Nat Med | He ala multi-omics no ke kaha kiʻi ʻana i ka puʻupuʻu i hoʻohui ʻia

Nat Med | ʻO kahi ala multi-omics i ka palapala ʻana i ka ʻāina tumor i hoʻohui ʻia, ka pale ʻana a me ka microbial o ke kanesa colorectal e hōʻike ana i ka pilina o ka microbiome me ka ʻōnaehana pale.
ʻOiai ua aʻo nui ʻia nā biomarkers no ke kanesa colon mua i nā makahiki i hala iho nei, ʻo nā alakaʻi lapaʻau o kēia manawa e hilinaʻi wale ana i ka tumor-lymph node-metastasis staging a me ka ʻike ʻana i nā hemahema hoʻoponopono mismatch DNA (MMR) a i ʻole ka microsatellite instability (MSI) (me ka hoʻāʻo pathology maʻamau) e hoʻoholo i nā ʻōlelo aʻoaʻo lapaʻau. Ua ʻike nā kānaka noiʻi i ka nele o ka pilina ma waena o nā pane pale i hoʻokumu ʻia i ka gene expression, nā microbial profiles, a me ka tumor stroma i loko o ka Cancer Genome Atlas (TCGA) colorectal cancer cohort a me ke ola o ka mea maʻi.

I ka holomua ʻana o ka noiʻi, ua hōʻike ʻia nā ʻano helu o ke kanesa colorectal mua, me ke ʻano cellular cancer, immune, stromal, a microbial paha o ke kanesa, e pili pono ana i nā hopena lapaʻau, akā ua kaupalena ʻia ka ʻike pehea e pili ai kā lākou pilina i nā hopena o ka mea maʻi.
No ka wehewehe ʻana i ka pilina ma waena o ka paʻakikī phenotypic a me ka hopena, ua hoʻomohala koke nei kahi hui o nā mea noiʻi mai ka Sidra Institute of Medical Research ma Qatar a ua hōʻoia i kahi helu i hoʻohui ʻia (mICRoScore) e ʻike ana i kahi hui o nā maʻi me nā helu ola maikaʻi ma o ka hoʻohui ʻana i nā ʻano microbiome a me nā constants rejection immune (ICR). Ua hana ka hui i kahi loiloi genomic piha o nā laʻana hau hou mai 348 mau maʻi me ka maʻi ʻaʻai colorectal mua, me ka RNA sequencing o nā tumors a me nā ʻiʻo colorectal olakino i hoʻohālikelike ʻia, ka sequencing exome holoʻokoʻa, ka receptor T-cell hohonu a me ka 16S bacterial rRNA gene sequencing, i hoʻohui ʻia e ka sequencing genome tumor holoʻokoʻa e hoʻomaopopo hou aku i ka microbiome. Ua paʻi ʻia ke aʻo ʻana ma Nature Medicine ma ke ʻano he "An integrated tumor, immune and microbiome atlas of colon cancer".

ʻAtikala i paʻi ʻia ma Nature Medicine

ʻIkepili AC-ICAM

Ua hoʻohana nā kānaka noiʻi i kahi kahua genomic orthogonal e kālailai i nā hāpana tumo hou i hoʻopaʻa ʻia a hoʻohālikelike i nā ʻiʻo colon olakino e pili ana (nā hui tumo-maʻamau) mai nā poʻe maʻi me kahi hōʻailona histologic o ka maʻi ʻaʻai colon me ka ʻole o ka lāʻau lapaʻau systemic. Ma muli o ka whole-exome sequencing (WES), ka mana o ka maikaʻi o ka ʻikepili RNA-seq, a me ka nānā ʻana i nā pae hoʻokomo, ua mālama ʻia nā ʻikepili genomic mai 348 mau maʻi a hoʻohana ʻia no ka nānā ʻana ma hope me ka hahai ʻana o 4.6 mau makahiki. Ua kapa ka hui noiʻi i kēia kumuwaiwai ʻo Sidra-LUMC AC-ICAM: He palapala ʻāina a me ke alakaʻi i nā pilina immune-cancer-microbiome (Kiʻi 1).

Ka hoʻokaʻawale ʻana o nā molekala me ka hoʻohana ʻana i ka ICR

Ma ka hopu ʻana i kahi hoʻonohonoho modular o nā māka genetic immune no ka immunosurveillance cancer hoʻomau, i kapa ʻia ʻo ka immune constant of rejection (ICR), ua hoʻomaikaʻi ka hui noiʻi i ka ICR ma ka hoʻopili ʻana iā ia i loko o kahi panela 20-gene e uhi ana i nā ʻano maʻi kanesa like ʻole, me ka melanoma, ka maʻi ʻōpū, a me ka maʻi umauma. Ua pili pū ʻia ʻo ICR me ka pane immunotherapy i nā ʻano maʻi kanesa like ʻole, me ka maʻi umauma.

ʻO ka mea mua, ua hōʻoia nā mea noiʻi i ka pūlima ICR o ka hui AC-ICAM, me ka hoʻohana ʻana i kahi ʻano hoʻokaʻawale like ʻana o ka gene ICR e hoʻokaʻawale i ka hui i ʻekolu mau hui/nā ʻano like ʻole o ka pale ʻana: ICR kiʻekiʻe (nā ʻōpū wela), ICR waena a me ICR haʻahaʻa (nā ʻōpū anu) (Kiʻi 1b). Ua wehewehe nā mea noiʻi i ka ʻano pale ʻana e pili ana me nā ʻano like ʻole o ka molekala (CMS), kahi hoʻokaʻawale ʻana o ka maʻi ʻaʻai colon e pili ana i ka transcriptome. ʻO nā māhele CMS i hoʻokomo pū ʻia me CMS1/immune, CMS2/canonical, CMS3/metabolic a me CMS4/mesenchymal. Ua hōʻike ka loiloi ua pili maikaʻi ʻole nā ​​​​helu ICR me kekahi mau ala cell cancer i nā ʻano like ʻole o ka CMS, a ʻike ʻia nā pilina maikaʻi me nā ala immunosuppressive a me nā ala e pili ana i ka stromal i nā ʻōpū CMS4 wale nō.

Ma nā CMS āpau, ʻo ka nui o nā cell pepehi kanaka kūlohelohe (NK) a me nā subsets cell T ka mea kiʻekiʻe loa i nā subtypes pale kiʻekiʻe ICR, me ka ʻokoʻa nui aʻe i nā subsets leukocyte ʻē aʻe (Kiʻi 1c). He ʻokoʻa ka OS a me ka PFS o nā subtypes pale ICR, me ka piʻi holomua o ICR mai ka haʻahaʻa a i ke kiʻekiʻe (Kiʻi 1d), e hōʻoia ana i ke kuleana prognostic o ICR i ka maʻi ʻaʻai colorectal.

Kiʻi 1. Hoʻolālā haʻawina AC-ICAM, pūlima gene e pili ana i ka pale ʻana, nā ʻano ʻano pale ʻana a me nā molekala a me ke ola ʻana.
Hopu ʻo ICR i nā pūnaewele T i hoʻonui ʻia i ka tumor, clonally amplified
ʻO kahi hapa liʻiliʻi wale nō o nā pūnaewele T e komo ana i loko o ka ʻiʻo tumor ua hōʻike ʻia he kikoʻī no nā antigens tumor (ʻaʻole iʻoi aku ma mua o 10%). No laila, ʻo ka hapa nui o nā pūnaewele T intra-tumor i kapa ʻia ʻo nā pūnaewele T bystander (nā pūnaewele T bystander). ʻO ka pilina ikaika loa me ka helu o nā pūnaewele T maʻamau me nā TCR huahua i ʻike ʻia i loko o nā subpopulations cell stromal a me nā leukocyte (i ʻike ʻia e RNA-seq), hiki ke hoʻohana ʻia e kuhi i nā subpopulations cell T (Kiʻi 2a). I loko o nā hui ICR (ka hoʻokaʻawale ʻana o ka ICR a me CMS), ʻo ka clonality kiʻekiʻe loa o nā TCR SEQ immune i ʻike ʻia i loko o nā hui ICR-kiʻekiʻe a me CMS subtype CMS1/immune (Kiʻi 2c), me ka hapa nui loa o nā tumors ICR-kiʻekiʻe. Ma ka hoʻohana ʻana i ka transcriptome holoʻokoʻa (18,270 genes), ʻeono mau genes ICR (IFNG, STAT1, IRF1, CCL5, GZMA, a me CXCL10) i waena o nā genes he ʻumi kiʻekiʻe e pili pono ana me ka clonality TCR immune SEQ (Kiʻi 2d). ʻOi aku ka ikaika o ka pilina o ka ImmunoSEQ TCR clonality me ka hapa nui o nā genes ICR ma mua o nā pilina i ʻike ʻia me ka hoʻohana ʻana i nā māka CD8+ pane-tumor (Kiʻi 2f a me 2g). I ka hopena, hōʻike ka loiloi ma luna nei ua hopu ka pūlima ICR i ke alo o nā cell T i hoʻonui ʻia i ka tumor, i hoʻonui ʻia i ka clonally a hiki ke wehewehe i kona mau hopena prognostic.

Kiʻi 2. Nā ana TCR a me ka pilina me nā genes e pili ana i ka pale ʻana, nā ʻano ʻano pale ʻana a me nā molekala.
ʻO ka haku mele ʻana o ka Microbiome i loko o nā ʻiʻo olakino a me nā ʻiʻo kanesa colon
Ua hana nā kānaka noiʻi i ka hoʻonohonoho ʻana o 16S rRNA me ka hoʻohana ʻana i ka DNA i unuhi ʻia mai ka puʻupuʻu i kūlike a me ka ʻiʻo kolona olakino mai 246 mau maʻi (Kiʻi 3a). No ka hōʻoia ʻana, ua kālailai hou nā kānaka noiʻi i ka ʻikepili hoʻonohonoho gene 16S rRNA mai kahi 42 mau laʻana puʻupuʻu hou aʻe i loaʻa ʻole ka DNA maʻamau i kūlike no ka nānā ʻana. ʻO ka mea mua, ua hoʻohālikelike nā kānaka noiʻi i ka nui o nā flora ma waena o nā puʻupuʻu i kūlike a me ka ʻiʻo kolona olakino. Ua hoʻonui nui ʻia ʻo Clostridium perfringens i loko o nā puʻupuʻu i hoʻohālikelike ʻia me nā laʻana olakino (Kiʻi 3a-3d). ʻAʻohe ʻokoʻa koʻikoʻi i ka ʻokoʻa alpha (ʻokoʻa a me ka nui o nā ʻano i loko o hoʻokahi laʻana) ma waena o ka puʻupuʻu a me nā laʻana olakino, a ua ʻike ʻia kahi emi iki o ka ʻokoʻa microbial i nā puʻupuʻu ICR-kiʻekiʻe e pili ana i nā puʻupuʻu ICR-haʻahaʻa.
No ka ʻike ʻana i nā pilina pili i ke kauka ma waena o nā ʻikepili microbial a me nā hopena lapaʻau, ua manaʻo nā mea noiʻi e hoʻohana i ka ʻikepili hoʻonohonoho gene 16S rRNA e ʻike i nā hiʻohiʻona microbiome e wānana i ke ola. Ma AC-ICAM246, ua holo nā mea noiʻi i kahi kumu hoʻohālike regression OS Cox i koho i 41 mau hiʻohiʻona me nā coefficients non-zero (e pili ana me ka pilikia make like ʻole), i kapa ʻia ʻo MBR classifiers (Kiʻi 3f).
Ma kēia hui hoʻomaʻamaʻa (ICAM246), ua pili ka helu MBR haʻahaʻa (MBR<0, MBR haʻahaʻa) me ka emi nui o ka make (85%). Ua hōʻoia nā kānaka noiʻi i ka pilina ma waena o ka MBR haʻahaʻa (pilikia) a me ka OS lōʻihi i ʻelua mau hui i hōʻoia kūʻokoʻa ʻia (ICAM42 a me TCGA-COAD). (Kiʻi 3) Ua hōʻike ke aʻo ʻana i kahi pilina ikaika ma waena o ka cocci endogastric a me nā helu MBR, i like like i ka tumor a me ka ʻiʻo colon olakino.

Kiʻi 3. Microbiome i loko o ka puʻupuʻu a me nā ʻiʻo olakino a me ka pilina me ICR a me ke ola ʻana o ka mea maʻi.
Hopena
ʻO ke ʻano multi-omics i hoʻohana ʻia ma kēia haʻawina e hiki ai ke ʻike pono a me ka nānā ʻana i ka pūlima molekala o ka pane pale ma ke kanesa colorectal a hōʻike i ka pilina ma waena o ka microbiome a me ka ʻōnaehana pale. Ua hōʻike ka hoʻonohonoho hohonu ʻana o ka TCR o ka tumor a me nā ʻiʻo olakino e hiki ke hopena prognostic o ICR ma muli o kona hiki ke hopu i nā clones cell T i hoʻonui ʻia i ka tumor a me ka tumor antigen-specific.

Ma ka nānā ʻana i ka haku mele ʻana o ka microbiome tumor me ka hoʻohana ʻana i ka hoʻonohonoho ʻana o ka gene 16S rRNA i nā laʻana AC-ICAM, ua ʻike ka hui i kahi pūlima microbiome (helu pilikia MBR) me ka waiwai prognostic ikaika. ʻOiai ua loaʻa kēia pūlima mai nā laʻana tumor, aia kahi pilina ikaika ma waena o ke colorectum olakino a me ka helu pilikia MBR tumor, e hōʻike ana e hiki i kēia pūlima ke hopu i ka haku mele microbiome ʻōpū o nā maʻi. Ma ka hoʻohui ʻana i nā helu ICR a me MBR, ua hiki ke ʻike a hōʻoia i kahi biomarker haumāna multi-omic e wānana ana i ke ola ʻana i nā maʻi me ka maʻi ʻaʻai colon. Hāʻawi ka ʻikepili multi-omic o ke aʻo ʻana i kahi kumuwaiwai e hoʻomaopopo maikaʻi i ka biology kanesa colon a kōkua i ka ʻike ʻana i nā ʻano therapeutic pilikino.

Kuhikuhi:
Roelands, J., Kuppen, PJK, Ahmed, EI et al. ʻO kahi tumo i hoʻohui ʻia, immune a me ka microbiome atlas o ka maʻi maʻi ʻaʻai. Nat Med 29, 1273–1286 (2023).