Nat Med | Uburyo-butandukanye bwo gushushanya ikibyimba cyahujwe

Nat Med | Uburyo butandukanye bwo gushushanya ikarita yibibyimba, immunite na mikorobe ya kanseri yibara ryerekana imikoranire ya mikorobe na sisitemu yumubiri.
Nubwo biomarkers ya kanseri yibanze yibyigishijwe cyane mumyaka yashize, amabwiriza yubuvuzi ashingiye gusa kubibyimba-lymph node-metastasis kubika no gutahura inenge zidahuye na ADN (MMR) cyangwa ihungabana rya microsatellite (MSI) (usibye kwipimisha bisanzwe). Abashakashatsi bavuze ko kubura ishyirahamwe hagati ya Gene mvugo - imyirondoro ya mikorobe, kandi ikibyimba cya kanseri ya kanseri ya kanseri (TCGA).

Nkuko ubushakashatsi bumaze gutera imbere, ibimenyetso biranga kanseri yibanze ya kanseri yibara, harimo kanseri ya kanseri, immunite, tromal, cyangwa mikorobe ya kanseri, byavuzwe ko bifitanye isano cyane n’ibyavuye mu mavuriro, ariko haracyari imyumvire mike y’ukuntu imikoranire yabo igira ingaruka ku barwayi.
Kugira ngo habeho gutandukanya isano iri hagati ya fenotipiki n’ibisubizo, itsinda ry’abashakashatsi bo mu kigo cy’ubushakashatsi cy’ubuvuzi cya Sidra muri Qatar giherutse gukora kandi cyemeza amanota ahuriweho (mICRoScore) agaragaza itsinda ry’abarwayi bafite ubuzima bwiza bahuza imiterere ya mikorobe hamwe no kwanga ubudahangarwa bw'umubiri (ICR). Iri tsinda ryakoze isesengura ryimbitse ry’ubushakashatsi bwakozwe ku barwayi 348 barwaye kanseri y’ibanze y’ibanze, harimo RNA ikurikirana ibibyimba hamwe nuduce twiza twa colorectal, ibyakurikiranye byose, reseptor ya T-selile hamwe na 16S ya bagiteri ya RRNA ikurikirana, ikongerwaho na genome ikurikirana ikomeza kuranga mikorobe. Ubushakashatsi bwasohotse mu buvuzi bwa Kamere nka “Ikibyimba cyuzuye, immunite na microbiome atlas ya kanseri y'amara”.

Ingingo yatangajwe mu buvuzi bwa Kamere

Incamake ya AC-ICAM

Abashakashatsi bifashishije urubuga rwa genomic orthogonal kugira ngo basesengure ibibyimba bishya bikonje kandi bihuye nuduce twiza twiza twitwa colon (ibibyimba-bisanzwe byombi) kubarwayi bafite isuzumabumenyi rya gistologique ya kanseri yumura badafite uburyo bwo kuvura. Hashingiwe ku buryo bukurikiranye (WES), kugenzura ubuziranenge bw'amakuru ya RNA-seq, no gusuzuma ibipimo ngenderwaho, amakuru ya genomic yavuye ku barwayi 348 yagumishijwe kandi akoreshwa mu gusesengura epfo na ruguru akurikirana imyaka 4.6. Itsinda ry’ubushakashatsi ryise uyu mutungo Sidra-LUMC AC-ICAM: Ikarita nuyobora mu gukingira indwara ya kanseri-mikorobe (Ishusho 1).

Ibyiciro bya molekulari ukoresheje ICR

Itsinda ry’ubushakashatsi ryafashe uburyo butandukanye bwerekana ibimenyetso by’ubudahangarwa bw'umubiri kugira ngo bikingire kanseri ikingira indwara, bita immunité duhoraho yo kwangwa (ICR), itsinda ry’ubushakashatsi ryateje imbere ICR mu kuyihuza na gene 20 ikubiyemo ubwoko butandukanye bwa kanseri, harimo melanoma, kanseri y'uruhago, na kanseri y'ibere. ICR kandi yagiye ifitanye isano no gukingira indwara mu bwoko butandukanye bwa kanseri, harimo na kanseri y'ibere.

Ubwa mbere, abashakashatsi bemeje umukono wa ICR wa cohort ya AC-ICAM, bakoresheje uburyo bwa ICR bushingiye ku bufatanye bwo gushyira mu byiciro ibice bitatu / ubudahangarwa bw'umubiri: ICR ndende (ibibyimba bishyushye), ICR yo hagati na ICR yo hasi (ibibyimba bikonje) (Ishusho 1b). Abashakashatsi bagaragaje ubudahangarwa bw'umubiri bujyanye na subtypes zumvikanyweho (CMS), zishingiye ku nyandiko-mvugo ya kanseri y'amara. ibyiciro bya CMS birimo CMS1 / immunite, CMS2 / Canonical, CMS3 / metabolic na CMS4 / mesenchymal. Isesengura ryerekanye ko amanota ya ICR yari afitanye isano mibi n'inzira zimwe na zimwe za kanseri ya kanseri mu bwoko bwose bwa CMS, kandi isano iri hagati y'inzira ikingira indwara hamwe na tromal yagaragaye gusa mu bibyimba bya CMS4.

Muri CMS zose, ubwinshi bwubwicanyi karemano (NK) hamwe na T selile ya selile bwari hejuru cyane muri ICR yo hejuru y’ubudahangarwa bw'umubiri, hamwe no guhinduka kwinshi mubindi bice bya leukocyte (Igicapo 1c) .Ubwoko bw’ubudahangarwa bwa ICR bwari bufite OS na PFS zitandukanye, hamwe no kwiyongera kwa ICR kuva hasi kugera hejuru (Ishusho 1d), byemeza uruhare rwa kanseri ya ICR mu mabara.

Igishushanyo 1. AC-ICAM igishushanyo mbonera cyo kwiga, umukono wa gene ujyanye n'ubudahangarwa, ubudahangarwa bw'umubiri na molekuline no kubaho.
ICR ifata ibibyimba bikungahaye ku bibyimba, byongerewe ingufu za T selile
Gusa umubare muto w'uturemangingo T twinjira mubice by'ibibyimba byavuzwe ko byihariye kuri antigene yibibyimba (munsi ya 10%). Kubwibyo, ubwinshi bwingirabuzimafatizo T-selile zitwa selile T selile (by selile T selile). Isano rikomeye n'umubare w'utugingo ngengabuzima T dusanzwe hamwe na TCR itanga umusaruro byagaragaye muri selile tromal na leukocyte subpopulations (byagaragaye na RNA-seq), ishobora gukoreshwa mu kugereranya umubare w'uturemangingo twa T (Ishusho 2a). Mu matsinda ya ICR (muri rusange na CMS yashyizwe mu byiciro), clonality nyinshi y’ubudahangarwa SEQ TCRs yagaragaye mu itsinda rya ICR-hejuru na CMS subtype CMS1 / immunite (Ishusho 2c), hamwe n’ibibyimba byinshi bya ICR. Ukoresheje transcriptome yose (genes 18.270), genes esheshatu za ICR (IFNG, STAT1, IRF1, CCL5, GZMA, na CXCL10) zari mubice icumi byambere bifitanye isano neza na TCR immunite SEQ clonality (Ishusho 2d). ImmunoSEQ TCR clonality ifitanye isano cyane na genes nyinshi za ICR kuruta isano yagaragaye hakoreshejwe ibimenyetso bya CD8 + byakira ibibyimba (Ishusho 2f na 2g). Mu gusoza, isesengura ryavuzwe haruguru ryerekana ko umukono wa ICR ufata utugingo ngengabuzima T dukungahaye cyane, twongerewe clonone kandi ushobora gusobanura ingaruka zavuzwe mbere.

Igishushanyo 2. Ibipimo bya TCR hamwe nisano hamwe ningirabuzimafatizo zijyanye na immunite, immunite na molekile subtypes.
Microbiome yibigize mubice bya kanseri nzima
Abashakashatsi bakoze urutonde rwa 16S rRNA bakoresheje ADN yakuwe mu kibyimba gihuye hamwe na tissue nzima nziza ku barwayi 246 (Ishusho 3a). Kugira ngo yemeze, abashakashatsi bongeye gusesengura amakuru ya 16S rRNA ya gen ikurikirana uhereye ku bindi byitegererezo 42 by'ibibyimba bidahuye na ADN isanzwe iboneka kugira ngo isesengurwe. Ubwa mbere, abashakashatsi bagereranije ubwinshi bwibimera hagati yibibyimba bihuye hamwe nuduce twiza twiza. Clostridium perfringens yariyongereye cyane mubyimba ugereranije nicyitegererezo cyiza (Ishusho 3a-3d). Nta tandukaniro rikomeye ryagaragaye mu gutandukana kwa alfa (ubudasa n'ubwinshi bw'amoko mu cyitegererezo kimwe) hagati y'ibibyimba hamwe n'ingero nzima, kandi kugabanuka gukabije kwa mikorobe byagaragaye mu bibyimba byinshi bya ICR ugereranije n'ibibyimba bike bya ICR.
Kugirango hamenyekane amashyirahamwe ajyanye nubuvuzi hagati yimyirondoro ya mikorobe nibisubizo byubuvuzi, abashakashatsi bagamije gukoresha amakuru akurikirana ya 16S rRNA kugirango bamenye ibimenyetso bya mikorobe byerekana kubaho. Kuri AC-ICAM246, abashakashatsi bakoze moderi ya OS Cox yo kwisubiramo yahisemo ibintu 41 bifite coefficient zitari zeru (bifitanye isano nimpanuka ziterwa nimpfu zitandukanye), byitwa MBR ibyiciro (Ishusho 3f).
Muri aya mahugurwa (ICAM246), amanota make ya MBR (MBR <0, MBR yo hasi) yajyanye n’impanuka nke z’urupfu (85%). Abashakashatsi bemeje isano iri hagati ya MBR (risque) na OS igihe kirekire mubice bibiri byemewe byigenga (ICAM42 na TCGA-COAD). .

Igishushanyo 3. Microbiome mubyimba nuduce twiza nubusabane na ICR no kubaho kwabarwayi.
Umwanzuro
Uburyo bwa-omics bukoreshwa muri ubu bushakashatsi butuma hamenyekana neza no gusesengura neza umukono wa molekuline w’ubudahangarwa bw'umubiri wa kanseri yibara kandi ugaragaza imikoranire hagati ya mikorobe na sisitemu y’umubiri. Ikurikiranwa ryimbitse rya TCR ryibibyimba hamwe nuduce twiza twerekanye ko ingaruka za ICR zishobora guterwa nubushobozi bwayo bwo gufata ibibyimba bikungahaye cyane kandi bishoboka ko ibibyimba antigen yihariye ya T selile.

Mu gusesengura ibibyimba bya mikorobe ikoresheje 16S rRNA ikurikirana mu byitegererezo bya AC-ICAM, itsinda ryerekanye umukono wa microbiome (amanota ya MBR) ifite agaciro gakomeye ko gutangaza. Nubwo uyu mukono wakomotse ku byitegererezo by’ibibyimba, hari isano rikomeye hagati ya colorectum nzima n’ikibyimba MBR ishobora guhura n’impanuka, byerekana ko uyu mukono ushobora gufata mikorobe yo mu nda y’abarwayi. Muguhuza amanota ya ICR na MBR, byashobokaga kumenya no kwemeza biomarker yabanyeshuri-omic benshi bahanura kubaho kubarwayi barwaye kanseri yumura. Ubushakashatsi bwakozwe na dataset nyinshi butanga ibikoresho kugirango dusobanukirwe neza ibinyabuzima bya kanseri yibyondo no gufasha kuvumbura uburyo bwihariye bwo kuvura.

Reba:
Roelands, J., Kuppen, PJK, Ahmed, EI n'abandi. Ikibyimba cyuzuye, immunite na microbiome atlas ya kanseri yumura. Nat Med 29, 1273–1286 (2023).