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Nat Med | Njira yama multi-omics popanga chotupa chophatikizika, chitetezo chamthupi komanso tizilombo tating'onoting'ono ta khansa ya colorectal chikuwonetsa kuyanjana kwa microbiome ndi chitetezo chamthupi.
Ngakhale ma biomarkers a khansa ya m'matumbo oyambilira aphunziridwa kwambiri m'zaka zaposachedwa, malangizo azachipatala apano amadalira pa tumor-lymph node-metastasis staging ndikuzindikira zolakwika za DNA mismatch kukonza (MMR) kapena kusakhazikika kwa microsatellite (MSI) (kuphatikiza pakuyezetsa wamba. ) kuti mudziwe zoyenera kuchita. Ofufuzawo awona kusowa kwa mgwirizano pakati pa mayankho amtundu wa jini, mbiri ya tizilombo tating'onoting'ono, ndi tumor stroma mu gulu la khansa ya colorectal Cancer Genome Atlas (TCGA) komanso kupulumuka kwa odwala.
Pamene kafukufuku wapita patsogolo, kuchuluka kwa khansa ya colorectal, kuphatikizapo ma cell a khansa, chitetezo cha mthupi, stromal, kapena tizilombo tating'onoting'ono ta khansayo, akuti akugwirizana kwambiri ndi zotsatira zachipatala, komabe kumvetsetsa pang'ono za momwe machitidwe awo amakhudzira zotsatira za odwala. .
Pofuna kusiyanitsa mgwirizano pakati pa zovuta za phenotypic ndi zotsatira zake, gulu la ofufuza a Sidra Institute of Medical Research ku Qatar posachedwapa linapanga ndikutsimikizira chiwerengero chophatikizika (mICRoScore) chomwe chimazindikiritsa gulu la odwala omwe ali ndi moyo wabwino pophatikiza makhalidwe a microbiome ndi kukana chitetezo cha mthupi. zokhazikika (ICR). Gululo lidasanthula mwatsatanetsatane za zitsanzo zatsopano zachisanu kuchokera kwa odwala 348 omwe ali ndi khansa yoyambirira ya colorectal, kuphatikiza kusanja kwa zotupa za RNA ndikufananiza minofu yathanzi, ma exome sequencing, cholandilira chakuya cha T-cell ndi 16S bacterial rRNA gene sequencing, kuwonjezeredwa ndi chotupa chonse. kutsatizana kwa ma genome kuti awonetserenso ma microbiome. Kafukufukuyu adasindikizidwa mu Nature Medicine monga "Chotupa chophatikizika, chitetezo cha mthupi komanso ma microbiome a khansa ya m'matumbo".
Nkhani yofalitsidwa mu Natural Medicine
AC-ICAM mwachidule
Ofufuza adagwiritsa ntchito nsanja ya orthogonal genomic kuti aunike zitsanzo zatsopano za chotupa chozizira ndikufananiza minofu yamtundu wamtundu wapamtima (mawiri awiri odziwika bwino) kuchokera kwa odwala omwe adazindikira kuti ali ndi khansa ya m'matumbo popanda chithandizo chamankhwala. Kutengera kutsata kwamtundu wonse (WES), kuwongolera kwa data ya RNA-seq, ndikuwunika kwa njira zophatikizira, ma data a genomic ochokera kwa odwala 348 adasungidwa ndikugwiritsidwa ntchito pakuwunika kutsika ndi kutsata kwapakatikati kwa zaka 4.6. Gulu lofufuzalo lidatcha gweroli Sidra-LUMC AC-ICAM: Mapu ndi kalozera wokhudzana ndi chitetezo chamthupi-cancer-microbiome (Chithunzi 1).
Gulu la mamolekyulu pogwiritsa ntchito ICR
Kutenga ma modular ma genetic markers opitilira kuwunika kwa khansa, yotchedwa immune constant of rejection (ICR), gulu lofufuza lidakulitsa ICR poyiyika mu gulu la 20-gene lomwe limakhala ndi mitundu yosiyanasiyana ya khansa, kuphatikiza khansa ya khansa, khansa ya chikhodzodzo, ndi khansa. khansa ya m'mawere. ICR idalumikizidwanso ndi kuyankha kwa immunotherapy mumitundu yosiyanasiyana ya khansa, kuphatikiza khansa ya m'mawere.
Choyamba, ofufuzawo adatsimikizira siginecha ya ICR ya gulu la AC-ICAM, pogwiritsa ntchito njira ya ICR gene-based co-classification kuti agawire gululo m'magulu atatu / magulu achitetezo a chitetezo chamthupi: ICR yapamwamba (zotupa zotentha), ICR yapakatikati ndi ICR yotsika (ozizira. zotupa) (Chithunzi 1b). Ofufuzawo adawonetsa kukhudzika kwa chitetezo chamthupi komwe kumalumikizidwa ndi consuss molecular subtypes (CMS), gulu lochokera ku transcriptome la khansa ya m'matumbo. magulu a CMS anaphatikizapo CMS1/immune, CMS2/canonical, CMS3/metabolic ndi CMS4/mesenchymal. Kuwunika kunawonetsa kuti kuchuluka kwa ICR kumalumikizidwa moyipa ndi njira zina zama cell a khansa m'magawo onse a CMS, ndipo zolumikizana zabwino ndi njira zoteteza chitetezo chathupi komanso zokhudzana ndi stromal zidangowonedwa muzotupa za CMS4 zokha.
Mu CMS yonse, kuchuluka kwa ma cell akupha (NK) cell ndi T cell subsets kunali kwapamwamba kwambiri mu ICR high immune subtypes, ndi kusinthasintha kwakukulu m'magulu ena a leukocyte (Figure 1c) .ICR immune subtypes inali ndi OS ndi PFS yosiyana, ndi kuwonjezeka kwapang'onopang'ono mu ICR kuchokera pansi mpaka pamwamba (Chithunzi 1d), kutsimikizira gawo la ICR mu khansa yapakhungu.
Chithunzi 1. Mapangidwe a maphunziro a AC-ICAM, siginecha ya jini yokhudzana ndi chitetezo cha mthupi, chitetezo cha mthupi ndi maselo aang'ono ndi kupulumuka.
ICR imagwira ma T cell omwe ali ndi chotupa, opangidwa ndi clonally
Ma cell ochepa chabe a T omwe amalowetsa minofu ya chotupa adanenedwa kuti ndi enieni a antigen (ochepera 10%). Chifukwa chake, ma cell a intra-tumor T ambiri amatchedwa maselo a T omwe amangoyimilira (ma cell T oyimilira). Kulumikizana kolimba kwambiri ndi kuchuluka kwa maselo ochiritsira a T omwe ali ndi TCRs obala kunawonedwa mu cell stromal cell ndi leukocyte subpopulations (omwe apezeka ndi RNA-seq), omwe angagwiritsidwe ntchito kuyerekezera kuchuluka kwa T cell (Chithunzi 2a). M'magulu a ICR (anthu onse ndi CMS), kuphatikizika kwapamwamba kwambiri kwa chitetezo chamthupi cha SEQ TCR kunawonedwa mu ICR-high ndi CMS subtype CMS1/magulu ammune (Chithunzi 2c), okhala ndi gawo lalikulu kwambiri la zotupa za ICR. Pogwiritsa ntchito transcriptome yonse (majini a 18,270), majini asanu ndi limodzi a ICR (IFNG, STAT1, IRF1, CCL5, GZMA, ndi CXCL10) anali m'gulu la majini khumi omwe amagwirizanitsidwa bwino ndi TCR immune SEQ clonality (Chithunzi 2d). ImmunoSEQ TCR clonality imalumikizana mwamphamvu kwambiri ndi majini ambiri a ICR kuposa momwe amagwiritsidwira ntchito pogwiritsa ntchito zolembera za CD8+ zoyankha chotupa (Chithunzi 2f ndi 2g). Pomaliza, kuwunika komweku kukuwonetsa kuti siginecha ya ICR imagwira kukhalapo kwa maselo a T omwe ali ndi chotupa, opangidwa ndi clonally ndipo atha kufotokozera zotsatira zake.
Chithunzi 2. TCR ma metrics ndi mgwirizano ndi majini okhudzana ndi chitetezo cha mthupi, chitetezo cha mthupi ndi ma cell subtypes.
Kapangidwe ka Microbiome mumatumbo athanzi komanso a khansa ya m'matumbo
Ofufuzawo anachita 16S rRNA kutsatizana pogwiritsa ntchito DNA yotengedwa ku chotupa chofananira ndi minofu yathanzi yamatumbo kuchokera kwa odwala 246 (Chithunzi 3a). Kuti atsimikizire, ofufuzawo adasanthulanso zambiri zamtundu wa 16S rRNA kuchokera ku zitsanzo zina 42 zotupa zomwe sizinafanane ndi DNA wamba yomwe ikupezeka kuti iwunikenso. Choyamba, ofufuzawo adayerekezera kuchuluka kwa zomera pakati pa zotupa zofananira ndi minofu yathanzi yamatumbo. Clostridium perfringens inawonjezeka kwambiri m'matumbo poyerekeza ndi zitsanzo zathanzi (Chithunzi 3a-3d). Panalibe kusiyana kwakukulu pamitundu yosiyanasiyana ya alpha (kusiyanasiyana ndi kuchuluka kwa zamoyo pachitsanzo chimodzi) pakati pa chotupa ndi zitsanzo zathanzi, komanso kuchepa pang'ono kwa mitundu ya tizilombo tating'onoting'ono kunawonedwa mu zotupa za ICR-zambiri zokhudzana ndi zotupa zotsika za ICR.
Kuti azindikire mayanjano okhudzana ndi zamankhwala pakati pa mbiri yazachipatala ndi zotsatira zachipatala, ofufuzawo adafuna kugwiritsa ntchito 16S rRNA gene sequencing data kuti azindikire mawonekedwe a microbiome omwe amalosera kupulumuka. Pa AC-ICAM246, ochita kafukufuku adayendetsa chitsanzo cha OS Cox chowongolera chomwe chinasankha zinthu za 41 zomwe zili ndi ma coefficients osakhala a zero (zokhudzana ndi chiopsezo cha imfa), otchedwa MBR classifiers (Chithunzi 3f).
Mu gulu la maphunziro awa (ICAM246), chiwerengero chochepa cha MBR (MBR <0, chochepa MBR) chinagwirizanitsidwa ndi chiopsezo chochepa cha imfa (85%). Ofufuza adatsimikizira mgwirizano pakati pa MBR (zowopsa) ndi OS yayitali m'magulu awiri ovomerezeka (ICAM42 ndi TCGA-COAD). (Chithunzi 3) Kafukufukuyu adawonetsa kugwirizana kwakukulu pakati pa endogastric cocci ndi MBR zambiri, zomwe zinali zofanana ndi chotupa ndi minofu yathanzi ya colon.
Chithunzi 3. Microbiome mu chotupa ndi minofu yathanzi komanso ubale ndi ICR ndi kupulumuka kwa odwala.
Mapeto
Njira yama multi-omics yomwe imagwiritsidwa ntchito mu kafukufukuyu imathandizira kuzindikira ndikuwunika bwino kwa siginecha ya maselo a chitetezo chamthupi mu khansa ya colorectal ndikuwulula kuyanjana pakati pa microbiome ndi chitetezo chamthupi. Tsatanetsatane wakuya wa TCR wa chotupa ndi minyewa yathanzi idavumbulutsa kuti tsogolo la ICR likhoza kukhala chifukwa cha kuthekera kwake kugwira ma cell a chotupa omwe ali ndi chotupa komanso mwina chotupa cha antigen-specific T cell.
Posanthula kapangidwe ka chotupa cha microbiome pogwiritsa ntchito ma 16S rRNA gene mu zitsanzo za AC-ICAM, gululo lidazindikira siginecha ya microbiome (MBR risk score) yokhala ndi chiyembekezo champhamvu. Ngakhale siginecha iyi idachokera ku zitsanzo za chotupa, panali kulumikizana kwamphamvu pakati pa colorectum wathanzi ndi chotupa cha MBR pachiwopsezo, kutanthauza kuti siginecha iyi imatha kujambula matumbo a odwala. Mwa kuphatikiza kuchuluka kwa ICR ndi MBR, zinali zotheka kuzindikira ndikutsimikizira biomarker ya ophunzira ambiri omwe amalosera kupulumuka kwa odwala omwe ali ndi khansa ya m'matumbo. Zolemba zambiri za kafukufukuyu zimapereka chida chothandizira kumvetsetsa bwino biology ya khansa ya m'matumbo ndikuthandizira kupeza njira zochizira makonda.
Nthawi yotumiza: Jun-15-2023
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