II, III kanye ne-IV zingu-18.6%, 42.5%, 30.7% no-8.2% ngokulandelana. Iziguli ezingaphezu kuka-80% zisesigabeni esimaphakathi nesemuva, kanti u-44% wazo unama-metastases akude ngesikhathi esisodwa noma ama-heterochronic esibindini nasemaphashini, athinta kakhulu isikhathi sokuphila, abeke engozini impilo yezakhamuzi zethu futhi abangele ubunzima bezenhlalakahle nezomnotho. umthwalo. Ngokwezibalo zeNational Cancer Center, ukukhuphuka okujwayelekile konyaka kwezindleko zokwelashwa komdlavuza we-colorectal e-China cishe ku-6.9% kuya ku-9.2%, kanti izindleko zezempilo zomuntu siqu zeziguli zingakapheli unyaka owodwa zokuxilongwa zingathatha ama-60% eziguli. imali yomndeni. Iziguli ezinomdlavuza ziphethwe yilesi sifo futhi zingaphansi kwengcindezi enkulu yezomnotho [2].
Amaphesenti angu-90 amanxeba omdlavuza we-colorectal angasuswa ngokuhlinzwa, futhi lapho isimila sitholwa ngaphambi kwesikhathi, izinga lokusinda leminyaka emihlanu liphakeme ngemva kokuhlinzwa ngokuhlinzwa okukhulu, kodwa izinga lokuphinda liphindeke ngemva kokuhlinzwa okukhulu lisecishe libe ngu-30%. Amazinga okusinda kweminyaka emihlanu komdlavuza we-colorectal kubantu baseShayina angu-90.1%, 72.6%, 53.8% no-10.4% ezigabeni I, II, III kanye ne-IV, ngokulandelana.
I-Minimal Residual Disease (MRD) iyimbangela enkulu yokubuya kwesimila ngemva kokwelashwa okukhulu. Eminyakeni yamuva, ubuchwepheshe bokutholwa kwe-MRD yamathumba aqinile buye bathuthuka ngokushesha, futhi izifundo ezimbalwa zokuhlola nokungenelela kwe-heavyweight ziye zaqinisekisa ukuthi isimo se-postoperative MRD singabonisa ingozi yokuphindaphinda ngemuva kokuhlinzwa komdlavuza we-colorectal. Ukuhlolwa kwe-ctDNA kunezinzuzo zokungahlaseli, kulula, kuyashesha, nokufinyeleleka kwesampula ephezulu kanye nokunqoba ukuhlukahluka kwesimila.
Imihlahlandlela yase-US NCCN yomdlavuza wekoloni kanye nemihlahlandlela yaseChina ye-CSCO yomdlavuza we-colorectal zombili zithi ekunqumeni ubungozi bokuphindaphinda kwangemva kokuhlinzwa kanye nokukhetha i-adjuvant chemotherapy kumdlavuza wekoloni, ukuhlolwa kwe-ctDNA kunganikeza imininingwane yokubikezela nokubikezela ukusiza ezinqumweni zokwelashwa kwe-adjuvant ezigulini ezinesigaba II. noma umdlavuza we-colon III. Kodwa-ke, izifundo eziningi ezikhona zigxile ekuguqulweni kwe-ctDNA okusekelwe kubuchwepheshe bokulandelana kwe-high-throughput (NGS), enenqubo eyinkimbinkimbi, isikhathi eside sokuhola, kanye nezindleko eziphezulu [3], ngokuntuleka okuncane kokujwayelekile kanye nokutholakala okuphansi phakathi kweziguli ezinomdlavuza.
Esimeni seziguli zomdlavuza we-colorectal esigabeni sesi-III, ukuqapha okuguquguqukayo kwe-CTDNA okusekelwe ku-NGS kubiza kufika ku-$10,000 ngokuvakasha okukodwa futhi kudinga isikhathi sokulinda esingafika kumaviki amabili. Ngokuhlolwa kwe-multigene methylation kulolu cwaningo, i-ColonAiQ®, iziguli zingaba nokuqapha kwe-ctDNA okunamandla engxenyeni yeshumi yezindleko futhi zithole umbiko esikhathini esingangezinsuku ezimbili.
Ngokusho kwamacala amasha angama-560,000 omdlavuza we-colorectal e-China unyaka ngamunye, iziguli zasemtholampilo ikakhulukazi ezinomdlavuza we-colorectal wesigaba II-III (ingxenye cishe i-70%) zinesidingo esiphuthumayo sokuqapha okunamandla, bese kuba nosayizi wemakethe wokuqapha okunamandla kwe-MRD umdlavuza we-colorectal ufinyelela izigidi zabantu unyaka ngamunye.
Kungabonakala ukuthi imiphumela yocwaningo inokubaluleka okubalulekile kwesayensi nokusebenzayo. Ngezifundo ezinkulu ezizoba khona zemitholampilo, sekuqinisekisile ukuthi ubuchwepheshe be-PCR-based ctDNA multigene methylation bungasetshenziselwa ukubikezela ukuvela komdlavuza we-colorectal kanye nokuqapha ukuphinda kwakho kokubili ukuzwela, ukufika ngesikhathi kanye nempumelelo yezindleko, okwenza kangcono imithi enembile ukuze kuzuze iziguli ezinomdlavuza. . Ucwaningo lusekelwe ku-ColonAiQ®, ukuhlolwa kwe-methylation yezakhi eziningi zomdlavuza we-colorectal owenziwe i-KUNY, okubaluleka kwayo komtholampilo ekuhlolweni kokuqala nokuxilongwa kuye kwaqinisekiswa ucwaningo lwezokwelapha olumaphakathi.
I-Gastroenterology (IF33.88), iphephabhuku eliphezulu lamazwe ngamazwe emkhakheni wezifo zesisu ngo-2021, libike imiphumela yocwaningo oluningi lwe-Zhongshan Hospital yaseFudan University, iCancer Hospital yaseFudan University kanye nezinye izikhungo zezokwelapha ezigunyaziwe ngokubambisana ne-KUNYAN Biological, okuqinisekisile. ukusebenza okuhle kakhulu kwe-ColonAiQ® ChangAiQ® ekuhlolweni kusenesikhathi kanye nokuhlonzwa kusenesikhathi komdlavuza we-colorectal, futhi kwaqale kwahlola i-It futhi ihlola ukusetshenziswa okungase kube khona ekuqaphelweni kwe-prognosis yomdlavuza we-colorectal.

Ukuze kuqhutshekwe kuqinisekiswe ukusetshenziswa komtholampilo kwe-ctDNA methylation ekuhlukaniseni ubungozi, izinqumo zokwelashwa eziqondisayo kanye nokuqapha ukuvela kabusha kwangaphambi kwesikhathi esigabeni I-III somdlavuza we-colorectal, ithimba labacwaningi lalihlanganisa iziguli ezingama-299 ezinomdlavuza we-colorectal wesigaba I-III ezahlinzwa kakhulu futhi zaqoqa amasampula egazi iphuzu ngalinye lokulandelela (izinyanga ezintathu ngokwehlukana) lingakapheli isonto elilodwa ngaphambi kokuhlinzwa, inyanga eyodwa ngemva kokuhlinzwa, kanye nasekwelashweni kwe-adjuvant ngemva kokuhlinzwa ukuhlolwa kwe-ctDNA yegazi ashukumisayo.
Okokuqala, kwatholakala ukuthi ukuhlolwa kwe-ctDNA kungabikezela ingozi yokuphindelela ezigulini ezinomdlavuza we-colorectal kusenesikhathi, ngaphambi kokuhlinzwa nangaphambi kokuhlinzwa. Iziguli ezine-ctDNA-positive ngaphambi kokuhlinzwa zazinethuba eliphezulu lokuphinda kwenzeke ngemva kokuhlinzwa kuneziguli ezingenayo i-ctDNA yangaphambi kokuhlinzwa (22.0%> 4.7%). Ukuhlolwa kwe-ctDNA yangemva kokuhlinzwa kwakusabikezele ingozi yokuphinda iphinde ibe khona: inyanga eyodwa ngemva kokuhlinzwa okukhulu, iziguli ezine-ctDNA-positive zazinethuba eliphindwe izikhathi ezingu-17.5 lokuphinda ziphindele kuneziguli ezingezinhle; ithimba liphinde lathola ukuthi ukuhlolwa kwe-ctDNA kanye ne-CEA okuhlanganisiwe kuthuthukise ukusebenza kancane ekutholeni ukuphindeka (AUC=0.849), kodwa umehluko wawungabalulekile uma kuqhathaniswa nokuhlolwa kwe-ctDNA (AUC=0.839) iyodwa Umehluko wawungekho omkhulu uma kuqhathaniswa ne-ctDNA iyodwa (AUC= 0.839).
Isiteji semitholampilo esihlanganiswe nezici eziyingozi njengamanje yisisekelo esiyinhloko sokuhlukaniswa kwengozi yeziguli ezinomdlavuza, futhi esimweni samanje, inani elikhulu leziguli lisabuya [4], futhi kunesidingo esiphuthumayo samathuluzi angcono wokuhlukanisa njengokwelashwa ngokweqile kanye ukuhlala kancane emtholampilo. Ngokusekelwe kulokhu, ithimba lihlukanise iziguli ezinomdlavuza we-colorectal esigabeni sesi-III zaba amaqeqebana ahlukene ngokusekelwe ekuhlolweni kwengozi yokuphinda emtholampilo (ingozi enkulu (T4/ N2) kanye nengozi ephansi (T1-3N1)) kanye nesikhathi sokwelashwa kwe-adjuvant (izinyanga ezi-3/6). Ukuhlaziywa kwathola ukuthi iziguli eziseqenjini elincane leziguli ezine-ctDNA-positive zinezinga eliphansi lokuphindaphinda uma zithola izinyanga eziyisithupha zokwelashwa kwe-adjuvant; eqenjini elincane elinobungozi obuncane beziguli ezine-ctDNA-positive, kwakungekho umehluko ophawulekayo phakathi komjikelezo wokwelapha we-adjuvant kanye nemiphumela yesiguli; kuyilapho iziguli ezingenayo i-ctDNA zinesimo esingcono kakhulu sokubikezela kuneziguli ezine-ctDNA kanye nenkathi ende yangemva kokuhlinzwa yokuphindaphinda (RFS); Isigaba I kanye nesigaba II somdlavuza we-colorectal onengozi ephansi Zonke iziguli ezingenayo i-ctDNA azizange ziphinde zivele phakathi neminyaka emibili; ngakho-ke, ukuhlanganiswa kwe-ctDNA nezici zomtholampilo kulindeleke ukuthi kuthuthukise ukuhlukaniswa kwengozi futhi kubikezele kangcono ukuphindeka.

Umfanekiso 1. Ukuhlaziywa kwe-Plasma ctDNA ku-POM1 ukuze kutholwe kusenesikhathi ukuvela kabusha komdlavuza we-colorectal
Eminye imiphumela yokuhlolwa kwe-ctDNA eguquguqukayo ibonise ukuthi ingozi yokuphinda iphinde ibe phezulu kakhulu ezigulini ezinokuhlolwa kwe-ctDNA eguquguqukayo kuneziguli ezine-ctDNA engeyinhle ngesikhathi sesigaba sokuqapha ukuphindwa kwesifo ngemva kokwelashwa okuqondile (ngemuva kokuhlinzwa okukhulu + nokwelashwa kwe-adjuvant) (Umfanekiso 3ACD), nokuthi i-ctDNA ingakhombisa ukuphindeka kwesimila kuze kufike ezinyangeni ezingama-20 ngaphambi kokuthwebula (Umfanekiso 3B), enikeza ithuba lokutholwa kwesifo kusenesikhathi. ukuphindaphinda kanye nokungenelela okufika ngesikhathi.

Umfanekiso 2. Ukuhlaziywa kwe-ctDNA okusekelwe ku-longitudinal cohort ukuze kutholwe ukuvela komdlavuza we-colorectal

“Inani elikhulu lezifundo zemithi yokuhumusha kumdlavuza we-colorectal zihola isiyalo, ikakhulukazi ukuhlolwa kwe-MRD okusekelwe ku-ctDNA kubonisa amandla amakhulu okuthuthukisa ukuphathwa kwangemva kokuhlinzwa kweziguli ezinomdlavuza we-colorectal ngokunika amandla ukuhlukaniswa kwengozi yokuphindelela, izinqumo zokwelashwa eziqondisayo kanye nokuqapha ukuvela kabusha kwangaphambi kwesikhathi.

Inzuzo yokukhetha i-DNA methylation njengenoveli yomaka we-MRD phezu kokutholwa koguquko ukuthi ayidingi ukuhlolwa okuphelele kokulandelana kwe-genome kwezicubu zesimila, isetshenziselwa ngokuqondile ukuhlolwa kwegazi, futhi igwema imiphumela engemihle ngenxa yokutholwa kokuguqulwa kwe-somatic okuvela kokujwayelekile. izicubu, izifo ezingezinhle, kanye ne-clonal hematopoiesis.
Lolu cwaningo kanye nolunye ucwaningo oluhlobene luqinisekisa ukuthi ukuhlolwa kwe-MRD okusekelwe ku-ctDNA kuyisici esibaluleke kakhulu esizimele engozini yokuphindelela komdlavuza we-colorectal wesigaba I-III futhi kungasetshenziswa ukusiza ukuqondisa izinqumo zokwelashwa, okuhlanganisa "ukwenyuka" kanye "nokwehliswa" kokwelashwa kwe-adjuvant. I-MRD iyisici esibaluleke kakhulu esizimele esiyingozi sokuphindeka ngemva kokuhlinzwa kwesigaba I-III somdlavuza we-colorectal.
Inkambu ye-MRD ithuthuka ngokushesha ngenani lokuqanjwa kabusha, ukuzwela kakhulu kanye nokuhlola okuqondile okusekelwe ku-epigenetics (i-DNA methylation ne-fragmentomics) kanye ne-genomics (ukulandelana okuhlosiwe okujule kakhulu noma ukulandelana kwegenome lonke). Silindele ukuthi i-ColonAiQ® iqhubeke nokuhlela izifundo ezinkulu zemitholampilo futhi ingaba inkomba entsha yokuhlolwa kwe-MRD ehlanganisa ukufinyeleleka, ukusebenza okuphezulu kanye nokufinyeleleka kwayo futhi ingasetshenziswa kabanzi emisebenzini yomtholampilo evamile. "
Izithenjwa
[1] Mo S, Ye L, Wang D, Han L, Zhou S, Wang H, Dai W, Wang Y, Luo W, Wang R, Xu Y, Cai S, Liu R, Wang Z, Cai G. Ukutholwa Early ye-Molecular Residual Disease kanye ne-Risk Stratification yeSigaba I kuya ku-III Umdlavuza Wamabala nge-Circulating Tumor DNA Methylation. JAMA Oncol. 2023 Ephreli 20.
[2] “Umthwalo wesifo somdlavuza we-colorectal kubantu baseShayina: ingabe ushintshile eminyakeni yamuva nje? , I-Chinese Journal of Epidemiology, Umq. 41, No. 10, Okthoba 2020.
[3] Tarazona N, Gimeno-Valiente F, Gambardella V, et al. Ukulandelana okuhlosiwe kwesizukulwane esilandelayo se-circulating-tumor DNA ukuze kulandelelwe isifo esincane esiyinsalela kumdlavuza wekholoni wendawo. U-Ann Oncol. Nov 1, 2019;30(11):1804-1812.
[4] U-Taieb J, u-André T, u-Auclin E. Ukucwenga i-adjuvant therapy yomdlavuza we-colon non-metastatic, izindinganiso ezintsha kanye nemibono. Ukwelapha Umdlavuza Rev. 2019;75:1-11.