Ucwaningo oluzayo: Ubuchwepheshe be-methylation ye-ctDNA yegazi esekwe ku-PCR buvula inkathi entsha yokubhekwa kwe-MRD komdlavuza we-colorectal

Muva nje, i-JAMA Oncology (IF 33.012) ishicilele umphumela obalulekile wocwaningo [1] yithimba likaProf. Cai Guo-ring waseCancer Hospital of Fudan University kanye noProf. Wang Jing waseRenji Hospital of Shanghai Jiao Tong University School of Medicine, ngokubambisana ne-KUNYUAN BIOLOGY: “Ukutholwa Kwasekuqaleni Kwesifo Esisele Sama-Molecular kanye Nokuhlukaniswa Kwengozi Kwesigaba I kuya Kwesi-3 Somdlavuza We-Colorectal nge-Circulating Tumor DNA Methylation kanye Nokuhlukaniswa Kwengozi)”. Lolu cwaningo luwucwaningo lokuqala olunezikhungo eziningi emhlabeni olusebenzisa ubuchwepheshe be-PCR-based blood ctDNA multigene methylation yokubikezela ukuphinda komdlavuza we-colorectal kanye nokuqapha ukuphinda komdlavuza, oluhlinzeka ngendlela yobuchwepheshe nesisombululo esingabizi kakhulu uma kuqhathaniswa nezindlela zobuchwepheshe zokuthola i-MRD ezikhona, okulindeleke ukuthi kuthuthukise kakhulu ukusetshenziswa kwemitholampilo kokubikezela nokuqapha ukuphinda komdlavuza we-colorectal, futhi kuthuthukise kakhulu ukusinda kwesiguli kanye nekhwalithi yokuphila. Lolu cwaningo luhlolwe kakhulu yiphephabhuku kanye nabahleli balo, futhi lubhalwe njengephepha eliyisincomo elibalulekile kulolu daba, kanti uSolwazi uJuan Ruiz-Bañobre waseSpain kanye noSolwazi u-Ajay Goel wase-United States bamenyiwe ukuthi balubuyekeze. Lolu cwaningo luphinde lwabikwa yi-GenomeWeb, inkampani ehamba phambili kwezokwelapha e-United States.

Umdlavuza we-Colorectal (CRC) uyisimila esibi esivamile sendlela yokugaya ukudla eShayina. Idatha ye-International Agency for Research on Cancer (IARC) ka-2020 ikhombisa ukuthi amacala amasha angu-555,000 eShayina ahlanganisa cishe i-1/3 yomhlaba, kanti izinga lokwanda kwezifo lehla liye endaweni yesibili yomdlavuza ovamile eShayina; ukufa okungu-286,000 kuhlanganisa cishe i-1/3 yomhlaba, okubalwa njengembangela yesihlanu evame kakhulu yokufa komdlavuza eShayina. Imbangela yesihlanu yokufa eShayina. Kuyaphawuleka ukuthi phakathi kweziguli ezitholakale zinesifo, izigaba ze-TNM I, II, III kanye ne-IV ziyi-18.6%, 42.5%, 30.7% kanye no-8.2% ngokulandelana. Iziguli ezingaphezu kuka-80% zisesigabeni esiphakathi nesokugcina, kanti ezingama-44% zazo zine-metastases ezikude ngesikhathi esisodwa noma ezingapheli esibindini nasemaphashini, ezithinta kakhulu isikhathi sokusinda, zibeka impilo yezakhamuzi zethu engozini futhi zibangele umthwalo onzima kwezenhlalo nakwezomnotho. Ngokwezibalo zeNational Cancer Center, isilinganiso sokwenyuka kwaminyaka yonke kwezindleko zokwelapha umdlavuza we-colon eShayina singaba ngu-6.9% kuya ku-9.2%, kanti izindleko zempilo yomuntu siqu zeziguli zingakapheli unyaka owodwa zixilongiwe zingathatha u-60% wemali engenayo yomndeni. Iziguli zomdlavuza zihlushwa yilesi sifo futhi zingaphansi kwengcindezi enkulu yezomnotho [2].
Amaphesenti angamashumi ayisishiyagalolunye ezilonda zomdlavuza we-colorectal zingasuswa ngokuhlinzwa, futhi uma isimila sitholakala ngokushesha, izinga lokusinda leminyaka emihlanu ngemva kokuhlinzwa kabusha, kodwa izinga lokubuyela emuva ngemva kokuhlinzwa kabusha lisengaba ngu-30%. Amazinga okusinda kweminyaka emihlanu omdlavuza we-colorectal kubantu baseShayina angama-90.1%, 72.6%, 53.8% kanye no-10.4% ezigabeni I, II, III kanye ne-IV, ngokulandelana.
Isifo esincane esisele (i-MRD) siyimbangela enkulu yokuphinda kuvele isimila ngemva kokwelashwa okukhulu. Eminyakeni yamuva nje, ubuchwepheshe bokuthola i-MRD yezimila eziqinile buthuthuke ngokushesha, futhi izifundo eziningana zokuhlola nokungenelela ezisindayo ziqinisekisile ukuthi isimo se-MRD sangemva kokuhlinzwa singabonisa ingozi yokuphinda kuvele umdlavuza we-colorectal ngemva kokuhlinzwa. Ukuhlolwa kwe-ctDNA kunezinzuzo zokuba okungahlaseli, okulula, okusheshayo, okufinyeleleka kakhulu kwesampula kanye nokunqoba ukungafani kwesimila.
Iziqondiso ze-US NCCN zomdlavuza wamathumbu amakhulu kanye neziqondiso ze-CSCO zaseShayina zomdlavuza wamathumbu amakhulu zithi ekunqumeni ingozi yokubuyela emuva ngemva kokuhlinzwa kanye nokukhethwa kwe-chemotherapy ehambisanayo kumdlavuza wamathumbu amakhulu, ukuhlolwa kwe-ctDNA kunganikeza ulwazi lokubikezela kanye nolwazi lokubikezela ukusiza ezinqumweni zokwelapha ezihambisanayo zeziguli ezine-cancer yamathumbu amakhulu yesigaba sesi-II noma sesi-III. Kodwa-ke, izifundo eziningi ezikhona zigxile ekuguqulweni kwe-ctDNA okusekelwe kubuchwepheshe bokulandelana kwe-high-throughput (NGS), obunenqubo eyinkimbinkimbi, isikhathi eside sokuhola, kanye nezindleko eziphakeme [3], ngokuntuleka okuncane kokujwayelekile kanye nokusabalala okuphansi phakathi kweziguli ezinomdlavuza.
Uma kwenzeka iziguli ezinomdlavuza we-colorectal esigabeni sesi-3, ukuqapha okunamandla kwe-ctDNA okusekelwe kwi-NGS kubiza kufika ku-$10,000 ngokuvakasha okukodwa futhi kudinga isikhathi sokulinda esingafika emavikini amabili. Ngokuhlolwa kwe-methylation yezakhi zofuzo eziningi kulolu cwaningo, i-ColonAiQ®, iziguli zingaba nokuqapha okunamandla kwe-ctDNA ngentengo yeshumi futhi zithole umbiko ezinsukwini ezimbili nje kuphela.
Ngokusho kwamacala amasha angu-560,000 omdlavuza we-colon eShayina minyaka yonke, iziguli ezithola umdlavuza we-colon osezingeni lesi-II kuya kwelesi-III (isilinganiso singama-70%) zinesidingo esiphuthumayo sokuqapha okunamandla, bese kuthi ubukhulu bemakethe yokuqapha okunamandla kwe-MRD komdlavuza we-colon bufinyelela izigidi zabantu minyaka yonke.
Kungabonakala ukuthi imiphumela yocwaningo inokubaluleka okubalulekile kwesayensi nokusebenzayo. Ngezifundo ezinkulu zezokwelapha ezilindelekile, kuqinisekisile ukuthi ubuchwepheshe be-methylation ye-multigene yegazi esekwe ku-PCR bungasetshenziswa ekubikezeleni ukuphinda komdlavuza we-colorectal kanye nokuqapha ukuphinda komdlavuza ngokuzwela, ngesikhathi kanye nokusebenza kahle kwezindleko, okwenza kangcono umuthi onembile uzuze iziguli eziningi zomdlavuza. Ucwaningo lusekelwe ku-ColonAiQ®, ukuhlolwa kwe-methylation yezakhi zofuzo eziningi komdlavuza we-colorectal okwakhiwe yi-KUNY, okunenani lokusetshenziswa kwayo emtholampilo ekuhlolweni nasekuxilongweni kwasekuqaleni okuqinisekiswe ucwaningo lwezokwelapha oluphakathi.
I-Gastroenterology (IF33.88), iphephabhuku elihamba phambili emhlabeni wonke emkhakheni wezifo zamathumbu ngo-2021, libike ngemiphumela yocwaningo olunezikhungo eziningi lwe-Zhongshan Hospital of Fudan University, i-Cancer Hospital of Fudan University kanye nezinye izikhungo zezokwelapha ezigunyaziwe ngokubambisana ne-KUNYAN Biological, okuqinisekisile ukusebenza okuhle kakhulu kwe-ColonAiQ® ChangAiQ® ekuhlolweni kwasekuqaleni nasekuxilongweni kwasekuqaleni komdlavuza we-colorectal, futhi ekuqaleni lihlole ukusetshenziswa okungenzeka ekuqapheni ukubikezela komdlavuza we-colorectal.

Ukuze kuqinisekiswe ukusetshenziswa kwemitholampilo kwe-ctDNA methylation ekuhlukaniseni izingozi, kuqondiswe izinqumo zokwelapha kanye nokuqapha ukuphinda kuvele umdlavuza we-colorectal wesigaba I-III, ithimba locwaningo lihlanganise iziguli ezingu-299 ezine-colorectal cancer yesigaba I-III ezahlinzwa kakhulu futhi zaqoqa amasampula egazi endaweni ngayinye yokulandelela (izinyanga ezintathu zihlukene) zingakapheli isonto elilodwa ngaphambi kokuhlinzwa, inyanga eyodwa ngemva kokuhlinzwa, kanye nokwelashwa kwe-adjuvant ngemva kokuhlinzwa kokuhlolwa kwe-ctDNA yegazi okunamandla.
Okokuqala, kwatholakala ukuthi ukuhlolwa kwe-ctDNA kungabikezela ingozi yokuphinda kuvele ezigulini ezinomdlavuza we-colonectal kusenesikhathi, kokubili ngaphambi kokuhlinzwa kanye nangaphambi kokuhlinzwa. Iziguli ezine-ctDNA yangaphambi kokuhlinzwa zazinethuba eliphezulu lokuphinda kuvele ngemva kokuhlinzwa kuneziguli ezine-ctDNA yangaphambi kokuhlinzwa (22.0% > 4.7%). Ukuhlolwa kwe-ctDNA yangaphambi kokuhlinzwa kwakusabikezela ingozi yokuphinda kuvele: inyanga eyodwa ngemuva kokususwa okunamandla, iziguli ezine-ctDNA zazinamathuba aphindwe ka-17.5 okuphinda kuvele kuneziguli ezine-negative; ithimba liphinde lathola ukuthi ukuhlolwa kwe-ctDNA kanye ne-CEA okuhlanganisiwe kuthuthukise kancane ukusebenza ekutholeni ukuphinda kuvele (AUC=0.849), kodwa umehluko wawungabalulekile uma kuqhathaniswa nokuhlolwa kwe-ctDNA (AUC=0.839) kuphela Umehluko wawungabalulekile uma kuqhathaniswa ne-ctDNA yodwa (AUC=0.839).
Ukuhlelwa kwesigaba semitholampilo kanye nezici eziyingozi njengamanje kuyisisekelo esiyinhloko sokuhlelwa kwezigaba zezingozi zeziguli zomdlavuza, futhi kulo mbono wamanje, inani elikhulu leziguli lisaphinde libuye [4], futhi kunesidingo esiphuthumayo samathuluzi angcono okuhlelwa kwezigaba njengoba ukwelashwa ngokweqile kanye nokwelashwa okungaphelele kuhambisana emtholampilo. Ngokusekelwe kulokhu, ithimba lihlukanise iziguli ezine-cancer ye-colorectal yesigaba sesi-3 zibe amaqembu amancane ahlukene ngokusekelwe ekuhlolweni kwengozi yokubuyela emuva kwezokwelapha (ingozi ephezulu (T4/ N2) kanye nengozi ephansi (T1-3N1)) kanye nesikhathi sokwelashwa kwe-adjuvant (izinyanga ezi-3/6). Ukuhlaziywa kuthole ukuthi iziguli eqenjini elincane leziguli ezine-ctDNA elinengozi ephezulu zazinezinga eliphansi lokubuyela emuva uma zithola ukwelashwa kwe-adjuvant izinyanga eziyisithupha; eqenjini elincane leziguli ezine-ctDNA elinengozi ephansi, kwakungekho mehluko omkhulu phakathi komjikelezo wokwelashwa kwe-adjuvant kanye nemiphumela yeziguli; kuyilapho iziguli ezine-ctDNA ezinengozi zazine-prognosis engcono kakhulu kuneziguli ezine-ctDNA kanye nesikhathi eside sokungasebenzi kabusha ngemva kokuhlinzwa (RFS); Isigaba I kanye nomdlavuza we-colorectal wesigaba II onengozi ephansi Zonke iziguli ezingenayo i-ctDNA azizange ziphinde zivele zingakapheli iminyaka emibili; ngakho-ke, ukuhlanganiswa kwe-ctDNA nezici zezokwelapha kulindeleke ukuthi kuthuthukise kakhulu ukuhlukaniswa kwezingozi futhi kubikezele kangcono ukuphinda kuvele.

Isithombe 1. Ukuhlaziywa kwe-plasma ctDNA ku-POM1 ukuze kutholakale kusenesikhathi umdlavuza we-colorectal uphinde ubuye
Imiphumela eyengeziwe yokuhlolwa kwe-dynamic ctDNA ibonise ukuthi ingozi yokuphinda ivele yayiphezulu kakhulu ezigulini ezine-positive dynamic ctDNA testing kunasezigulini ezine-negative ctDNA ngesikhathi sesigaba sokuqapha ukuphinda kwesifo ngemva kokwelashwa okuqondile (ngemuva kokuhlinzwa okukhulu + ukwelashwa okungeziwe) (Isithombe 3ACD), nokuthi i-ctDNA ingabonisa ukuphinda kwesifo kuze kube yizinyanga ezingu-20 ngaphambi kokuthatha izithombe (Isithombe 3B), okunikeza ithuba lokutholakala kusenesikhathi kokuphinda kwesifo kanye nokungenelela ngesikhathi.

Isithombe 2. Ukuhlaziywa kwe-ctDNA okusekelwe eqenjini elide ukuthola ukuphinda kuvele umdlavuza we-colorectal

"Inani elikhulu lezifundo zezokwelapha ezihunyushwayo kumdlavuza we-colonectal zihola emkhakheni, ikakhulukazi ukuhlolwa kwe-MRD okusekelwe ku-ctDNA kubonisa amandla amakhulu okuthuthukisa ukuphathwa kweziguli ezinomdlavuza we-colonectal ngemva kokuhlinzwa ngokuvumela ukuhlukaniswa kwezingozi zokuphinda kuvele, ukuqondisa izinqumo zokwelashwa kanye nokuqapha ukuphinda kuvele kusenesikhathi."

Inzuzo yokukhetha i-DNA methylation njengophawu olusha lwe-MRD kunokutholwa kokuguqulwa kwezakhi zofuzo ukuthi ayidingi ukuhlolwa kokulandelana kwezakhi zofuzo okuphelele kwezicubu zesimila, isetshenziswa ngqo ekuhlolweni kwegazi, futhi igwema imiphumela engamanga ngenxa yokutholakala kokuguqulwa kwezakhi zofuzo okuvela ezicutshini ezivamile, izifo ezingelapheki, kanye ne-clonal hematopoiesis.
Lolu cwaningo kanye nezinye izifundo ezihlobene nalo ziqinisekisa ukuthi ukuhlolwa kwe-MRD okusekelwe ku-ctDNA kuyisici esibaluleke kakhulu esizimele sengozi yokuphinda kuvele umdlavuza we-colorectal esigabeni I-III futhi kungasetshenziswa ukusiza ekuqondiseni izinqumo zokwelapha, okuhlanganisa "ukwanda" kanye "nokwehlisa" ukwelashwa kwe-adjuvant. I-MRD iyisici esibaluleke kakhulu esizimele sengozi yokuphinda kuvele ngemva kokuhlinzwa komdlavuza we-colorectal esigabeni I-III.
Insimu ye-MRD ishintsha ngokushesha ngezivivinyo eziningana ezintsha, ezizwela kakhulu futhi eziqondile ezisekelwe ku-epigenetics (i-DNA methylation kanye ne-fragmentomics) kanye ne-genomics (ukulandelana okuqondiswe kakhulu noma ukulandelana kwe-genome ephelele). Silindele ukuthi i-ColonAiQ® iqhubeke nokuhlela izifundo ezinkulu zezokwelapha futhi ingaba inkomba entsha yokuhlolwa kwe-MRD ehlanganisa ukufinyeleleka, ukusebenza okuphezulu kanye nokungabizi futhi ingasetshenziswa kabanzi emisebenzini yezokwelapha evamile.
Izinkomba
[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 Kwasekuqaleni Kwesifo Esisele Sama-Molecular kanye Nokuhlukaniswa Kwengozi Kwesigaba Sokuqala kuya Kwesi-III Somdlavuza We-Colorectal nge-Circulating Tumor DNA Methylation. I-JAMA Oncol. 2023 Ephreli 20.
[2] “Umthwalo wesifo somdlavuza we-colorectal kubantu baseShayina: ingabe ushintshile eminyakeni yamuva nje? , I-Chinese Journal of Epidemiology, uMqulu 41, No. 10, Okthoba 2020.
[3] Tarazona N, Gimeno-Valiente F, Gambardella V, et al. Uqondise ukulandelana kwesizukulwane esilandelayo kwe-DNA yesimila esijikelezayo ukuze kulandelwe izifo ezincane ezisele kumdlavuza wamathumbu wendawo. Ann Oncol. Nov 1, 2019;30(11):1804-1812.
[4] Taieb J, André T, Auclin E. Ukwelapha okungeziwe kokwelapha okungeyona i-metastatic colon cancer, amazinga amasha kanye nemibono. Cancer Treat Rev. 2019;75:1-11.