Nat Med | Ib txoj hauv kev ntau yam los kos duab qhov mob qog noj ntshav uas sib xyaw ua ke

Nat Med | Ib txoj hauv kev ntau yam los kos duab qhov mob qog noj ntshav, kev tiv thaiv kab mob thiab cov kab mob me me ntawm mob qog noj ntshav hauv plab hnyuv qhia txog kev sib cuam tshuam ntawm cov kab mob me me nrog lub cev tiv thaiv kab mob
Txawm hais tias cov cim qhia txog mob qog noj ntshav hauv plab hnyuv tau raug kawm ntau heev nyob rau xyoo tas los no, cov lus qhia kho mob tam sim no tsuas yog siv rau kev ntsuas qhov mob qog noj ntshav thiab kev kuaj pom cov teeb meem DNA tsis sib xws (MMR) lossis microsatellite instability (MSI) (ntxiv rau kev kuaj mob tus qauv) los txiav txim siab cov lus pom zoo kho mob. Cov kws tshawb fawb tau sau tseg tias tsis muaj kev sib txuas ntawm cov lus teb tiv thaiv kab mob raws li kev qhia tawm ntawm cov noob caj noob ces, cov qauv microbial, thiab cov qog noj ntshav stroma hauv Cancer Genome Atlas (TCGA) mob qog noj ntshav hauv plab hnyuv thiab kev ciaj sia ntawm cov neeg mob.

Raws li kev tshawb fawb tau nce qib, cov yam ntxwv ntawm tus kab mob qog nqaij hlav thawj zaug, suav nrog tus kab mob qog nqaij hlav ntawm lub cev, lub cev tiv thaiv kab mob, stromal, lossis microbial, tau tshaj tawm tias muaj feem cuam tshuam nrog cov txiaj ntsig kho mob, tab sis tseem muaj kev nkag siab tsawg txog seb lawv cov kev sib cuam tshuam cuam tshuam li cas rau cov txiaj ntsig ntawm tus neeg mob.
Txhawm rau txiav txim siab qhov sib raug zoo ntawm qhov nyuaj ntawm phenotypic thiab qhov tshwm sim, ib pab neeg tshawb fawb los ntawm Sidra Institute of Medical Research hauv Qatar nyuam qhuav tsim thiab lees paub qhov qhab nia sib xyaw (mICRoScore) uas txheeb xyuas ib pawg neeg mob uas muaj feem ciaj sia zoo los ntawm kev sib xyaw cov yam ntxwv ntawm microbiome thiab cov kev tsis lees paub tiv thaiv kab mob (ICR). Pab neeg tau ua qhov kev tshuaj xyuas genomic ntawm cov qauv khov tshiab los ntawm 348 tus neeg mob uas muaj mob qog noj ntshav thawj zaug, suav nrog RNA sequencing ntawm cov qog thiab phim cov nqaij noj qab haus huv ntawm cov qog noj ntshav, tag nrho exome sequencing, tob T-cell receptor thiab 16S bacterial rRNA gene sequencing, ntxiv los ntawm tag nrho cov qog genome sequencing kom paub ntxiv txog microbiome. Txoj kev tshawb fawb tau luam tawm hauv Nature Medicine ua "Ib qho kev sib xyaw ua ke ntawm qog noj ntshav, tiv thaiv kab mob thiab microbiome atlas ntawm mob qog noj ntshav hauv plab".

Tsab xov xwm luam tawm hauv Nature Medicine

Kev Txheeb Xyuas Txog AC-ICAM

Cov kws tshawb nrhiav tau siv lub platform genomic orthogonal los tshuaj xyuas cov qauv qog nqaij hlav tshiab thiab phim cov nqaij mos ntawm txoj hnyuv loj uas noj qab nyob zoo (cov khub qog nqaij hlav-ib txwm) los ntawm cov neeg mob uas muaj kev kuaj mob qog nqaij hlav tsis muaj kev kho mob. Raws li kev txheeb xyuas tag nrho-exome sequencing (WES), kev tswj xyuas cov ntaub ntawv RNA-seq, thiab kev tshuaj xyuas cov qauv kev koom ua ke, cov ntaub ntawv genomic los ntawm 348 tus neeg mob tau khaws cia thiab siv rau kev tshuaj xyuas downstream nrog kev saib xyuas nruab nrab ntawm 4.6 xyoo. Pab pawg tshawb fawb tau muab lub npe rau qhov chaw no Sidra-LUMC AC-ICAM: Daim ntawv qhia thiab phau ntawv qhia rau kev sib cuam tshuam ntawm cov kab mob tiv thaiv kab mob-qog nqaij hlav-microbiome (Daim Duab 1).

Kev faib tawm molecular siv ICR

Thaum ntes tau ib pawg modular ntawm cov cim qhia txog kev tiv thaiv kab mob rau kev soj ntsuam kab mob qog noj ntshav tas mus li, hu ua kev tiv thaiv kab mob tsis tu ncua ntawm kev tsis lees paub (ICR), pab pawg tshawb fawb tau ua kom zoo dua ICR los ntawm kev muab nws tso rau hauv 20-gene vaj huam sib luag uas npog ntau hom kab mob qog noj ntshav, suav nrog melanoma, mob qog noj ntshav zais zis, thiab mob qog noj ntshav mis. ICR kuj tau cuam tshuam nrog kev teb rau kev kho mob hauv ntau hom kab mob qog noj ntshav, suav nrog mob qog noj ntshav mis.

Ua ntej, cov kws tshawb fawb tau lees paub qhov kos npe ICR ntawm AC-ICAM cohort, siv txoj hauv kev sib koom ua ke raws li ICR gene los faib pawg neeg ua peb pawg / hom kab mob tiv thaiv kab mob: ICR siab (mob kub), ICR nruab nrab thiab ICR qis (mob txias) (Daim Duab 1b). Cov kws tshawb fawb tau piav qhia txog kev tiv thaiv kab mob cuam tshuam nrog kev pom zoo molecular subtypes (CMS), kev faib tawm raws li transcriptome ntawm mob qog noj ntshav hauv plab hnyuv. Cov pawg CMS suav nrog CMS1 / immune, CMS2 / canonical, CMS3 / metabolic thiab CMS4 / mesenchymal. Kev tshuaj xyuas qhia tau hais tias cov qhab nia ICR tau sib raug zoo tsis zoo nrog qee txoj hauv kev mob qog noj ntshav hauv txhua CMS subtypes, thiab kev sib raug zoo nrog kev tiv thaiv kab mob thiab stromal-related pathways tau pom tsuas yog hauv CMS4 qog.

Hauv txhua CMS, qhov muaj ntau ntawm cov hlwb tua neeg ntuj (NK) thiab cov hlwb T yog qhov siab tshaj plaws hauv ICR cov hlwb tiv thaiv kab mob siab, nrog rau kev hloov pauv ntau dua hauv lwm cov hlwb leukocyte (Daim Duab 1c). Cov hlwb tiv thaiv kab mob ICR muaj OS thiab PFS sib txawv, nrog rau kev nce ntxiv hauv ICR los ntawm qis mus rau siab (Daim Duab 1d), lees paub lub luag haujlwm kwv yees ntawm ICR hauv mob qog noj ntshav colorectal.

Daim Duab 1. Kev tsim qauv kev tshawb fawb AC-ICAM, cov cim qhia txog cov noob caj noob ces uas cuam tshuam nrog kev tiv thaiv kab mob, cov hom kab mob tiv thaiv kab mob thiab cov noob caj noob ces thiab kev ciaj sia.
ICR ntes cov qe ntshav T uas muaj ntau yam kab mob qog nqaij hlav, thiab clonally amplified
Tsuas yog ib feem tsawg ntawm cov T cell uas nkag mus rau hauv cov nqaij mob qog nqaij hlav tau tshaj tawm tias tshwj xeeb rau cov antigens ntawm qog nqaij hlav (tsawg dua 10%). Yog li ntawd, feem ntau ntawm cov T cell hauv qog nqaij hlav raug xa mus rau bystander T cell (bystander T cell). Qhov sib raug zoo tshaj plaws nrog tus lej ntawm cov T cell ib txwm muaj nrog cov TCR tsim tau zoo tau pom hauv cov stromal cell thiab leukocyte subpopulations (nrhiav tau los ntawm RNA-seq), uas tuaj yeem siv los kwv yees cov T cell subpopulations (Daim Duab 2a). Hauv ICR clusters (kev faib tawm tag nrho thiab CMS), qhov clonality siab tshaj plaws ntawm cov immune SEQ TCRs tau pom hauv ICR-high thiab CMS subtype CMS1/immune pawg (Daim Duab 2c), nrog rau qhov feem pua ​​​​​​siab tshaj plaws ntawm cov qog nqaij hlav ICR-high. Siv tag nrho cov transcriptome (18,270 noob), rau ICR noob (IFNG, STAT1, IRF1, CCL5, GZMA, thiab CXCL10) yog cov ntawm kaum noob saum toj kawg nkaus uas cuam tshuam zoo nrog TCR immune SEQ clonality (Daim Duab 2d). ImmunoSEQ TCR clonality muaj feem cuam tshuam nrog feem ntau ntawm cov noob ICR dua li cov kev sib raug zoo uas pom siv cov cim CD8+ uas teb rau qhov mob qog (Daim Duab 2f thiab 2g). Xaus lus, qhov kev tshuaj xyuas saum toj no qhia tias ICR kos npe ntes tau qhov muaj cov qog-nplua nuj, clonally amplified T cell thiab tej zaum yuav piav qhia nws cov kev cuam tshuam prognostic.

Daim Duab 2. Cov ntsuas TCR thiab kev sib raug zoo nrog cov noob caj noob ces uas cuam tshuam nrog kev tiv thaiv kab mob, kev tiv thaiv kab mob thiab cov subtypes molecular.
Cov qauv ntawm cov kab mob microbiome hauv cov nqaij noj qab haus huv thiab cov nqaij mob qog nqaij hlav
Cov kws tshawb fawb tau ua 16S rRNA sequencing siv DNA rho tawm los ntawm qog nqaij hlav thiab cov nqaij mos ntawm txoj hnyuv loj uas sib phim los ntawm 246 tus neeg mob (Daim Duab 3a). Txhawm rau kom paub tseeb, cov kws tshawb fawb kuj tau tshuaj xyuas cov ntaub ntawv 16S rRNA gene sequencing los ntawm 42 tus qauv qog nqaij hlav ntxiv uas tsis muaj DNA sib phim uas muaj rau kev tshuaj xyuas. Ua ntej, cov kws tshawb fawb tau piv qhov muaj ntau ntawm cov nroj tsuag ntawm cov qog nqaij hlav sib phim thiab cov nqaij mos ntawm txoj hnyuv loj uas noj qab nyob zoo. Clostridium perfringens tau nce ntxiv ntau hauv cov qog nqaij hlav piv rau cov qauv noj qab nyob zoo (Daim Duab 3a-3d). Tsis muaj qhov sib txawv tseem ceeb hauv alpha diversity (kev sib txawv thiab kev muaj ntau hom tsiaj hauv ib qho qauv) ntawm qog nqaij hlav thiab cov qauv noj qab nyob zoo, thiab kev txo qis me ntsis hauv microbial diversity tau pom hauv cov qog nqaij hlav ICR-siab piv rau cov qog nqaij hlav ICR-qis.
Txhawm rau nrhiav kev sib raug zoo ntawm cov kab mob me me thiab cov txiaj ntsig kho mob, cov kws tshawb fawb tau tsom mus siv cov ntaub ntawv 16S rRNA gene sequencing los txheeb xyuas cov yam ntxwv ntawm microbiome uas kwv yees qhov muaj sia nyob. Ntawm AC-ICAM246, cov kws tshawb fawb tau khiav OS Cox regression qauv uas xaiv 41 yam ntxwv nrog cov coefficients tsis yog xoom (cuam tshuam nrog kev pheej hmoo tuag sib txawv), hu ua MBR classifiers (Daim Duab 3f).
Hauv pawg neeg kawm no (ICAM246), qhov qhab nia MBR qis (MBR <0, MBR qis) tau cuam tshuam nrog kev pheej hmoo tuag qis dua (85%). Cov kws tshawb fawb tau lees paub qhov kev sib raug zoo ntawm MBR qis (kev pheej hmoo) thiab OS ntev hauv ob pawg neeg tau lees paub ywj pheej (ICAM42 thiab TCGA-COAD). (Daim Duab 3) Kev tshawb fawb tau qhia txog kev sib raug zoo ntawm endogastric cocci thiab MBR cov qhab nia, uas zoo sib xws hauv qog thiab cov nqaij mos plab hnyuv noj qab haus huv.

Daim Duab 3. Cov kab mob me me hauv cov qog thiab cov nqaij noj qab haus huv thiab kev sib raug zoo nrog ICR thiab kev ciaj sia ntawm tus neeg mob.
Xaus lus
Txoj kev siv ntau yam kev kho mob siv rau hauv txoj kev tshawb fawb no ua rau pom thiab tshuaj xyuas cov cim qhia txog kev tiv thaiv kab mob hauv cov qog nqaij hlav thiab qhia txog kev sib cuam tshuam ntawm cov kab mob me me thiab lub cev tiv thaiv kab mob. Kev tshawb nrhiav TCR tob tob ntawm cov qog nqaij hlav thiab cov nqaij noj qab haus huv tau qhia tias qhov cuam tshuam ntawm ICR tej zaum yuav yog vim nws muaj peev xwm ntes cov qog nqaij hlav uas muaj ntau yam thiab tej zaum cov qog nqaij hlav tshwj xeeb rau cov T cell clones.

Los ntawm kev tshuaj xyuas cov kab mob me me hauv cov qog nqaij hlav siv 16S rRNA gene sequencing hauv AC-ICAM cov qauv, pab pawg tau txheeb xyuas cov cim microbiome (MBR risk score) nrog rau qhov muaj txiaj ntsig zoo. Txawm hais tias cov cim no tau los ntawm cov qauv qog nqaij hlav, muaj kev sib raug zoo ntawm cov kab mob colorectum noj qab haus huv thiab cov qhab nia MBR risk ntawm qog nqaij hlav, qhia tias cov cim no yuav ntes tau cov kab mob hauv plab ntawm cov neeg mob. Los ntawm kev sib xyaw cov qhab nia ICR thiab MBR, nws muaj peev xwm txheeb xyuas thiab lees paub cov cim biomarker ntawm cov tub ntxhais kawm ntau-omic uas kwv yees kev ciaj sia nyob hauv cov neeg mob uas muaj mob qog nqaij hlav plab. Cov ntaub ntawv multi-omic ntawm kev tshawb fawb muab cov peev txheej los nkag siab zoo dua txog kab mob qog nqaij hlav plab thiab pab tshawb nrhiav cov kev kho mob tus kheej.

Siv rau:
Roelands, J., Kuppen, PJK, Ahmed, EI et al. Ib qho kev sib xyaw qog, tiv thaiv kab mob thiab microbiome atlas ntawm txoj hnyuv loj. Nat Med 29, 1273–1286 (2023).