Kafukufuku wotsogola: Ukadaulo wa methylation wa ctDNA m'magazi wozikidwa pa PCR ukutsegula nthawi yatsopano yowunikira khansa ya m'matumbo

Posachedwapa, JAMA Oncology (IF 33.012) yafalitsa zotsatira zofunika kwambiri za kafukufuku [1] ndi gulu la Pulofesa Cai Guo-ring wochokera ku Cancer Hospital of Fudan University ndi Pulofesa Wang Jing wochokera ku Renji Hospital of Shanghai Jiao Tong University School of Medicine, mogwirizana ndi KUNYUAN BIOLOGY: “Kuzindikira Matenda Otsalira a Molecular ndi Kugawa kwa Ziwopsezo za Khansa ya m'matumbo Gawo I mpaka III kudzera mu Circulating Tumor DNA Methylation ndi Kugawa kwa Ziwopsezo)”. Kafukufukuyu ndi kafukufuku woyamba wa m'malo osiyanasiyana padziko lonse lapansi wogwiritsa ntchito ukadaulo wa PCR-based blood ctDNA multigene methylation powunikira kubwerezabwereza kwa khansa ya m'matumbo ndi kuwunika kubwerezabwereza, kupereka njira yaukadaulo yotsika mtengo komanso yankho poyerekeza ndi njira zamakono zodziwira MRD zomwe zilipo, zomwe zikuyembekezeka kusintha kwambiri kugwiritsa ntchito kwachipatala kwa kuneneratu kubwerezabwereza kwa khansa ya m'matumbo ndi matumbo, ndikukweza kwambiri moyo wa wodwala komanso moyo wabwino. Kafukufukuyu adawunikidwanso kwambiri ndi magaziniyi ndi akonzi ake, ndipo adalembedwa ngati pepala lofunika kwambiri lolimbikitsa nkhaniyi, ndipo Pulofesa Juan Ruiz-Bañobre wochokera ku Spain ndi Pulofesa Ajay Goel wochokera ku United States adaitanidwa kuti awunikenso. Kafukufukuyu adanenedwanso ndi GenomeWeb, kampani yotsogola yofalitsa nkhani zachipatala ku United States.

Khansa ya m'matumbo (CRC) ndi chotupa chofala kwambiri cha m'mimba ku China. Deta ya 2020 International Agency for Research on Cancer (IARC) ikuwonetsa kuti milandu yatsopano 555,000 ku China imapanga pafupifupi 1/3 ya dziko lapansi, ndipo kuchuluka kwa khansa kukwera kufika pa malo achiwiri a khansa yofala ku China; Imfa 286,000 zimapanga pafupifupi 1/3 ya dziko lapansi, zomwe zili pachiwopsezo chachisanu cha imfa za khansa ku China. Chifukwa chachisanu cha imfa ku China. Ndikofunikira kudziwa kuti pakati pa odwala omwe apezeka ndi matendawa, magawo a TNM I, II, III ndi IV ndi 18.6%, 42.5%, 30.7% ndi 8.2% motsatana. Odwala opitilira 80% ali pakati ndi kumapeto, ndipo 44% mwa iwo ali ndi metastases yakutali nthawi imodzi kapena heterochronic kupita ku chiwindi ndi mapapo, zomwe zimakhudza kwambiri nthawi yopulumuka, zimaika pachiwopsezo thanzi la anthu okhala m'dera lathu ndikuyambitsa mavuto azachuma komanso azachuma. Malinga ndi ziwerengero za National Cancer Center, kukwera kwapakati pachaka kwa mtengo wochizira khansa ya m'matumbo ku China ndi pafupifupi 6.9% mpaka 9.2%, ndipo ndalama zomwe odwala amawononga paumoyo wawo mkati mwa chaka chimodzi atapezeka ndi matendawa zimatha kutenga 60% ya ndalama zomwe mabanja amapeza. Odwala khansa akuvutika ndi matendawa komanso ali pamavuto azachuma [2].
Maperesenti makumi asanu ndi anayi pa zana a zilonda za khansa ya m'matumbo amatha kuchotsedwa mwa opaleshoni, ndipo chotupa chikapezeka msanga, kuchuluka kwa moyo wa zaka zisanu pambuyo pochita opaleshoni yochotsa ziwalo zoberekera, koma kuchuluka kwa khansa ya m'matumbo yomwe imabwereranso pambuyo pochotsa ziwalo zoberekera ...
Matenda ochepa otsalira (MRD) ndi omwe amachititsa kuti chotupa chibwererenso pambuyo pa chithandizo chamankhwala champhamvu. M'zaka zaposachedwapa, ukadaulo wozindikira MRD wa zotupa zolimba wapita patsogolo mofulumira, ndipo maphunziro angapo olemera komanso owunikira atsimikizira kuti momwe MRD imakhalira pambuyo pa opaleshoni ingasonyeze chiopsezo cha kubwereranso kwa khansa ya m'matumbo pambuyo pa opaleshoni. Kuyesa kwa ctDNA kuli ndi ubwino wosakhala wovulaza, wosavuta, wachangu, wokhala ndi zitsanzo zambiri komanso kuthana ndi kusiyana kwa chotupa.
Malangizo a US NCCN okhudza khansa ya m'matumbo ndi malangizo a ku China a CSCO okhudza khansa ya m'matumbo onse amanena kuti pofuna kudziwa chiopsezo chobwereranso pambuyo pa opaleshoni komanso kusankha mankhwala othandizira khansa ya m'matumbo, kuyezetsa kwa ctDNA kungapereke chidziwitso cholosera komanso cholosera kuti chithandize pakupanga zisankho zothandizira odwala omwe ali ndi khansa ya m'matumbo ya gawo lachiwiri kapena lachitatu. Komabe, maphunziro ambiri omwe alipo amayang'ana kwambiri kusintha kwa ctDNA kutengera ukadaulo wapamwamba wotsatizana (NGS), womwe uli ndi njira yovuta, nthawi yayitali yotsogolera, komanso mtengo wokwera [3], ndi kusowa pang'ono kwa generalizability komanso kufalikira kochepa pakati pa odwala khansa.
Pankhani ya odwala khansa ya m'matumbo a m'mimba ya gawo lachitatu, kuyang'anira kwa ctDNA kochokera ku NGS kumawononga ndalama zokwana $10,000 paulendo umodzi ndipo kumafuna nthawi yodikira mpaka milungu iwiri. Ndi mayeso a multigene methylation mu kafukufukuyu, ColonAiQ®, odwala amatha kuyang'anira ctDNA yowonjezereka pa gawo limodzi mwa magawo khumi a mtengo wake ndikupeza lipoti mkati mwa masiku awiri okha.
Malinga ndi milandu yatsopano 560,000 ya khansa ya m'matumbo ku China chaka chilichonse, odwala omwe ali ndi khansa ya m'matumbo ya gawo lachiwiri mpaka lachitatu (chiŵerengero chake ndi pafupifupi 70%) ali ndi kufunikira kwakukulu koyang'aniridwa mwachangu, pomwe kukula kwa msika wa MRD dynamic monitoring khansa ya m'matumbo kumafikira anthu mamiliyoni ambiri chaka chilichonse.
Zikuoneka kuti zotsatira za kafukufukuyu zili ndi tanthauzo lofunika la sayansi komanso lothandiza. Kudzera mu maphunziro akuluakulu azachipatala, zatsimikizira kuti ukadaulo wa PCR-based blood ctDNA multigene methylation ungagwiritsidwe ntchito poneneratu kubwereranso kwa khansa ya m'matumbo ndi kuwunika kubwereranso kwa khansa pogwiritsa ntchito kusamala, nthawi yake komanso kugwiritsa ntchito bwino ndalama, zomwe zimathandiza kuti mankhwala olondola apindule odwala ambiri a khansa. Kafukufukuyu akuchokera pa ColonAiQ®, mayeso a methylation a majini ambiri a khansa ya m'matumbo yopangidwa ndi KUNY, yomwe kufunika kwake poyesa ndi kuzindikira matenda koyambirira kwatsimikiziridwa ndi kafukufuku wapakati wazachipatala.
Gastroenterology (IF33.88), magazini yapamwamba yapadziko lonse lapansi pankhani ya matenda am'mimba mu 2021, inanena za zotsatira za kafukufuku wa Zhongshan Hospital of Fudan University, Cancer Hospital of Fudan University ndi mabungwe ena azachipatala odziwika bwino mogwirizana ndi KUNYAN Biological, zomwe zatsimikizira bwino kwambiri ntchito ya ColonAiQ® ChangAiQ® poyesa koyambirira komanso kuzindikira khansa ya m'matumbo, ndipo poyamba idafufuza momwe ingagwiritsire ntchito poyang'anira khansa ya m'matumbo.

Pofuna kutsimikiziranso momwe ctDNA methylation imagwiritsidwira ntchito pochiza matenda osiyanasiyana, kutsogolera zisankho za chithandizo ndi kuyang'anira msanga khansa ya m'matumbo ya gawo I-III, gulu lofufuzali linaphatikizapo odwala 299 omwe ali ndi khansa ya m'matumbo ya gawo I-III omwe adachitidwa opaleshoni yayikulu ndikusonkhanitsa zitsanzo za magazi nthawi iliyonse yotsatiridwa (miyezi itatu yosiyana) mkati mwa sabata imodzi opaleshoni isanachitike, mwezi umodzi opaleshoni itatha, komanso chithandizo chothandizira pambuyo pa opaleshoni kuti ayesedwe magazi a ctDNA.
Choyamba, zinapezeka kuti kuyezetsa kwa ctDNA kumatha kulosera chiopsezo cha kubwereranso kwa odwala khansa ya m'matumbo msanga, onse asanayambe opaleshoni komanso atangomaliza opaleshoni. Odwala omwe ali ndi ctDNA asanachite opaleshoni anali ndi mwayi waukulu wobwereranso pambuyo pa opaleshoni kuposa odwala omwe alibe ctDNA asanachite opaleshoni (22.0% > 4.7%). Kuyezetsa kwa ctDNA koyambirira pambuyo pa opaleshoni kunaneneratube chiopsezo chobwereranso: mwezi umodzi pambuyo pa opaleshoni yochotsa ziwalo, odwala omwe ali ndi ctDNA anali ndi mwayi wobwerezabwereza nthawi 17.5 kuposa odwala omwe alibe; gululo linapezanso kuti kuyezetsa kwa ctDNA ndi CEA pamodzi kunathandiza pang'ono kuzindikira kubwereranso (AUC=0.849), koma kusiyana sikunali kwakukulu poyerekeza ndi kuyezetsa kwa ctDNA (AUC=0.839) kokha Kusiyana sikunali kwakukulu poyerekeza ndi ctDNA yokha (AUC=0.839).
Kugawa matenda pamodzi ndi zinthu zoopsa pakadali pano ndiye maziko akuluakulu ogawa matenda a khansa m'magulu, ndipo m'malingaliro amakono, odwala ambiri akubwereranso [4], ndipo pakufunika njira zabwino zogawa matenda chifukwa chithandizo chopitirira muyeso komanso chosakwanira chithandizo chimachitika nthawi zonse m'chipatala. Kutengera izi, gululo linagawa odwala omwe ali ndi khansa ya m'matumbo a gawo lachitatu m'magulu ang'onoang'ono kutengera kuwunika kwa chiopsezo chobwerezabwereza kuchipatala (chiwopsezo chachikulu (T4/ N2) ndi chiopsezo chochepa (T1-3N1)) ndi nthawi yothandizidwa ndi adjuvant (miyezi 3/6). Kusanthulaku kunapeza kuti odwala omwe ali m'gulu la odwala omwe ali ndi chiopsezo chachikulu cha ctDNA anali ndi chiwopsezo chochepa chobwerezabwereza ngati adalandira chithandizo cha adjuvant kwa miyezi isanu ndi umodzi; m'gulu la odwala omwe ali ndi chiopsezo chochepa cha ctDNA, panalibe kusiyana kwakukulu pakati pa nthawi yolandira chithandizo cha adjuvant ndi zotsatira za odwala; pomwe odwala omwe alibe ctDNA anali ndi chiyembekezo chabwino kwambiri kuposa odwala omwe ali ndi ctDNA komanso nthawi yayitali yopanda kubwerezabwereza pambuyo pa opaleshoni (RFS); Gawo Loyamba ndi Khansa ya m'matumbo ya Gawo Lachiwiri yomwe ili pachiwopsezo chochepa Odwala onse opanda ctDNA sanabwererenso mkati mwa zaka ziwiri; Chifukwa chake, kuphatikiza kwa ctDNA ndi zizindikiro zachipatala kukuyembekezeka kupititsa patsogolo kugawa kwa chiopsezo ndikulosera bwino kubwereranso.

Chithunzi 1. Kusanthula kwa plasma ctDNA pa POM1 kuti mudziwe msanga kubwereranso kwa khansa ya m'matumbo
Zotsatira zina za mayeso a dynamic ctDNA zinasonyeza kuti chiopsezo chobwereranso chinali chachikulu kwambiri mwa odwala omwe ali ndi mayeso abwino a dynamic ctDNA kuposa odwala omwe ali ndi ctDNA yoipa panthawi yowunikira kubwereranso kwa matendawa pambuyo pa chithandizo chotsimikizika (pambuyo pa opaleshoni yayikulu + chithandizo chowonjezera) (Chithunzi 3ACD), ndipo ctDNA ikhoza kusonyeza kubwereranso kwa chotupa mpaka miyezi 20 isanafike kujambula (Chithunzi 3B), zomwe zikupereka mwayi wozindikira msanga kubwereranso kwa matendawa ndikuchitapo kanthu panthawi yake.

Chithunzi 2. Kusanthula kwa ctDNA kutengera gulu la longitudinal kuti mudziwe kubwereranso kwa khansa ya m'matumbo

"Kuchuluka kwa kafukufuku wamankhwala omasulira khansa ya m'matumbo ang'onoang'ono kumatsogolera maphunzirowa, makamaka mayeso a MRD ochokera ku ctDNA akuwonetsa kuthekera kwakukulu kowongolera kasamalidwe ka odwala khansa ya m'matumbo ang'onoang'ono akachitidwa opaleshoni polola kugawa chiopsezo chobwereranso, kutsogolera zisankho za chithandizo ndikuwunika koyambirira kwa kubwereranso."

Ubwino wosankha DNA methylation ngati chizindikiro chatsopano cha MRD m'malo mozindikira kusintha kwa majini ndikuti sichifuna kufufuza maselo onse a chotupa, chimagwiritsidwa ntchito mwachindunji poyesa magazi, ndipo chimapewa zotsatira zabodza chifukwa chozindikira kusintha kwa thupi komwe kumachokera ku minofu yachibadwa, matenda osaopsa, ndi magazi otuluka m'magazi.
Kafukufukuyu ndi maphunziro ena ofanana akutsimikizira kuti kuyezetsa kwa MRD kochokera ku ctDNA ndiye chinthu chofunikira kwambiri chodziyimira pawokha chomwe chingayambitse kubwereranso kwa khansa ya m'matumbo ya gawo I-III ndipo chingagwiritsidwe ntchito kutsogolera zisankho za chithandizo, kuphatikizapo "kukwera" ndi "kutsika" kwa chithandizo chothandizira. MRD ndiye chinthu chofunikira kwambiri chodziyimira pawokha chomwe chingayambitse kubwereranso pambuyo pa opaleshoni ya khansa ya m'matumbo ya gawo I-III.
Gawo la MRD likusintha mofulumira ndi mayeso angapo atsopano, okhudzidwa kwambiri komanso enieni ozikidwa pa epigenetics (DNA methylation ndi fragmentomics) ndi genomics (ultra-deep targeted sequencing kapena whole genome sequencing). Tikuyembekeza kuti ColonAiQ® ikupitiliza kukonza maphunziro azachipatala akuluakulu ndipo ikhoza kukhala chizindikiro chatsopano cha mayeso a MRD omwe amaphatikiza kupezeka mosavuta, magwiridwe antchito apamwamba komanso mtengo wotsika ndipo angagwiritsidwe ntchito kwambiri muzochita zamankhwala zachizolowezi.
Zolemba
[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. Kuzindikira Koyambirira kwa Matenda Otsalira a Molecular ndi Kugawa Koopsa kwa Khansa ya M'matumbo Gawo I mpaka III kudzera mu Methylation ya DNA ya Tumor. JAMA Oncol. 2023 Epulo 20.
[2] “Kulemera kwa matenda a khansa ya m’matumbo mwa anthu aku China: kodi kwasintha m’zaka zaposachedwapa? , Chinese Journal of Epidemiology, Vol. 41, No. 10, Okutobala 2020.
[3] Tarazona N, Gimeno-Valiente F, Gambardella V, ndi ena. Anayang'ana kwambiri kutsata kwa DNA ya chotupa cha m'badwo wotsatira kuti atsatire matenda ochepa otsala mu khansa ya m'matumbo. Ann Oncol. Nov 1, 2019;30(11):1804-1812.
[4] Taieb J, André T, Auclin E. Kukonzanso chithandizo chothandizira khansa ya m'matumbo yopanda kufalikira kwa maselo, miyezo yatsopano ndi malingaliro. Cancer Treat Rev. 2019;75:1-11.