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 wocwaningo obalulekile [1] yithimba likaProf. Cai Guo-ring waseCancer Hospital yaseFudan University kanye noProf. Wang Jing waseRenji Hospital yaseShanghai Jiao Tong University School of Medicine, ngokubambisana ne-KUNYUAN BIOLOGY: “Ukutholwa Kwangaphambi Kokutholwa Kwe-Molecular Residual kanye Nomdlavuza I-Strategic Residual Residual I-Circulating Tumor DNA Methylation kanye ne-Risk Stratification) ”. Lolu cwaningo luwucwaningo lokuqala lwe-multicenter emhlabeni ukusebenzisa ubuchwepheshe be-PCR-based ctDNA multigene methylation ye-PCR yokubikezela ukuphindaphinda komdlavuza we-colorectal kanye nokuqapha ukuphindaphinda, okuhlinzeka ngendlela yobuchwepheshe engabizi kakhulu nesisombululo uma kuqhathaniswa nezindlela zobuchwepheshe zokuthola i-MRD ezikhona, okulindeleke ukuthi zithuthukise kakhulu ukusetshenziswa komtholampilo komdlavuza we-colorectal kanye nokuqapha izinga lokuphila kwesiguli. 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. Isizathu sesihlanu sokufa 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 umthwalo osindayo wezenhlalo nezomnotho. Ngokwezibalo zeNational Cancer Center, ukukhuphuka okujwayelekile konyaka kwezindleko zokwelashwa komdlavuza we-colorectal eChina cishe ku-6.9% kuya ku-9.2%, kanti izindleko zezempilo zomuntu siqu zeziguli zingakapheli unyaka owodwa zokuxilongwa zingathatha u-60% wemali engenayo 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 nje, ubuchwepheshe bokutholwa kwe-MRD yamathumba aqinile buye bathuthuka ngokushesha, futhi izifundo ezimbalwa zokuhlola nokungenelela kwe-heavyweight ziye zaqinisekisa ukuthi isimo se-MRD se-postoperative 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 neziqondiso zaseChina ze-CSCO zomdlavuza 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 ezinomdlavuza wekholoni wesigaba II noma sesi-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 engama-70%) zinesidingo esiphuthumayo sokuqapha okunamandla, bese usayizi wemakethe wokuqapha okunamandla kwe-MRD umdlavuza we-colorectal ufinyelela izigidi zabantu unyaka ngamunye.
Kungabonakala ukuthi imiphumela yocwaningo inokubaluleka okubalulekile kwesayensi nokusebenzayo. Ngezifundo zomtholampilo ezilindelekile ezinkulu, kuqinisekisile ukuthi ubuchwepheshe begazi be-PCR-based ctDNA multigene methylation bungasetshenziselwa ukubikezela ukuvela kabusha komdlavuza we-colorectal kanye nokuqapha ukuphinda kwakho kokubili ukuzwela, ukufika ngesikhathi kanye nempumelelo yezindleko, okwenza kangcono umuthi onembile ukuze uzuze 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 yase-Fudan University, i-Cancer Hospital yase-Fudan University kanye nezinye izikhungo zezokwelapha ezigunyaziwe ngokubambisana ne-KUNYAN Biological, eqinisekisa ukusebenza okuhle kakhulu kwe-ColonAiQ® ChangAiQ® ekuhlolweni kokuqala komdlavuza kanye nokuhlolwa kokuqala komdlavuza. futhi ihlola ukusetshenziswa okungase kube khona ekuqaphelweni kwe-prognosis yomdlavuza we-colorectal.

Ukuze kuqhutshekwe kuqinisekiswe ukusetshenziswa komtholampilo kwe-ctDNA methylation ekuhlukaniseni engcupheni, izinqumo zokwelashwa eziqondisayo kanye nokuqapha ukuphindeka kwangaphambi kwesikhathi esigabeni I-III somdlavuza ogqamile, ithimba labacwaningi lalihlanganisa iziguli ezingu-299 ezinomdlavuza we-colorectal wesigaba I-III ezahlinzwa kakhulu futhi zaqoqa amasampula egazi endaweni ngayinye yokulandelela (izinyanga ezintathu ngokuhlukana, ngemva kwezinyanga ezintathu zokuhlinzwa, ngemva kokuhlinzwa, isonto elilodwa ngaphambi kokuhlinzwa, nokuhlinzwa 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 ukuhlola kwe-ctDNA ne-CEA okuhlanganisiwe kuthuthuke kancane ukusebenza ekutholeni ukuphindeka (AUC=0.849), kodwa umehluko wawungabalulekile uma kuqhathaniswa nokuhlolwa kwe-ctDNA (AUC=0.839) iyodwa Umehluko wawungabalulekile uma kuqhathaniswa ne-ctDNA iyodwa (AUC=0.839).
Isiteji semitholampilo esihlanganiswe nezici eziyingozi njengamanje isisekelo esiyinhloko sokuhlukaniswa kwengozi yeziguli ezinomdlavuza, futhi esimweni samanje, isibalo esikhulu seziguli sisabuya [4], futhi kunesidingo esiphuthumayo samathuluzi angcono wokuhlukanisa njengoba ukwelashwa ngokweqile nokungaphansi kokwelashwa kuhlangene 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 yokuphindaphinda yayiphezulu kakhulu ezigulini ezinokuhlolwa kwe-ctDNA eguquguqukayo kuneziguli ezine-ctDNA engalungile ngesikhathi sesigaba sokuqapha ukuphindaphinda kwesifo ngemva kokwelashwa okuqondile (ngemuva kokuhlinzwa okukhulu + nokwelashwa kwe-adjuvant) (Umfanekiso 3ACD), nokuthi i-ctDNA ingabonisa ukuthi kungenzeka ukuthi isisu siphinde sivele ngaphambi kwezinyanga ezingu-3B 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 kokuguqulwa koguquko ukuthi ayidingi ukuhlolwa okuphelele kokulandelana kwe-genome kwezicubu zesimila, isetshenziselwa ngokuqondile ukuhlolwa kwegazi, futhi igwema imiphumela engemihle ngenxa yokutholwa kokuguqulwa kwe-somatic okuvela ezicutshini ezivamile, izifo ezinobungozi, kanye ne-clonal hematopoiesis.
Lolu cwaningo kanye nolunye ucwaningo oluhlobene luqinisekisa ukuthi ukuhlolwa kwe-MRD okusekelwe ku-ctDNA kuyisici esibaluleke kakhulu esizimele esiyingozi sokuphindaphinda komdlavuza we-colorectal wesigaba I-III futhi kungasetshenziswa ukusiza ukuqondisa izinqumo zokwelashwa, okuhlanganisa "ukwenyuka" kanye "nokwehliswa" kokwelashwa kwe-adjuvant MRD iyisici esiyingozi esizimele esibaluleke kakhulu sokuphindaphinda 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 Kwangaphambi Kwezifo Ezinsalela Zamangqamuzana Nokufakwa Kwengozi Kwesigaba I kuya ku-III I-Colorectal Tumor. JAMA Oncol. 2023 Ephreli 20.
[2] “Umthwalo wesifo somdlavuza we-colorectal kubantu baseShayina: ingabe ushintshile eminyakeni yamuva nje? , I-Chinese Journal of Epidemiology, Vol. 41, No. 10, October 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.
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