Ukuphonononga okulindelweyo: Itekhnoloji ye-PCR esekwe kwigazi le-ctDNA methylation ivula ixesha elitsha lokujongwa kwe-MRD kumhlaza webala.

Kungekudala, i-JAMA Oncology (IF 33.012) ipapashe umphumo obalulekileyo wophando [1] liqela likaProf Cai Guo-ring ovela kwiSibhedlele seCancer saseFudan University kunye noProf. Wang Jing ovela kwiSibhedlele saseRenji saseShanghai Jiao Tong School School of Medicine, ngokubambisana ne-KUNYUAN BIOLOGY: "Ukufunyanwa kwangaphambili kweSifo seMolekyuli kunye neSifo soMbala kwi-Cancer III Ukujikeleza i-Tumor DNA Methylation kunye ne-Risk Stratification) ". Olu phononongo luphononongo lokuqala lwe-multicenter kwihlabathi lokusebenzisa itekhnoloji yegazi esekwe kwi-PCR ye-CTDNA ye-multigene methylation yokuqikelela umhlaza we-colorectal kunye nokujongwa kwakhona, ukubonelela ngendlela yobugcisa eneendleko ezingaphezulu kunye nesisombululo xa kuthelekiswa neendlela ezikhoyo zetekhnoloji zokufumanisa i-MRD, ekulindeleke ukuba iphucule kakhulu ukusetyenziswa kweklinikhi yomhlaza we-colorectal kunye nokuphucula kakhulu ukuxela kwangaphambili kunye nokubeka iliso kwimpilo yesigulana. Olu phononongo luphinde lwavavanywa kakhulu yijenali kunye nabahleli bayo, kwaye lwadweliswa njengephepha lengcebiso ephambili kulo mba, kwaye uNjingalwazi uJuan Ruiz-Bañobre waseSpain kunye noNjingalwazi Ajay Goel waseUnited States bamenywa ukuba bawuphonononge. Uphononongo luphinde lwabikwa nguGenomeWeb, i-media ehamba phambili ye-biomedical e-United States.

Umhlaza weColorectal (CRC) lithumba elibi eliqhelekileyo lendlela yesisu eTshayina. I-2020 ye-Arhente yamazwe ngamazwe yoPhando lweCancer (IARC) idatha ibonisa ukuba i-555,000 yamatyala amatsha e-China i-akhawunti malunga ne-1 / 3 yehlabathi, kunye nezinga lokutsibela kwindawo yesibini ye-cancer eqhelekileyo e-China; I-286,000 yokusweleka ibalelwa malunga ne-1/3 yehlabathi, ibekwe njengeyesihlanu eyona nto ixhaphakileyo yokusweleka komhlaza eTshayina. Unobangela wesihlanu wokufa eTshayina. Kuyaphawuleka ukuba phakathi kwezigulane ezifunyenweyo, izigaba ze-TNM I, II, III kunye ne-IV ziyi-18.6%, 42.5%, 30.7% kunye ne-8.2% ngokulandelanayo. Ngaphezulu kwe-80% yezigulane ziphakathi kunye nezigaba zamva, kwaye i-44% yazo ine-metastases ekude ngexesha elinye okanye i-heterochronic kwisibindi nemiphunga, echaphazela kakhulu ixesha lokusinda, ibeka engozini impilo yabahlali bethu kwaye ibangele umthwalo onzima wentlalo kunye noqoqosho. Ngokwezibalo zeZiko loMhlaza leSizwe, ukunyuka okuqhelekileyo ngonyaka kwiindleko zonyango lomhlaza we-colorectal e-China malunga ne-6.9% ukuya kwi-9.2%, kunye nenkcitho yempilo yobuqu yezigulane kunyaka omnye wokuxilongwa kunokuthatha i-60% yengeniso yosapho. Izigulane zomhlaza ziphethwe sesi sifo kwaye ziphantsi koxinzelelo olukhulu lwezoqoqosho [2].
Amashumi alithoba eepesenti amanxeba omhlaza webala anokususwa ngotyando, kwaye okukhona ithumba libhaqwe kwangethuba, kokukhona liphezulu izinga lokusinda leminyaka emihlanu emva koqhaqho loqhaqho, kodwa izinga lokuphinda liphinde libekho emva koqhaqho lokuqhawuka lisemalunga nama-30%. Amazinga okusinda kweminyaka emihlanu yomhlaza we-colorectal kubantu baseTshayina yi-90.1%, 72.6%, 53.8% kunye ne-10.4% kwizigaba I, II, III kunye ne-IV, ngokulandelanayo.
Isifo esincinci se-residual (MRD) yimbangela enkulu yokuphindaphinda kwe-tumor emva konyango olunzulu. Kwiminyaka yakutshanje, itekhnoloji yokufumanisa i-MRD yee-tumors ezomeleleyo iqhubele phambili ngokukhawuleza, kwaye izifundo ezininzi zokujonga ubunzima kunye nokungenelela ziye zaqinisekisa ukuba imeko ye-MRD yangemva kokusebenza ingabonisa umngcipheko wokuphinda utyandwe umhlaza we-colorectal. Uvavanyo lwe-ctDNA lunoncedo lokungaxhaphakanga, lulula, lukhawuleza, kunye nofikelelo oluphezulu lwesampulu kunye nokoyisa i-tumor heterogeneity.
Izikhokelo ze-NCCN ze-US ze-colon cancer kunye nezikhokelo zaseTshayina zeCSCO zomhlaza we-colorectal zombini zixela ukuba ukumiselwa komngcipheko wokuphindaphinda kwasemva kotyando kunye nokukhethwa kwe-adjuvant chemotherapy kumhlaza wekoloni, uvavanyo lwe-ctDNA lunokubonelela ngeprognostic kunye nolwazi oluqikelelweyo ukunceda kwizigqibo zonyango lwe-adjuvant kwizigulana ezinenqanaba le-II okanye le-III lomhlaza wekoloni. Nangona kunjalo, uninzi lwezifundo ezikhoyo zijolise kutshintsho lwe-ctDNA olusekwe kwitekhnoloji yokulandelelanisa i-high-throughput (NGS), enenkqubo entsonkothileyo, ixesha elide lokukhokela, kunye neendleko eziphezulu [3], kunye nokunqongophala okuncinci kwe-generalizability kunye nokuxhaphaka okuphantsi phakathi kwezigulane ezinomhlaza.
Kwimeko yenqanaba le-III lezigulane ezinomhlaza we-colorectal, ukujongwa okuguquguqukayo kwe-NGS-based ctDNA kubiza ukuya kuthi ga kwi-10,000 yeedola kutyelelo olunye kwaye kufuna ixesha lokulinda ukuya kwiiveki ezimbini. Ngovavanyo lwe-multigene methylation kolu phononongo, i-ColonAiQ®, izigulana zinokuba nokujongwa okuguquguqukayo kwe-ctDNA kwisahlulo seshumi seendleko kwaye zifumana ingxelo ngeentsuku nje ezimbini.
Ngokweemeko ezitsha ezingama-560,000 zomhlaza we-colorectal e-China minyaka le, izigulana zeklinikhi ubukhulu becala ezinenqanaba le-II-III lomhlaza webala (umyinge umalunga nama-70%) zinemfuno engxamisekileyo yokubeka iliso okuguquguqukayo, emva koko ubungakanani bentengiso ye-MRD yokubeka iliso eguquguqukayo yomhlaza we-colorectal ifikelela kwizigidi zabantu nyaka ngamnye.
Kungabonwa ukuba iziphumo zophando zinokubaluleka okubalulekileyo kwenzululwazi kunye nokusebenzayo. Ngezifundo zeklinikhi ezinkulu ezilindelekileyo, kuye kwaqinisekisa ukuba itekhnoloji ye-PCR-based ctDNA multigene methylation ingasetyenziselwa uqikelelo lokuphindaphinda komhlaza kunye nokuhlolwa okuphindayo kunye nobuntununtunu, ixesha kunye nokusebenza kakuhle kweendleko, ukwenza ngcono amayeza achanekileyo ukuba axhamle ngakumbi izigulane ezinomhlaza. Uphononongo lusekelwe kwi-ColonAiQ®, uvavanyo lwe-methylation ye-multi-gene yomhlaza we-colorectal ophuhliswe ngu-KUNY, ixabiso lesicelo seklinikhi ekuhlolweni kwangaphambili kunye nokuxilongwa kuye kwaqinisekiswa ngophando oluphakathi lwekliniki.
I-Gastroenterology (IF33.88), iphephancwadi eliphezulu lamazwe ngamazwe kwinkalo yezifo zesisu kwi-2021, ibike iziphumo zophando ezininzi zeSibhedlele saseZhongshan saseFudan University, iSibhedlele seCancer seYunivesithi yaseFudan kunye namanye amaziko onyango agunyazisiweyo ngokubambisana ne-KUNYAN Biological, eqinisekisile ukusebenza kakuhle kweColonAiQ® ChangAiQ® ChangAiQd ukuxilongwa komhlaza kunye nokuphonononga ukuxilongwa kwangaphambili komhlaza kunye nokuxilongwa kwangaphambili komhlaza. kwakhona iphonononga isicelo esinokubakho ekujongweni kwe-prognosis yomhlaza wesisu.

Ukuqinisekisa ngakumbi ukusetyenziswa kweklinikhi ye-ctDNA methylation kwi-stratification yomngcipheko, izigqibo ezikhokelayo zonyango kunye nokujongwa kwakhona kwangethuba kwinqanaba le-I-III lomhlaza we-colorectal, iqela lophando libandakanya izigulane ze-299 ezinesigaba se-I-III somhlaza we-cancer owenziwe utyando olukhulu kwaye waqokelela iisampulu zegazi kwindawo nganye yokulandelela (iinyanga ezintathu ezihlukeneyo, utyando oluhlukeneyo, kwisithuba senyanga enye emva kotyando, emva kweveki enye emva kotyando). uvavanyo lwegazi lwe-ctDNA oluguqukayo.
Okokuqala, kwafunyaniswa ukuba uvavanyo lwe-ctDNA lunokuqikelela umngcipheko wokuphinda ubekho kwizigulana ezinomhlaza we-colorectal kwangethuba, phambi koqhaqho kwangethuba. Izigulane ezine-ctDNA yangaphambi kotyando zazinethuba eliphezulu lokuphinda uqhaqho emva kotyando kunezigulane ezingenayo i-ctDNA-negative (22.0%> 4.7%). Uvavanyo lwe-ctDNA lwangethuba lwasemva kotyando lusaxela kwangaphambili umngcipheko wokuphinda ubuyele: kwinyanga enye emva koqhaqho oluqilima, izigulane ezine-ctDNA ezine-ctDNA zazinamathuba angama-17.5 okuba ziphinde zenzeke kunezigulana ezingalunganga; iqela liphinde lafumanisa ukuba uvavanyo oludibeneyo lwe-ctDNA kunye ne-CEA luphucule kancinci ukusebenza ekufumaneni ukuphindaphinda (AUC=0.849), kodwa umahluko wawungabalulekanga xa kuthelekiswa novavanyo lwe-ctDNA (AUC=0.839) yodwa Umahluko wawungabalulekanga xa kuthelekiswa ne-ctDNA yodwa (AUC=0.839).
Isiteji seklinikhi esidityaniswe nezinto ezinobungozi okwangoku sisiseko esisisiseko somngcipheko wezigulane zomhlaza, kwaye kwi-paradigm yangoku, inani elikhulu lezigulane lisaphinda libuyele [4], kwaye kukho imfuneko engxamisekileyo yezixhobo ezingcono ze-stratification njengoko unyango olugqithisileyo kunye nonyango olungaphantsi luhlala ekliniki. Ngokusekelwe kule nto, iqela lahlula izigulane ezinesigaba se-III somhlaza we-colorectal zibe ngamacandelo ahlukeneyo ngokusekelwe kuvavanyo lomngcipheko wokuphindaphinda kweklinikhi (umngcipheko ophezulu (T4 / N2) kunye nomngcipheko ophantsi (T1-3N1)) kunye nexesha lonyango lwe-adjuvant (iinyanga ezi-3 / 6). Uhlalutyo lufumene ukuba izigulane kwi-subgroups yengozi ye-ctDNA-positive izigulane zinezinga eliphantsi lokuphindaphinda ukuba zifumana iinyanga ezintandathu zonyango lwe-adjuvant; kwi-subgroup-risk subgroup yezigulane ezine-ctDNA-positive, kwakungekho mmahluko omkhulu phakathi komjikelo wonyango we-adjuvant kunye neziphumo zesigulane; ngelixa izigulane ezine-ctDNA-negative zine-prognosis engcono kakhulu kunezigulane ezine-ctDNA-positive kunye nexesha elide lasemva kotyando lokuphindaphinda-free (RFS); Inqanaba I kunye nenqanaba lomngcipheko ophantsi we-II womhlaza we-colorectal Zonke izigulane ezingenayo i-ctDNA azizange ziphinde zivele kwiminyaka emibini; ke ngoko, ukudityaniswa kwe-ctDNA kunye neempawu zeklinikhi kulindeleke ukuba kuphuculwe ngakumbi ukucwangciswa komngcipheko kunye nokuqikelela ngcono ukuphindaphinda.

Umzobo 1. Uhlalutyo lwe-Plasma ctDNA kwi-POM1 yokufunyaniswa kwangoko kokuphindaphinda komhlaza we-colorectal
Iziphumo ezongezelelweyo zovavanyo lwe-ctDNA oluguquguqukayo lubonise ukuba umngcipheko wokuphindaphinda uphezulu kakhulu kwizigulana ezinovavanyo lwe-ctDNA oluguquguqukayo kunezigulana ezine-ctDNA engalunganga ngexesha lesigaba sokuhlola ukuphinda isifo emva konyango oluqinisekileyo (emva kotyando olukhulu + nonyango lwe-adjuvant) (Umzobo 3ACD), kwaye ukuba i-ctDNA ingabonisa ukuba kunokwenzeka ukuvela kwe-tumor ngaphambi kweenyanga ezingama-20 (i-Figure 3ACD) ukuphindaphinda kunye nokungenelela ngexesha.

Umzobo 2. Uhlalutyo lwe-ctDNA olusekwe kwi-longitudinal cohort ukufumanisa ukuphindaphinda komhlaza we-colorectal

“Inani elikhulu lezifundo zeyeza loguqulo kumhlaza womhlaza zikhokelela elululekweni, ngakumbi uvavanyo lwe-MRD olusekwe kwi-ctDNA lubonisa amandla amakhulu okuphucula ulawulo lwasemva kotyando lwezigulane ezinomhlaza ngokuvumela ukuphinda kuvele umngcipheko, izigqibo ezikhokelayo zonyango kunye nokujongwa kwakhona kwangethuba.

Inzuzo yokukhetha i-DNA methylation njengenoveli ye-MRD marker phezu kokufunyanwa kokuguqulwa kwenguqu kukuba ayifuni ukuhlolwa kwe-genome yonke ngokulandelelana kwezicubu ze-tumor, isetyenziselwa ngokuthe ngqo ukuvavanywa kwegazi, kwaye igweme iziphumo ezingezizo zobuxoki ngenxa yokufumanisa ukuguqulwa kwe-somatic okuvela kwizicubu eziqhelekileyo, izifo ze-benign, kunye ne-clonal hematopoiesis.
Olu pho nonongo kunye nezinye izifundo ezinxulumeneyo ziqinisekisa ukuba uvavanyo lwe-MRD olusekelwe kwi-ctDNA yeyona nto ibalulekileyo yomngcipheko ozimeleyo wokuphindaphinda isigaba se-I-III somhlaza we-colorectal kwaye ingasetyenziselwa ukukhokela izigqibo zonyango, kuquka "ukunyuka" kunye "nokwehliswa" kwe-adjuvant therapy i-MRD yeyona nto ibalulekileyo yomngcipheko ozimeleyo wokuphindaphinda emva kotyando kwisigaba I-III somhlaza we-colorectal.
Intsimi ye-MRD ikhula ngokukhawuleza kunye nenani lezinto ezintsha, ezinovelwano kunye novavanyo oluthile olusekelwe kwi-epigenetics (i-DNA methylation kunye ne-fragmentomics) kunye ne-genomics (i-ultra-deep targeting sequencing okanye i-genome sequencing). Silindele ukuba i-ColonAiQ® iqhubeke nokuququzelela izifundo zeklinikhi ezinkulu kwaye inokuba sisalathisi esitsha sovavanyo lwe-MRD oludibanisa ukufikeleleka, ukusebenza okuphezulu kunye nokufikeleleka kwaye inokusetyenziswa ngokubanzi kwiinkqubo zesiqhelo zeklinikhi. "
Iimbekiselo
[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. Ukufunyaniswa kwangaphambili kweSifo seMolekyuli kunye neSicwangciso soMngcipheko kwiSigaba I ukuya kwi-III yoMhlaza weColorectal nge-DNA Circulating. JAMA Oncol. 2023 Epreli 20.
[2] “Umthwalo wesifo somhlaza wesisu kubantu baseTshayina: ngaba utshintshile kwiminyaka yakutshanje? , Ijenali yaseTshayina ye-Epidemiology, uMqulu 41, No.
[3] Tarazona N, Gimeno-Valiente F, Gambardella V, et al. Ulandelelwano olujoliswe kwisizukulwana esilandelayo se-DNA ye-tumor ejikelezayo yokulandelela isifo esincinci esishiyekileyo kumhlaza wekoloni. Ann Oncol. Nov 1, 2019;30(11):1804-1812.
[4] Taieb J, André T, Auclin E. Ukucokisa unyango lwe-adjuvant for non-metastatic colon cancer, imigangatho emitsha kunye nemibono. Unyango lweCancer Rev. 2019;75:1-11.