Kev tshawb nrhiav yav tom ntej: PCR-based ntshav ctDNA methylation technology qhib lub sijhawm tshiab ntawm MRD kev saib xyuas rau mob qog noj ntshav colorectal

Tsis ntev los no, JAMA Oncology (IF 33.012) tau tshaj tawm cov txiaj ntsig tshawb fawb tseem ceeb [1] los ntawm pab pawg ntawm Prof. Cai Guo-ring los ntawm Cancer Hospital ntawm Fudan University thiab Prof. Wang Jing los ntawm Renji Hospital ntawm Shanghai Jiao Tong University School of Medicine, koom tes nrog KUNYUAN BIOLOGY: "Kev Tshawb Pom Thaum Ntxov ntawm Molecular Residual Disease thiab Risk Stratification rau Theem I txog III Colorectal Cancer ntawm Circulating Tumor DNA Methylation thiab Risk Stratification)". Kev tshawb fawb no yog thawj zaug kev tshawb fawb ntau lub chaw hauv ntiaj teb los siv PCR-based ntshav ctDNA multigene methylation technology rau kev kwv yees rov qab mob qog noj ntshav colorectal thiab kev saib xyuas rov qab, muab txoj hauv kev thiab kev daws teeb meem zoo dua piv rau cov txheej txheem MRD nrhiav pom uas twb muaj lawm, uas xav tias yuav txhim kho kev siv tshuaj kho mob ntawm kev kwv yees rov qab mob qog noj ntshav colorectal thiab kev saib xyuas, thiab txhim kho kev ciaj sia ntawm tus neeg mob thiab lub neej zoo. Txoj kev tshawb fawb no kuj tau raug soj ntsuam zoo los ntawm phau ntawv xov xwm thiab nws cov neeg kho, thiab tau teev tseg ua ib daim ntawv tseem ceeb hauv tsab ntawv no, thiab Xibfwb Juan Ruiz-Bañobre los ntawm Spain thiab Xibfwb Ajay Goel los ntawm Tebchaws Meskas tau raug caw tuaj tshuaj xyuas nws. Txoj kev tshawb fawb no kuj tau tshaj tawm los ntawm GenomeWeb, ib lub koom haum xov xwm biomedical hauv Tebchaws Meskas.

Mob qog noj ntshav hauv plab hnyuv (CRC) yog ib hom mob qog noj ntshav phem uas feem ntau tshwm sim hauv Suav teb. Cov ntaub ntawv los ntawm Lub Chaw Tshawb Fawb Txog Mob Qog Noj Ntshav Thoob Ntiaj Teb xyoo 2020 (IARC) qhia tias muaj 555,000 tus neeg mob tshiab hauv Suav teb uas yog li ntawm 1/3 ntawm lub ntiaj teb, thiab tus nqi ntawm tus kab mob no nce mus rau qib thib ob ntawm cov mob qog noj ntshav uas feem ntau tshwm sim hauv Suav teb; muaj 286,000 tus neeg tuag uas yog li ntawm 1/3 ntawm lub ntiaj teb, thiab yog qhov thib tsib ua rau neeg tuag los ntawm mob qog noj ntshav hauv Suav teb. Qhov thib tsib ua rau neeg tuag hauv Suav teb. Nws yog ib qho tseem ceeb uas cov neeg mob uas tau kuaj pom tias muaj mob qog noj ntshav, theem TNM I, II, III thiab IV yog 18.6%, 42.5%, 30.7% thiab 8.2%. Ntau tshaj 80% ntawm cov neeg mob nyob rau theem nruab nrab thiab theem kawg, thiab 44% ntawm lawv muaj cov qog noj ntshav sib kis mus rau daim siab thiab lub ntsws tib lub sijhawm lossis heterochronic, uas ua rau lub sijhawm muaj sia nyob tsis zoo, ua rau muaj kev phom sij rau kev noj qab haus huv ntawm peb cov neeg nyob hauv thiab ua rau muaj kev nyuaj siab rau kev sib raug zoo thiab kev lag luam. Raws li cov ntaub ntawv ntawm National Cancer Center, qhov nruab nrab txhua xyoo nce nqi kho mob qog noj ntshav hauv Suav teb yog li ntawm 6.9% txog 9.2%, thiab cov nqi kho mob ntawm cov neeg mob hauv ib xyoos ntawm kev kuaj mob tuaj yeem siv txog 60% ntawm cov nyiaj tau los hauv tsev neeg. Cov neeg mob qog noj ntshav raug kev txom nyem los ntawm tus kab mob thiab kuj nyob hauv kev nyuaj siab ntawm kev lag luam [2].
Cuaj caum feem pua ​​ntawm cov qog nqaij hlav ntawm txoj hnyuv loj tuaj yeem raug phais tshem tawm, thiab thaum ntxov pom cov qog nqaij hlav, qhov feem pua ​​​​​​ntawm kev ciaj sia tsib xyoos tom qab phais mob hnyav dua, tab sis qhov feem pua ​​​​​​ntawm kev rov tshwm sim tom qab phais mob hnyav tseem yog li 30%. Cov feem pua ​​​​​​ntawm kev ciaj sia tsib xyoos ntawm mob qog nqaij hlav ntawm txoj hnyuv loj hauv cov pej xeem Suav yog 90.1%, 72.6%, 53.8% thiab 10.4% rau theem I, II, III thiab IV, raws li.
Kab mob tsawg kawg nkaus (MRD) yog ib qho ua rau mob qog rov qab los tom qab kev kho mob hnyav. Nyob rau xyoo tas los no, kev siv tshuab MRD los nrhiav cov qog khov kho tau nce qib sai heev, thiab ntau qhov kev tshawb fawb soj ntsuam thiab kev cuam tshuam hnyav tau lees paub tias qhov xwm txheej MRD tom qab phais tuaj yeem qhia txog kev pheej hmoo ntawm kev rov qab los ntawm mob qog noj ntshav colorectal tom qab phais. Kev kuaj ctDNA muaj qhov zoo ntawm kev tsis ua rau mob, yooj yim, ceev ceev, nrog rau kev nkag mus rau cov qauv siab thiab kov yeej qhov sib txawv ntawm qog.
Cov lus qhia ntawm US NCCN rau mob qog noj ntshav hauv plab hnyuv thiab cov lus qhia ntawm Suav CSCO rau mob qog noj ntshav hauv plab hnyuv ob leeg hais tias rau kev txiav txim siab txog kev pheej hmoo rov tshwm sim tom qab phais thiab kev xaiv tshuaj kho mob qog noj ntshav hauv plab hnyuv, kev kuaj ctDNA tuaj yeem muab cov ntaub ntawv kwv yees thiab kev kwv yees los pab txiav txim siab txog kev kho mob rau cov neeg mob uas muaj mob qog noj ntshav theem II lossis III. Txawm li cas los xij, feem ntau cov kev tshawb fawb uas twb muaj lawm tsom mus rau kev hloov pauv ctDNA raws li kev siv tshuab sequencing siab (NGS), uas muaj cov txheej txheem nyuaj, lub sijhawm ua haujlwm ntev, thiab tus nqi siab [3], nrog rau qhov tsis muaj kev dav dav thiab qhov tshwm sim tsawg ntawm cov neeg mob qog noj ntshav.
Yog tias cov neeg mob uas muaj mob qog noj ntshav ntawm txoj hnyuv loj theem III, kev soj ntsuam ctDNA raws li NGS raug nqi txog li $10,000 rau ib zaug mus ntsib thiab yuav tsum tau tos txog li ob lub lis piam. Nrog rau kev kuaj methylation ntau hom noob hauv txoj kev tshawb fawb no, ColonAiQ®, cov neeg mob tuaj yeem soj ntsuam ctDNA raws li qhov xav tau ntawm tus nqi ib feem kaum thiab tau txais daim ntawv qhia hauv ob hnub xwb.
Raws li 560,000 tus neeg mob qog noj ntshav hauv Suav teb txhua xyoo, cov neeg mob feem ntau uas muaj mob qog noj ntshav theem II-III (feem pua ​​yog li 70%) muaj kev xav tau kev saib xyuas sai dua, ces qhov loj ntawm kev ua lag luam ntawm MRD kev saib xyuas qog noj ntshav hauv plab mus txog ntau lab tus tib neeg txhua xyoo.
Pom tau tias cov txiaj ntsig ntawm kev tshawb fawb muaj lub ntsiab lus tseem ceeb hauv kev tshawb fawb thiab kev siv tau. Los ntawm kev tshawb fawb loj hauv kev kho mob, nws tau lees paub tias PCR-based blood ctDNA multigene methylation technology siv tau rau kev kwv yees qhov rov tshwm sim ntawm mob qog noj ntshav hauv plab hnyuv thiab kev saib xyuas qhov rov tshwm sim nrog ob qho tib si kev nkag siab, lub sijhawm thiab kev siv nyiaj tsim nyog, ua rau kev kho mob kom raug zoo dua los pab cov neeg mob qog noj ntshav ntau dua. Kev tshawb fawb no yog raws li ColonAiQ®, kev kuaj mob ntau hom noob methylation rau mob qog noj ntshav hauv plab hnyuv uas tsim los ntawm KUNY, uas nws qhov txiaj ntsig ntawm kev siv tshuaj hauv kev kuaj mob thaum ntxov thiab kev kuaj mob tau lees paub los ntawm kev tshawb fawb hauv nruab nrab.
Gastroenterology (IF33.88), phau ntawv xov xwm thoob ntiaj teb saum toj kawg nkaus hauv kev kho mob plab hnyuv xyoo 2021, tau tshaj tawm cov txiaj ntsig tshawb fawb ntau lub chaw ntawm Tsev Kho Mob Zhongshan ntawm Fudan University, Tsev Kho Mob Cancer ntawm Fudan University thiab lwm lub tsev kho mob muaj cai ua ke nrog KUNYAN Biological, uas tau lees paub qhov kev ua tau zoo zoo ntawm ColonAiQ® ChangAiQ® hauv kev tshuaj ntsuam thaum ntxov thiab kev kuaj mob qog noj ntshav thaum ntxov, thiab pib tshawb nrhiav. Nws kuj tshawb nrhiav qhov siv tau hauv kev saib xyuas kev kwv yees ntawm qog noj ntshav hauv plab hnyuv.

Yuav kom paub tseeb ntxiv txog kev siv ctDNA methylation hauv kev faib cov kev pheej hmoo, kev coj kev txiav txim siab kho mob thiab kev saib xyuas thaum ntxov rov tshwm sim hauv theem I-III mob qog noj ntshav colorectal, pab pawg tshawb fawb suav nrog 299 tus neeg mob uas muaj theem I-III mob qog noj ntshav colorectal uas tau phais mob hnyav thiab sau cov ntshav kuaj ntawm txhua qhov chaw saib xyuas (peb lub hlis sib nrug) hauv ib lub lim tiam ua ntej phais, ib hlis tom qab phais, thiab hauv kev kho mob adjuvant tom qab phais rau kev kuaj ntshav ctDNA.
Ua ntej, nws pom tias kev kuaj ctDNA tuaj yeem kwv yees qhov kev pheej hmoo ntawm kev rov tshwm sim hauv cov neeg mob qog nqaij hlav colorectal thaum ntxov, ob qho tib si ua ntej phais thiab thaum ntxov tom qab phais. Cov neeg mob ua ntej phais ctDNA-positive muaj feem ntau dua ntawm kev rov tshwm sim tom qab phais dua li cov neeg mob ua ntej phais ctDNA-negative (22.0% > 4.7%). Kev kuaj ctDNA tom qab phais thaum ntxov tseem kwv yees qhov kev pheej hmoo rov tshwm sim: ib hlis tom qab radical resection, cov neeg mob ctDNA-positive muaj 17.5 npaug ntau dua li cov neeg mob tsis muaj; pab pawg kuj pom tias kev sib xyaw ua ke ctDNA thiab CEA kev kuaj me ntsis txhim kho kev ua tau zoo hauv kev kuaj pom kev rov tshwm sim (AUC = 0.849), tab sis qhov sib txawv tsis tseem ceeb piv rau ctDNA (AUC = 0.839) kev kuaj ib leeg. Qhov sib txawv tsis tseem ceeb piv rau ctDNA ib leeg (AUC = 0.839).
Kev ntsuas theem mob ua ke nrog cov yam txaus ntshai tam sim no yog lub hauv paus tseem ceeb rau kev faib cov neeg mob qog noj ntshav, thiab hauv cov qauv tam sim no, muaj coob tus neeg mob tseem rov qab mob dua [4], thiab muaj kev xav tau ceev ceev rau cov cuab yeej faib zoo dua vim tias kev kho mob ntau dhau thiab kev kho mob tsis txaus nyob ua ke hauv tsev kho mob. Raws li qhov no, pab pawg neeg tau faib cov neeg mob uas muaj mob qog noj ntshav theem III rau hauv ntau pawg me me raws li kev ntsuam xyuas kev pheej hmoo rov qab mob (kev pheej hmoo siab (T4 / N2) thiab kev pheej hmoo qis (T1-3N1)) thiab lub sijhawm kho mob adjuvant (3/6 lub hlis). Kev tshuaj xyuas pom tias cov neeg mob hauv pawg me me ntawm cov neeg mob ctDNA-zoo muaj tus nqi rov qab mob qis dua yog tias lawv tau txais rau lub hlis ntawm kev kho mob adjuvant; hauv pawg me me ntawm cov neeg mob ctDNA-zoo, tsis muaj qhov sib txawv tseem ceeb ntawm lub voj voog kho mob adjuvant thiab cov txiaj ntsig ntawm tus neeg mob; thaum cov neeg mob ctDNA-tsis zoo muaj kev kwv yees zoo dua li cov neeg mob ctDNA-zoo thiab lub sijhawm ntev dua tom qab phais mob tsis rov qab mob (RFS); theem I thiab theem II mob qog noj ntshav hauv plab hnyuv uas muaj kev pheej hmoo tsawg Txhua tus neeg mob ctDNA-negative tsis muaj kev rov tshwm sim hauv ob xyoos; yog li ntawd, kev koom ua ke ntawm ctDNA nrog cov yam ntxwv hauv kev kho mob yuav tsum ua kom zoo dua qhov kev faib tawm ntawm kev pheej hmoo thiab kwv yees qhov rov tshwm sim zoo dua.

Daim Duab 1. Kev tshuaj xyuas ctDNA hauv Plasma ntawm POM1 rau kev kuaj pom thaum ntxov ntawm kev rov tshwm sim ntawm mob qog noj ntshav hauv plab hnyuv.
Cov txiaj ntsig ntxiv ntawm kev kuaj ctDNA dynamic qhia tau hais tias qhov kev pheej hmoo ntawm kev rov tshwm sim dua siab dua rau cov neeg mob uas muaj kev kuaj ctDNA dynamic zoo dua li cov neeg mob uas muaj ctDNA tsis zoo thaum lub sijhawm saib xyuas kev rov tshwm sim ntawm tus kab mob tom qab kev kho mob tiav (tom qab phais mob radical + kev kho mob adjuvant) (Daim Duab 3ACD), thiab tias ctDNA tuaj yeem qhia txog kev rov tshwm sim ntawm tus kab mob txog li 20 lub hlis ua ntej kev thaij duab (Daim Duab 3B), muab qhov ua tau ntawm kev kuaj pom tus kab mob rov tshwm sim thiab kev cuam tshuam raws sijhawm.

Daim Duab 2. kev tshuaj xyuas ctDNA raws li kev tshawb nrhiav ntev los nrhiav kev rov tshwm sim ntawm mob qog noj ntshav hauv plab hnyuv

Muaj ntau txoj kev tshawb fawb txog kev kho mob qog noj ntshav hauv plab hnyuv loj ua tus thawj coj hauv kev qhuab qhia, tshwj xeeb tshaj yog kev kuaj MRD raws li ctDNA qhia tau tias muaj peev xwm zoo los txhim kho kev tswj hwm tom qab phais mob ntawm cov neeg mob qog noj ntshav hauv plab hnyuv loj los ntawm kev ua kom muaj kev faib tawm ntawm kev pheej hmoo rov tshwm sim, coj kev txiav txim siab kho mob thiab kev saib xyuas rov tshwm sim thaum ntxov.

Qhov zoo ntawm kev xaiv DNA methylation ua ib qho cim MRD tshiab dua li kev kuaj pom kev hloov pauv yog tias nws tsis tas yuav tsum tau kuaj xyuas tag nrho cov ntaub so ntswg ntawm cov qog nqaij hlav, siv ncaj qha rau kev kuaj ntshav, thiab zam kev tshwm sim cuav vim yog kev kuaj pom kev hloov pauv ntawm lub cev los ntawm cov ntaub so ntswg ib txwm muaj, cov kab mob tsis muaj mob, thiab cov ntshav clonal.
Txoj kev tshawb fawb no thiab lwm cov kev tshawb fawb cuam tshuam lees paub tias kev kuaj MRD raws li ctDNA yog qhov tseem ceeb tshaj plaws rau kev rov tshwm sim ntawm theem I-III mob qog noj ntshav hauv plab hnyuv thiab tuaj yeem siv los pab coj kev txiav txim siab kho mob, suav nrog "kev nce qib" thiab "kev txo qis" ntawm kev kho mob adjuvant MRD yog qhov tseem ceeb tshaj plaws rau kev rov tshwm sim tom qab phais rau theem I-III mob qog noj ntshav hauv plab hnyuv.
Lub teb ntawm MRD tab tom hloov pauv sai nrog ntau yam kev ntsuam xyuas tshiab, muaj kev nkag siab zoo thiab tshwj xeeb raws li epigenetics (DNA methylation thiab fragmentomics) thiab genomics (ultra-deep targeted sequencing lossis whole genome sequencing). Peb cia siab tias ColonAiQ® yuav txuas ntxiv npaj cov kev tshawb fawb loj hauv kev kho mob thiab tuaj yeem ua tus qhia tshiab ntawm kev kuaj MRD uas muab kev nkag tau yooj yim, kev ua tau zoo thiab kev pheej yig thiab tuaj yeem siv dav hauv kev kho mob niaj hnub.
Cov ntaub ntawv siv los ua piv txwv
[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. Kev Tshawb Pom Thaum Ntxov ntawm Cov Kab Mob Molecular Residual thiab Kev Pheej Hmoo Stratification rau Theem I txog III Colorectal Cancer ntawm Circulating Tumor DNA Methylation. JAMA Oncol. 2023 Plaub Hlis 20.
[2] “Lub nra hnyav ntawm tus kab mob qog nqaij hlav hauv cov pej xeem Suav: nws puas tau hloov pauv hauv xyoo tas los no? , Chinese Journal of Epidemiology, Vol. 41, No. 10, Lub Kaum Hli Ntuj xyoo 2020.
[3] Tarazona N, Gimeno-Valiente F, Gambardella V, thiab lwm tus. Kev tshuaj xyuas cov noob caj noob ces tom ntej ntawm cov DNA ntawm cov qog nqaij hlav rau kev taug qab cov kab mob seem tsawg kawg nkaus hauv mob qog nqaij hlav hauv plab. Ann Oncol. Kaum Ib Hlis 1, 2019; 30 (11): 1804-1812.
[4] Taieb J, André T, Auclin E. Kev kho mob adjuvant rau mob qog nqaij hlav tsis kis mus rau lwm qhov, cov qauv tshiab thiab cov kev xav. Cancer Treat Rev. 2019; 75: 1-11.