Uphando oluzayo: Itekhnoloji ye-methylation yegazi esekwe kwi-PCR ivula ixesha elitsha lokujonga umhlaza we-colorectal kwi-MRD

Kutshanje, i-JAMA Oncology (IF 33.012) ipapashe iziphumo zophando ezibalulekileyo [1] liqela likaNjingalwazi uCai Guo-ring waseSibhedlele soMhlaza kwiYunivesithi yaseFudan kunye noNjingalwazi uWang Jing waseSibhedlele saseRenji saseShanghai Jiao Tong University School of Medicine, ngokubambisana ne-KUNYUAN BIOLOGY: “Ukufunyaniswa kwangethuba kweSifo esiNcinci seMolekyuli kunye nokuHlukana koMngcipheko kwiSigaba soku-1 ukuya kwesesi-3 soMhlaza weColorectal nge-Circulating Tumor DNA Methylation kunye nokuHlukana koMngcipheko)”. Olu phononongo luphononongo lokuqala oluneziko ezininzi kwihlabathi lonke olusebenzisa itekhnoloji ye-methylation yegazi esekwe kwi-PCR ye-ctDNA multigene yokuqikelela ukuphinda kuvele umhlaza we-colorectal kunye nokujonga ukuphinda kuvele umhlaza, olubonelela ngendlela yobugcisa nesisombululo esingabizi kakhulu xa kuthelekiswa neendlela zobuchwepheshe bokufumanisa i-MRD ezikhoyo, okulindeleke ukuba kuphucule kakhulu ukusetyenziswa kweklinikhi kokuqikelela ukuphinda kuvele umhlaza we-colorectal, kwaye kuphucule kakhulu ukusinda kwesigulana kunye nomgangatho wobomi. Olu phononongo lukwavavanywe kakhulu yijenali kunye nabahleli bayo, kwaye ludweliswe njengephepha eliphambili leengcebiso kule phephancwadi, kwaye uNjingalwazi uJuan Ruiz-Bañobre waseSpain kunye noNjingalwazi uAjay Goel waseMelika bamenywa ukuba baluhlolisise. Olu phononongo lukwaxelwe yiGenomeWeb, ijenali ephambili yezonyango eMelika.

Umhlaza weColorectal (CRC) sisisu esibi esixhaphakileyo kwindlela yamathumbu eTshayina. Idatha ye-International Agency for Research on Cancer (IARC) ka-2020 ibonisa ukuba amatyala amatsha angama-555,000 eTshayina amalunga ne-1/3 yehlabathi, kunye nezinga lokwanda kwesifo linyuka liye kwindawo yesibini yomhlaza oxhaphakileyo eTshayina; ukufa okungama-286,000 kuhlanganisa malunga ne-1/3 yehlabathi, kubekwa njengesizathu sesihlanu esixhaphakileyo sokufa komhlaza eTshayina. Isizathu sesihlanu sokufa eTshayina. Kuyaphawuleka ukuba phakathi kwezigulana ezichongiweyo, izigaba ze-TNM I, II, III kunye ne-IV ziyi-18.6%, 42.5%, 30.7% kunye ne-8.2% ngokulandelelana. Ngaphezulu kwe-80% yezigulana zikwinqanaba eliphakathi nelisemva, kwaye ama-44% azo ane-metastases ekude ngaxeshanye okanye engaphelelanga ukuya kwisibindi nemiphunga, ezichaphazela kakhulu ixesha lokusinda, zibeka impilo yabemi bethu emngciphekweni kwaye zibangele umthwalo onzima kwezentlalo nakwezoqoqosho. Ngokwezibalo zeZiko leSizwe loMhlaza, ukunyuka okuqhelekileyo kweendleko zonyango lomhlaza wesisu eTshayina malunga ne-6.9% ukuya kwi-9.2%, kwaye iindleko zempilo zomntu ngamnye zezigulana kunyaka omnye emva kokufunyaniswa zingathatha i-60% yengeniso yosapho. Izigulana zomhlaza zihlushwa sesi sifo kwaye ziphantsi koxinzelelo olukhulu lwezoqoqosho [2].
Amashumi alithoba ekhulwini ezilonda zomhlaza we-colorectal zinokususwa ngotyando, kwaye okukhona ithumba lifunyanwa kwangoko, kokukhona izinga lokusinda kwiminyaka emihlanu emva kotyando olukhulu, kodwa izinga lokuphinda libuye emva kotyando olukhulu lisemalunga nama-30%. Amanqanaba okusinda kweminyaka emihlanu yomhlaza we-colorectal kubemi baseTshayina angama-90.1%, 72.6%, 53.8% kunye ne-10.4% kwizigaba I, II, III kunye ne-IV, ngokwahlukeneyo.
Isifo esincinci esisele (MRD) sisizathu esikhulu sokubuyela kwesi sifo emva konyango olukhulu. Kwiminyaka yakutshanje, ubuchwepheshe bokufumanisa i-MRD kwiithumba eziqinileyo buhambele phambili ngokukhawuleza, kwaye izifundo ezininzi zokujonga nokungenelela ziqinisekisile ukuba imeko ye-MRD emva kotyando inokubonisa umngcipheko wokubuyela kwesi sifo emva kotyando. Uvavanyo lwe-ctDNA luneengenelo zokuba aluhlaseli, lulula, lukhawuleza, lufikeleleka kakhulu kwisampulu kwaye loyise ukungafani kwethumba.
Izikhokelo ze-US NCCN zomhlaza wamathumbu amakhulu kunye nezikhokelo ze-CSCO zaseTshayina zomhlaza wamathumbu amakhulu zombini zithi ekumiselweni komngcipheko wokubuyela emva kotyando kunye nokukhetha i-chemotherapy encedisayo kumhlaza wamathumbu amakhulu, uvavanyo lwe-ctDNA lunokubonelela ngolwazi lokuxela kwangaphambili kunye nokuqikelela ukunceda kwizigqibo zonyango oluncedisayo kwizigulana ezine-stage II okanye III cancer yamathumbu amakhulu. Nangona kunjalo, uninzi lwezifundo ezikhoyo zigxile kwi-ctDNA mutations esekelwe kwi-high-throughput sequencing technology (NGS), enenkqubo enzima, ixesha elide, kunye neendleko eziphezulu [3], kunye nokungabikho kancinci kokuqheleka kunye nokuxhaphaka okuncinci phakathi kwezigulana ezinomhlaza.
Kwimeko yezigulane ezine-stage III yomhlaza we-colorectal, ukubekwa kweliso elinamandla le-ctDNA elisekelwe kwi-NGS kubiza ukuya kuthi ga kwi-$10,000 kutyelelo olunye kwaye kufuna ixesha lokulinda ukuya kuthi ga kwiiveki ezimbini. Ngovavanyo lwe-multigene methylation kolu phononongo, iColonAiQ®, izigulana zinokuba nokubekwa kweliso elinamandla le-ctDNA ngexabiso eliphantsi kweshumi kwaye zifumane ingxelo kwiintsuku nje ezimbini.
Ngokwezibalo ezintsha ezingama-560,000 zomhlaza we-colorectal eTshayina minyaka le, izigulane zonyango ikakhulu ezine-grade II-III colorectal cancer (umlinganiselo umalunga nama-70%) zifuna kakhulu ukubekwa esweni okunamandla, ngoko ke ubungakanani bemarike yokubekwa esweni okunamandla kwe-MRD yomhlaza we-colorectal bufikelela kwizigidi zabantu minyaka le.
Kuyabonakala ukuba iziphumo zophando zibaluleke kakhulu kwezenzululwazi nangokwemisebenzi. Ngezifundo ezinkulu zeklinikhi ezilindelekileyo, iqinisekisile ukuba iteknoloji ye-methylation ye-ctDNA ye-multigene yegazi esekwe kwi-PCR ingasetyenziselwa ukuqikelela ukuphinda kuvele umhlaza we-colorectal kunye nokujonga ukuphinda kuvele umhlaza ngobuchule, ngexesha elifanelekileyo kunye nokusebenza kakuhle kweendleko, okwenza ukuba amayeza achanekileyo ancede ngakumbi izigulane ezininzi ezinomhlaza. Olu phononongo lusekelwe kwiColonAiQ®, uvavanyo lwe-methylation ye-multi-gene yomhlaza we-colorectal oluphuhliswe yi-KUNY, enexabiso lesicelo sayo seklinikhi ekuhlolweni kwangethuba kunye nokuxilongwa okuqinisekisiweyo luphando lweklinikhi oluphakathi.
I-Gastroenterology (IF33.88), ijenali ephambili yamazwe ngamazwe kwicandelo lezifo zesisu ngo-2021, ibike iziphumo zophando oluneendawo ezininzi zeSibhedlele saseZhongshan kwiYunivesithi yaseFudan, iSibhedlele soMhlaza kwiYunivesithi yaseFudan kunye nezinye iziko zonyango ezigunyazisiweyo kunye ne-KUNYAN Biological, eqinisekisile ukusebenza okugqwesileyo kweColonAiQ® ChangAiQ® ekuhlolweni kwangethuba kunye nokuxilongwa kwangethuba komhlaza we-colorectal, kwaye ekuqaleni ihlolisise i-Ikwaphonononga ukusetyenziswa okunokwenzeka ekujongeni umhlaza we-colorectal.

Ukuqinisekisa ngakumbi ukusetyenziswa kwe-ctDNA methylation kwi-rathification yomngcipheko, ukukhokela izigqibo zonyango kunye nokujonga ukuphinda kuvele kwakhona kwi-I-III colorectal cancer, iqela lophando liquke izigulane ezingama-299 ezine-I-III colorectal cancer ezatyandwa kakhulu kwaye zaqokelela iisampulu zegazi kwindawo nganye yokulandelela (iinyanga ezintathu ngokwahlukeneyo) kwiveki enye ngaphambi kotyando, inyanga emva kotyando, kunye nonyango lwe-adjuvant emva kotyando lovavanyo lwe-dynamic blood ctDNA.
Okokuqala, kwafunyaniswa ukuba uvavanyo lwe-ctDNA lunokuqikelela umngcipheko wokuphinda ubuye kwizigulane ezinomhlaza we-colorectal kwangethuba, kokubini ngaphambi kotyando nasemva kotyando. Izigulane ezine-ctDNA ngaphambi kotyando zazinethuba eliphezulu lokuphinda ubuye emva kotyando kunezigulane ezine-ctDNA ngaphambi kotyando (22.0% > 4.7%). Uvavanyo lwe-ctDNA emva kotyando lwangethuba lwalusaxela umngcipheko wokuphinda ubuye: inyanga emva kokususwa kwe-radical, izigulane ezine-ctDNA zazinamathuba angama-17.5 okuphinda ubuye kunezigulane ezine-negative; iqela likwafumanise ukuba uvavanyo lwe-ctDNA kunye ne-CEA oludibeneyo luphucule kancinci ukusebenza ekufumaneni ukuphinda ubuye (AUC=0.849), kodwa umahluko wawungabalulekanga xa kuthelekiswa novavanyo lwe-ctDNA (AUC=0.839) lodwa Umahluko wawungabalulekanga xa kuthelekiswa ne-ctDNA yodwa (AUC=0.839).
Ukubekwa kwinqanaba leklinikhi kunye nezinto ezinobungozi okwangoku sisiseko esiphambili sokwahlulwahlulwa komngcipheko wezigulane ezinomhlaza, kwaye kwimeko yangoku, inani elikhulu lezigulane lisaphinda libuye [4], kwaye kukho imfuneko engxamisekileyo yezixhobo ezingcono zokwahlulahlula njengoko unyango olugqithisileyo kunye nonyango olungaphelelanga zikho kwikliniki. Ngokusekelwe koku, iqela lahlulahlula izigulane ezinesigaba sesi-3 somhlaza we-colorectal zibe ngamaqela ahlukeneyo ngokusekelwe kuvavanyo lomngcipheko wokuphinda ubuye kwiklinikhi (umngcipheko ophezulu (T4/ N2) kunye nomngcipheko ophantsi (T1-3N1)) kunye nexesha lonyango oluncedisayo (iinyanga ezi-3/6). Uhlalutyo lufumanise ukuba izigulane ezikwiqela elincinci lezigulane ezine-ctDNA ezinomngcipheko ophezulu zinezinga eliphantsi lokuphinda ubuye ukuba zifumene unyango oluncedisayo lweenyanga ezintandathu; kwiqela elincinci lezigulane ezine-ctDNA ezinomngcipheko ophantsi, bekungekho mahluko ubalulekileyo phakathi komjikelo wonyango oluncedisayo kunye neziphumo zesigulane; ngelixa izigulane ezine-ctDNA ezingenayo zine-prognosis engcono kakhulu kunezigulane ezine-ctDNA kunye nexesha elide emva kotyando elingenakuphinda ubuye (RFS); Isigaba I kunye nesigaba II somhlaza we-colorectal esinomngcipheko ophantsi Zonke izigulane ezingenayo i-ctDNA azizange ziphinde zibuye kwisithuba seminyaka emibini; ke ngoko, ukuhlanganiswa kwe-ctDNA kunye neempawu zonyango kulindeleke ukuba kuphucule ngakumbi ukwahlulwahlulwa komngcipheko kwaye kuqikelele ngcono ukuphinda kubuye.

Umfanekiso 1. Uhlalutyo lwe-plasma ctDNA kwi-POM1 ukuze kufunyanwe kwangethuba ukuphinda kuvele umhlaza we-colorectal
Iziphumo ezongezelelweyo zovavanyo lwe-ctDNA olunamandla zibonise ukuba umngcipheko wokubuyela umva wawuphezulu kakhulu kwizigulane ezine-ctDNA eguquguqukayo echanekileyo kunakwizigulane ezine-ctDNA engalunganga ngexesha lesigaba sokujonga ukubuyela umva kwesifo emva konyango oluqinisekileyo (emva kotyando olukhulu + unyango oluncedisayo) (Umfanekiso 3ACD), kwaye i-ctDNA inokubonisa ukubuyela umva kwethumba ukuya kuthi ga kwiinyanga ezingama-20 ngaphambi komfanekiso (Umfanekiso 3B), nto leyo enika ithuba lokubonwa kwangoko kokubuyela umva kwesifo kunye nokungenelela ngexesha elifanelekileyo.

Umfanekiso 2. Uhlalutyo lwe-ctDNA olusekelwe kwi-longitudinal cohort ukufumanisa ukuphinda kuvele umhlaza we-colorectal

"Inani elikhulu lezifundo zonyango oluguqulelweyo kumhlaza we-colorectal zikhokela kwicandelo, ingakumbi uvavanyo lwe-MRD olusekelwe kwi-ctDNA lubonisa amandla amakhulu okuphucula ulawulo lwezigulane zomhlaza we-colorectal emva kotyando ngokuvumela ukwahlulwahlulwa komngcipheko wokubuyela kwesi sifo, ukukhokela izigqibo zonyango kunye nokubeka esweni kwangethuba ukuphinda isifo."

Inzuzo yokukhetha i-DNA methylation njengophawu olutsha lwe-MRD kunokufumanisa utshintsho kukuba ayifuni ukuhlolwa kwe-genome sequencing epheleleyo yezicubu ze-tumor, isetyenziselwa ngqo uvavanyo lwegazi, kwaye ithintela iziphumo ezingezizo ezilungileyo ngenxa yokufumanisa utshintsho lwe-somatic oluvela kwizicubu eziqhelekileyo, izifo ezingezizo, kunye ne-clonal hematopoiesis.
Olu phononongo kunye nezinye izifundo ezinxulumene noko ziqinisekisa ukuba uvavanyo lwe-MRD olusekelwe kwi-ctDNA yeyona nto ibalulekileyo emele umngcipheko wokubuyela kwakhona komhlaza we-colorectal kwinqanaba I-III kwaye lunokusetyenziswa ukunceda ekukhokeleni izigqibo zonyango, kubandakanya "ukwanda" kunye "nokunciphisa" unyango oluncedisayo I-MRD yeyona nto ibalulekileyo emele umngcipheko wokubuyela kwakhona emva kotyando lomhlaza we-colorectal kwinqanaba I-III.
Intsimi ye-MRD itshintsha ngokukhawuleza ngenani lee-assays ezintsha, ezinobukrelekrele kakhulu nezithile ezisekelwe kwi-epigenetics (i-DNA methylation kunye ne-fragmentomics) kunye ne-genomics (ulandelelwano olujolise kakhulu okanye ulandelelwano lwe-genome epheleleyo). Silindele ukuba iColonAiQ® iqhubeke nokuququzelela izifundo ezinkulu zeklinikhi kwaye ingaba luphawu olutsha lovavanyo lwe-MRD oludibanisa ukufikeleleka, ukusebenza okuphezulu kunye nokufikeleleka kwaye lungasetyenziswa kakhulu kwimisebenzi yeklinikhi eqhelekileyo.
Iireferensi
[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. Ukufunyanwa Kwangethuba Kwesifo Esisele SeeMolecular kunye Nokuhlukaniswa Komngcipheko kwiSigaba soku-1 ukuya kwesesi-3 seColorectal Cancer nge-Circulating Tumor DNA Methylation. JAMA Oncol. 2023 Epreli 20.
[2] “Umthwalo wesifo somhlaza we-colorectal kubemi baseTshayina: ngaba utshintshile kwiminyaka yakutshanje? , Ijenali yaseTshayina ye-Epidemiology, uMqulu 41, No. 10, Okthobha 2020.
[3] Tarazona N, Gimeno-Valiente F, Gambardella V, et al. Ujolise kwisizukulwana esilandelayo sokulandelela isifo esincinci esisele kumhlaza wamathumbu amakhulu. Ann Oncol. Novemba 1, 2019;30(11):1804-1812.
[4] Taieb J, André T, Auclin E. Ukuhlaziya unyango oluncedisayo lomhlaza wamathumbu angaphantsi kwe-metastatic, imigangatho emitsha kunye neembono. Cancer Treat Rev. 2019;75:1-11.