Nata Med | Hanya mai yawa-omics don tsara taswirar hadedde ƙari

Nata Med | Hanya mai yawa-omics don tsara taswirar haɗaɗɗun ƙwayar cuta, rigakafi da yanayin yanayin ƙwayoyin cuta na ciwon daji na launi yana bayyana hulɗar microbiome tare da tsarin rigakafi.
Kodayake an yi nazarin abubuwan da ke haifar da ciwon daji na hanji na farko a cikin 'yan shekarun nan, jagororin asibiti na yanzu sun dogara ne kawai akan matakan ƙwayar cuta-lymph node-metastasis da gano lahani na DNA mismatch (MMR) lahani ko rashin zaman lafiya na microsatellite (MSI) (ban da daidaitaccen gwajin cututtukan cututtuka). ) don ƙayyade shawarwarin magani. Masu bincike sun lura da rashin haɗin kai tsakanin amsawar rigakafi na tushen maganganun kwayoyin halitta, bayanan ƙwayoyin cuta, da ƙari stroma a cikin ƙungiyar Cancer Genome Atlas (TCGA) ciwon daji na launin fata da kuma rayuwar haƙuri.

Yayin da bincike ya ci gaba, an ba da rahoton ƙididdiga masu ƙididdiga na ciwon daji na farko, ciki har da ciwon daji, na rigakafi, stromal, ko yanayin microbial na ciwon daji, don yin tasiri sosai tare da sakamakon asibiti, amma har yanzu akwai iyakacin fahimtar yadda hulɗar su ke shafar sakamakon haƙuri. .
Don rarraba alaƙar da ke tsakanin rikitarwa da sakamako, ƙungiyar masu bincike daga Cibiyar Nazarin Kiwon Lafiya ta Sidra a Qatar kwanan nan ta haɓaka kuma ta tabbatar da ƙimar haɗin gwiwa (mICRoScore) wanda ke gano ƙungiyar marasa lafiya tare da ƙimar rayuwa mai kyau ta hanyar haɗa halayen microbiome da ƙin yarda da rigakafi. Ƙaddamarwa (ICR). Tawagar ta yi cikakken nazarin kwayoyin halitta na sabbin samfuran daskararre daga marasa lafiya 348 da ke da ciwon daji na farko, gami da jerin RNA na ciwace-ciwacen ciwace-ciwacen ciwace da madaidaicin nama mai launi mai kyau, cikakken jerin abubuwan exome, mai karɓar ƙwayoyin T-cell mai zurfi da jerin kwayoyin rRNA na ƙwayoyin cuta na 16S, wanda ƙari gabaɗaya. genome sequencing don ƙara siffanta microbiome. An buga binciken a cikin Magungunan Nature a matsayin "Cutar da aka haɗa, rigakafi da microbiome atlas na ciwon daji na hanji".

Labarin da aka buga a cikin Magungunan yanayi

Bayanin AC-ICAM

Masu bincike sun yi amfani da dandali na genomic na orthogonal don tantance sabbin samfuran ciwace-ciwacen daskararre da kuma daidaita madaidaicin ƙwayar hanji mai lafiya (tumor-na al'ada nau'i-nau'i) daga marasa lafiya tare da binciken tarihin kansa na hanji ba tare da tsarin tsarin ba. Dangane da jeri na gaba ɗaya (WES), sarrafa ingancin bayanai na RNA-seq, da tantance ma'auni, an adana bayanan genomic daga marasa lafiya 348 kuma an yi amfani da su don bincike na ƙasa tare da bin tsaka-tsaki na shekaru 4.6. Ƙungiyar binciken ta sanya wa wannan albarkatu suna Sidra-LUMC AC-ICAM: Taswira da jagora zuwa hulɗar rigakafi-cancer-microbiome (Hoto 1).

Rarraba kwayoyin halitta ta amfani da ICR

Ɗauki nau'i na nau'i na nau'i na kwayoyin halitta na rigakafi don ci gaba da rigakafi na ciwon daji, wanda ake kira da ciwon rigakafi akai-akai (ICR), ƙungiyar bincike ta inganta ICR ta hanyar tattara shi a cikin wani nau'i na nau'i na 20 wanda ke rufe nau'in ciwon daji daban-daban, ciki har da melanoma, ciwon daji na mafitsara, da kuma ciwon nono. ICR kuma an haɗa shi da amsawar rigakafi a cikin nau'ikan ciwon daji iri-iri, gami da kansar nono.

Na farko, masu binciken sun tabbatar da sa hannun ICR na ƙungiyar AC-ICAM, ta amfani da tsarin haɗin kai na tushen tushen ICR don rarraba ƙungiyar zuwa rukuni uku / nau'in rigakafi: babban ICR (ciwon daji mai zafi), matsakaici ICR da ƙananan ICR (sanyi). ciwace-ciwace) (Hoto na 1b). Masu bincike sun ba da fifikon kariyar da ke da alaƙa da ijma'i na ƙwayoyin ƙwayoyin cuta (CMS), rabe-rabe mai tushe na ciwon daji na hanji. Rukunin CMS sun haɗa da CMS1/immune, CMS2/canonical, CMS3/metabolic da CMS4/mesenchymal. Bincike ya nuna cewa maki na ICR sun yi mummunar alaƙa tare da wasu hanyoyin ƙwayar cutar kansa a cikin dukkan nau'ikan CMS, kuma an lura da alaƙa mai kyau tare da hanyoyin rigakafi da hanyoyin da suka shafi stromal kawai a cikin ciwace-ciwacen CMS4.

A cikin dukkanin CMS, yawancin ƙwayoyin kisa na halitta (NK) da kuma ƙwayoyin T cell sun kasance mafi girma a cikin ICR high rigakafi subtypes, tare da mafi girma canji a cikin sauran leukocyte subsets (Figure 1c) .ICR rigakafi subtypes da daban-daban OS da PFS, tare da ci gaba karuwa. a cikin ICR daga ƙasa zuwa babba (Hoto na 1d), yana tabbatar da aikin hasashen ICR a cikin ciwon daji na launi.

Hoto 1. Tsarin nazarin AC-ICAM, sa hannun jinsin da ke da alaƙa da rigakafi, ƙwayoyin rigakafi da ƙwayoyin cuta da kuma rayuwa.
ICR tana ɗaukar ƙwararrun ƙwayoyin cuta, ƙwayoyin T masu haɓakawa
Wasu tsirarun ƙwayoyin T da ke kutsawa cikin ƙwayar ƙwayar cuta kawai an ba da rahoton cewa sun keɓance ga antigens na ƙari (kasa da 10%). Sabili da haka, yawancin ƙwayoyin T-tumor ana kiran su da ƙwayoyin T (kwayoyin T masu kusa). An lura da alaƙa mafi ƙarfi tare da adadin ƙwayoyin T na al'ada tare da TCRs masu albarka a cikin ƙwayoyin stromal cell da leukocytes (wanda aka gano ta RNA-seq), wanda za'a iya amfani da shi don ƙididdige yawan adadin ƙwayoyin T cell (Hoto 2a). A cikin gungu na ICR (gabaɗaya da rarrabuwa na CMS), an lura da mafi girman clonality na rigakafi na SEQ TCRs a cikin ICR-high da CMS subtype CMS1 / ƙungiyoyin rigakafi (Figure 2c), tare da mafi girman rabo na ICR-high ciwace-ciwacen daji. Yin amfani da dukkanin bayanan (18,270 genes), kwayoyin ICR guda shida (IFNG, STAT1, IRF1, CCL5, GZMA, da CXCL10) sun kasance daga cikin manyan kwayoyin halitta guda goma da suka dace da TCR na rigakafi SEQ clonality (Figure 2d). ImmunoSEQ TCR clonality yana da alaƙa da ƙarfi tare da mafi yawan ƙwayoyin ICR fiye da alaƙar da aka lura ta amfani da alamun CD8+ masu ɗaukar ƙari (Hoto 2f da 2g). A ƙarshe, binciken da ke sama yana nuna cewa sa hannu na ICR yana ɗaukar kasancewar wadatattun ƙwayoyin cuta, ƙwayoyin T masu haɓakawa kuma yana iya yin bayanin abubuwan hasashen sa.

Hoto 2. Ma'auni na TCR da haɗin kai tare da kwayoyin da ke da alaka da rigakafi, ƙwayoyin rigakafi da kwayoyin halitta.
Abubuwan da ke tattare da microbiome a cikin lafiyayyen ƙwayoyin cutar kansar hanji
Masu binciken sun yi jerin gwanon 16S rRNA ta amfani da DNA da aka fitar daga madaidaicin ƙwayar cuta da ƙwayar hanji mai lafiya daga marasa lafiya 246 (Hoto 3a). Don tabbatarwa, masu binciken sun kuma bincika bayanan jerin kwayoyin halittar 16S rRNA daga ƙarin samfuran ƙari guda 42 waɗanda ba su dace da DNA na yau da kullun don bincike ba. Na farko, masu binciken sun kwatanta dangin yalwar flora tsakanin ciwace-ciwacen da suka dace da ƙwayar hanji mai lafiya. Clostridium perfringens ya karu sosai a cikin ciwace-ciwacen da aka kwatanta da samfurori masu lafiya (Hoto 3a-3d). Babu wani bambanci mai mahimmanci a cikin nau'in alpha (bambanci da yawan nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'in nau'i nau'i nau'i nau'i nau'i nau'i nau'i nau'i nau'i nau'i nau'i nau'i nau'i nau'i nau'i nau'i nau'i nau'i)) tsakanin ciwon daji da samfurori masu lafiya, kuma an sami raguwa mai sauƙi a cikin ƙananan ƙwayoyin cuta a cikin ciwace-ciwacen ciwace-ciwacen ICR dangane da ciwace-ciwacen ICR-low.
Don gano ƙungiyoyin da suka dace da asibiti tsakanin bayanan ƙananan ƙwayoyin cuta da sakamakon asibiti, masu binciken sun yi niyyar amfani da bayanan jeri na 16S rRNA don gano abubuwan microbiome waɗanda ke hasashen rayuwa. A AC-ICAM246, masu binciken sun gudanar da wani samfurin regression OS Cox wanda ya zaɓi siffofi na 41 tare da ƙididdiga marasa sifili (wanda ke da alaƙa da bambancin mace-mace), wanda ake kira MBR classifiers (Figure 3f).
A cikin wannan ƙungiyar horarwa (ICAM246), ƙaramin maki MBR (MBR<0, ƙaramin MBR) yana da alaƙa da ƙarancin haɗarin mutuwa (85%). Masu bincike sun tabbatar da haɗin gwiwa tsakanin ƙananan MBR (haɗari) da OS mai tsawo a cikin ƙungiyoyi biyu masu zaman kansu (ICAM42 da TCGA-COAD). (Hoto na 3) Binciken ya nuna alaƙa mai ƙarfi tsakanin cocci na endogastric da maki MBR, waɗanda suka yi kama da ƙari da ƙwayar hanji mai lafiya.

Hoto 3. Microbiome a cikin ƙwayar cuta da ƙwayoyin lafiya da kuma dangantaka da ICR da rayuwa mai haƙuri.
Kammalawa
Hanyar multiomics da aka yi amfani da ita a cikin wannan binciken yana ba da damar ganowa sosai da kuma nazarin sa hannun kwayoyin halitta na amsawar rigakafi a cikin ciwon daji na launi da kuma bayyana hulɗar tsakanin microbiome da tsarin rigakafi. Tsarin TCR mai zurfi na ƙari da kyallen takarda masu lafiya sun bayyana cewa tasirin tsinkayar ICR na iya kasancewa saboda ikonsa na kama wadataccen ƙwayar ƙwayar cuta da yuwuwar ƙwayoyin ƙwayoyin ƙwayoyin ƙwayoyin ƙwayoyin ƙwayoyin ƙwayoyin ƙwayoyin ƙwayoyin cuta na antigen.

Ta hanyar nazarin abun da ke tattare da ƙwayar cuta ta ƙwayar cuta ta amfani da jerin abubuwan 16S rRNA a cikin samfuran AC-ICAM, ƙungiyar ta gano sa hannun microbiome (makin haɗarin MBR) tare da ƙima mai ƙarfi. Ko da yake an samo wannan sa hannun daga samfuran ƙari, akwai alaƙa mai ƙarfi tsakanin lafiyayyen launi da ƙari MBR haɗarin haɗari, yana ba da shawarar cewa wannan sa hannu na iya ɗaukar abun da ke tattare da ƙwayoyin cuta na hanji na marasa lafiya. Ta hanyar haɗa maki ICR da MBR, yana yiwuwa a gano da kuma tabbatar da ɗalibi mai ƙima mai ƙima wanda ke hasashen rayuwa a cikin marasa lafiya masu fama da ciwon hanji. Saitin bayanan omic da yawa na binciken yana ba da hanya don ƙarin fahimtar ilimin halittar cutar kansar hanji da taimakawa gano hanyoyin warkewa na keɓaɓɓen.

Magana:
Roelands, J., Kuppen, PJK, Ahmed, EI et al. Haɗaɗɗen ƙari, rigakafi da microbiome atlas na ciwon daji na hanji. Nat Med 29, 1273-1286 (2023).