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Nat Med |Ib txoj hauv kev ua ntau yam omics rau kev kos cov qog ua ke, kev tiv thaiv kab mob thiab microbial toj roob hauv pes ntawm mob qog noj ntshav qhia txog kev cuam tshuam ntawm microbiome nrog lub cev tiv thaiv kab mob.
Txawm hais tias biomarkers rau thawj tus mob qog noj ntshav tau raug kawm ntau nyob rau xyoo tas los no, cov txheej txheem kho mob tam sim no tsuas yog nyob ntawm qog-lymph node-metastasis staging thiab nrhiav pom DNA mismatch kho (MMR) qhov tsis xws lossis microsatellite instability (MSI) (ntxiv rau cov qauv kuaj kab mob. ) txhawm rau txiav txim siab txog kev kho mob.Cov kws tshawb fawb tau sau tseg tias tsis muaj kev sib koom ua ke ntawm cov noob tshuaj tiv thaiv kab mob, cov kab mob microbial, thiab qog stroma hauv Cancer Genome Atlas (TCGA) kab mob qog noj ntshav thiab cov neeg mob muaj sia nyob.
Raws li kev tshawb fawb tau nce zuj zus, cov yam ntxwv ntawm tus kab mob qog nqaij hlav hauv plab, suav nrog mob qog noj ntshav, tiv thaiv kab mob, stromal, lossis microbial xwm ntawm tus mob qog noj ntshav, tau raug tshaj tawm tias muaj feem cuam tshuam nrog cov txiaj ntsig kho mob, tab sis tseem muaj kev nkag siab tsawg ntawm lawv cov kev cuam tshuam cuam tshuam li cas rau cov neeg mob. .
Txhawm rau txheeb xyuas qhov kev sib raug zoo ntawm phenotypic complexity thiab qhov tshwm sim, ib pab pawg ntawm cov kws tshawb fawb los ntawm Sidra lub koom haum ntawm Kev Tshawb Fawb Kev Kho Mob hauv Qatar tsis ntev los no tau tsim thiab siv tau cov qhab nia sib xyaw (mICRoScore) uas txheeb xyuas cov pab pawg neeg mob uas muaj kev ciaj sia zoo los ntawm kev sib txuas cov yam ntxwv ntawm microbiome thiab kev tiv thaiv kab mob. tsis tu ncua (ICR).Pab neeg no tau ua tiav kev tshuaj ntsuam genomic ntawm cov qauv khov tshiab los ntawm 348 cov neeg mob uas muaj mob qog noj ntshav hauv plab, suav nrog RNA sequencing ntawm cov qog thiab ua kom cov nqaij mos noj qab nyob zoo, tag nrho exome sequencing, tob T-cell receptor thiab 16S kab mob rRNA gene sequencing, ntxiv los ntawm tag nrho cov qog. genome sequencing mus ntxiv tus yam ntxwv ntawm microbiome.Txoj kev tshawb no tau luam tawm nyob rau hauv Nature Medicine li "Ib lub qog ua ke, tiv thaiv kab mob thiab microbiome atlas ntawm txoj hnyuv loj".
Kab lus luam tawm hauv Nature Medicine
AC-ICAM Txheej txheem cej luam
Cov kws tshawb fawb siv lub orthogonal genomic platform los tshuaj xyuas cov qog nqaij hlav tshiab khov thiab sib koom ua ke cov nqaij mos noj qab nyob zoo (cov qog-ib txwm ua khub) los ntawm cov neeg mob uas muaj kev kuaj mob qog noj ntshav ntawm txoj hnyuv tsis muaj kev kho mob.Raws li tag nrho-exome sequencing (WES), RNA-seq cov ntaub ntawv tswj kom zoo, thiab kev soj ntsuam cov txheej txheem suav nrog, cov ntaub ntawv genomic los ntawm 348 tus neeg mob tau khaws cia thiab siv rau kev soj ntsuam hauv qab nrog kev soj ntsuam nruab nrab ntawm 4.6 xyoo.Pab neeg tshawb fawb hu ua cov peev txheej no Sidra-LUMC AC-ICAM: Daim ntawv qhia thiab qhia txog kev tiv thaiv kab mob qog noj ntshav-microbiome kev sib cuam tshuam (Daim duab 1).
Kev faib tawm molecular siv ICR
Kev ntes cov txheej txheem tiv thaiv kab mob tiv thaiv kab mob rau kev tiv thaiv kab mob qog noj ntshav tas li, hu ua lub cev tiv thaiv kab mob tsis tu ncua (ICR), pab pawg tshawb fawb tau ua kom zoo dua ICR los ntawm condensing nws mus rau hauv 20-gene vaj huam sib luag npog ntau hom mob qog noj ntshav, suav nrog melanoma, mob qog noj ntshav, thiab mob cancer mis.ICR kuj tau cuam tshuam nrog kev siv tshuaj tiv thaiv kab mob hauv ntau hom mob qog noj ntshav, suav nrog mob qog noj ntshav mis.
Ua ntej, cov kws tshawb fawb tau lees paub qhov ICR kos npe ntawm AC-ICAM pawg, siv ICR gene-based co-classification txoj hauv kev los faib cov pawg ua peb pawg / tiv thaiv kab mob: siab ICR (kub qog), nruab nrab ICR thiab qis ICR (txias. qog) (Daim duab 1b).Cov kws tshawb nrhiav pom lub cev tiv thaiv kab mob cuam tshuam nrog kev pom zoo molecular subtypes (CMS), kev faib tawm raws li kev faib tawm ntawm cov qog noj ntshav.cov CMS pawg suav nrog CMS1 / immune, CMS2 / canonical, CMS3 / metabolic thiab CMS4 / mesenchymal.Kev tshuaj xyuas tau pom tias cov qhab nia ICR tau cuam tshuam 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 cov kab mob stromal tau pom tsuas yog hauv CMS4 cov qog.
Nyob rau hauv tag nrho cov CMS, cov abundance ntawm natural killer (NK) cell thiab T cell subsets yog siab tshaj nyob rau hauv ICR high immune subtypes, nrog ntau variability nyob rau hauv lwm yam leukocyte subsets (Daim duab 1c).ICR immune subtypes muaj sib txawv OS thiab PFS, nrog ib tug zuj zus nce. nyob rau hauv ICR los ntawm qis mus rau siab (Daim duab 1d), validating lub prognostic lub luag hauj lwm ntawm ICR nyob rau hauv mob qog noj ntshav.
Daim duab 1. AC-ICAM txoj kev kawm tsim, kev tiv thaiv kab mob ntsig txog noob caj noob ces, kev tiv thaiv kab mob thiab molecular subtypes thiab ciaj sia taus.
ICR ntes cov qog-enriched, clonally amplified T hlwb
Tsuas yog ib pawg neeg ntawm T hlwb infiltrating cov qog nqaij hlav tau tshaj tawm tias tshwj xeeb rau cov qog antigens (tsawg dua 10%).Yog li ntawd, feem ntau ntawm cov qog nqaij hlav T hlwb raug xa mus rau los ntawm T cells (bystander T cells).Kev sib raug zoo nrog cov naj npawb ntawm cov pa T cell nrog cov khoom tsim TCRs tau pom nyob rau hauv stromal cell thiab leukocyte subpopulations (kuaj los ntawm RNA-seq), uas tuaj yeem siv los kwv yees T cell subpopulations (Daim duab 2a).Hauv pawg ICR (tag nrho thiab CMS kev faib tawm), qhov siab tshaj plaws clonality ntawm lub cev tiv thaiv kab mob SEQ TCRs tau pom nyob rau hauv ICR-siab thiab CMS subtype CMS1 / pawg tiv thaiv kab mob (Daim duab 2c), nrog rau feem ntau ntawm ICR-siab qog.Siv tag nrho cov ntawv sau tseg (18,270 genes), rau ICR genes (IFNG, STAT1, IRF1, CCL5, GZMA, thiab CXCL10) yog ib qho ntawm kaum sab saum toj zoo txuam nrog TCR tiv thaiv kab mob SEQ clonality (Daim duab 2d).ImmunoSEQ TCR clonality correlated ntau zog nrog feem ntau ICR genes dua li cov kev sib raug pom zoo siv cov qog-teb CD8+ cov cim (Daim duab 2f thiab 2g).Hauv kev xaus, qhov kev soj ntsuam saum toj no qhia tias ICR kos npe ntes cov qog-enriched, clonally amplified T hlwb thiab yuav piav qhia txog nws qhov kev cuam tshuam.
Daim duab 2. TCR metrics thiab correlation with immune-related genes, immune and molecular subtypes.
Microbiome muaj pes tsawg leeg hauv cov ntaub so ntswg noj qab haus huv thiab mob qog noj ntshav
Cov kws tshawb fawb tau ua 16S rRNA sequencing siv DNA muab rho tawm los ntawm cov qog nqaij hlav thiab cov hnyuv noj qab haus huv los ntawm 246 tus neeg mob (Daim duab 3a).Rau kev siv tau, cov kws tshawb fawb ntxiv tau txheeb xyuas 16S rRNA gene sequencing cov ntaub ntawv los ntawm ib qho ntxiv 42 cov qog qog uas tsis tau sib xws DNA ib txwm muaj rau kev tshuaj xyuas.Ua ntej, cov kws tshawb fawb tau sib piv cov txheeb ze ntawm cov nroj tsuag ntawm cov qog sib txuam thiab cov hnyuv noj qab haus huv.Clostridium perfringens tau nce ntau hauv cov qog piv rau cov qauv kev noj qab haus huv (Daim duab 3a-3d).Tsis muaj qhov sib txawv tseem ceeb hauv kev sib txawv ntawm alpha (kev sib txawv thiab ntau hom tsiaj hauv ib qho qauv) ntawm cov qog thiab cov qauv noj qab haus huv, thiab kev txo qis ntawm microbial ntau haiv neeg tau pom nyob rau hauv ICR-siab hlav ntsig txog ICR-tsawg qog.
Txhawm rau txheeb xyuas cov kev sib raug zoo hauv tsev kho mob ntawm cov kab mob microbial thiab cov txiaj ntsig kho mob, cov kws tshawb fawb tau tsom siv 16S rRNA gene sequencing cov ntaub ntawv los txheeb xyuas cov microbiome nta uas kwv yees muaj sia nyob.Ntawm AC-ICAM246, cov kws tshawb fawb tau khiav OS Cox regression qauv uas tau xaiv 41 cov yam ntxwv uas tsis yog xoom coefficients (txuas nrog cov kev pheej hmoo tuag sib txawv), hu ua MBR classifiers (Daim duab 3f).
Hauv qhov kev cob qhia no (ICAM246), qhov qhab nia MBR qis (MBR<0, qis MBR) tau cuam tshuam nrog kev pheej hmoo ntawm kev tuag (85%).Cov kws tshawb fawb tau lees paub qhov kev koom tes ntawm MBR qis (kev pheej hmoo) thiab ntev OS nyob rau hauv ob lub koom haum ywj pheej (ICAM42 thiab TCGA-COAD).(Daim duab 3) Txoj kev tshawb no pom muaj kev sib raug zoo ntawm endogastric cocci thiab MBR cov qhab nia, uas zoo sib xws hauv cov qog thiab cov nqaij mos noj qab haus huv.
Daim duab 3. Microbiome nyob rau hauv cov qog thiab cov ntaub so ntswg noj qab haus huv thiab kev sib raug zoo nrog ICR thiab cov neeg mob ciaj sia.
Xaus
Txoj kev siv ntau yam omics siv hauv txoj kev tshawb no ua kom paub meej thiab tsom xam ntawm molecular kos npe ntawm lub cev tiv thaiv kab mob hauv cov kab mob qog noj ntshav thiab qhia txog kev sib cuam tshuam ntawm microbiome thiab lub cev tiv thaiv kab mob.Sib sib zog nqus TCR sequencing ntawm qog thiab cov ntaub so ntswg noj qab nyob zoo qhia tau hais tias prognostic nyhuv ntawm ICR tej zaum yuav yog vim nws muaj peev xwm mus ntes cov qog-enriched thiab tej zaum qog antigen tshwj xeeb T cell clones.
Los ntawm kev txheeb xyuas cov qog microbiome muaj pes tsawg leeg siv 16S rRNA gene sequencing hauv AC-ICAM cov qauv, pab pawg tau txheeb xyuas qhov kos npe microbiome (MBR cov qhab nia txaus ntshai) nrog cov txiaj ntsig zoo.Txawm hais tias qhov kev kos npe no tau muab los ntawm cov qauv qog, muaj kev sib raug zoo ntawm kev noj qab haus huv ntawm lub plab thiab cov qog MBR qhov kev pheej hmoo, qhia tias qhov kos npe no tuaj yeem ntes cov plab hnyuv microbiome ntawm cov neeg mob.Los ntawm kev sib txuas cov qhab nia ICR thiab MBR, nws muaj peev xwm txheeb xyuas thiab siv tau ntau tus tub ntxhais kawm biomarker uas kwv yees muaj sia nyob hauv cov neeg mob qog noj ntshav.Txoj kev tshawb no ntau-omic dataset muab cov peev txheej kom nkag siab zoo dua kab mob qog noj ntshav hauv biology thiab pab nrhiav kev kho tus kheej.
Post lub sij hawm: Jun-15-2023