An integrated tumor, immune and microbiome atlas of colon cancer

Roeflands, J.; Kfuppen, P.J.K.; Ahmed, E.I.; Manll, R.; Masoodi, T.; Singh, P.; Monaco, G.; Raynaud, C.; Miranda, N.F.C.C. de; Ferraro, L.; Carneiro-Lobo, T.C.; Syed, N.; Rawat, A.; Awad, A.; Decock, J.; Mifsud, W.; Miller, L.D.; Sherif, S.; Mohamed, M.G.; Rinchai, D.; Eynde, M. van den; Sayaman, R.W.; Ziv, E.; Bertucci, F.; Petkar, M.A.; Lorenz, S.; Mathew, L.S.; Wang, K.; Murugesan, S.; Chaussabel, D.; Vahrmeijer, A.L.; Wang, E.; Ceccarelli, A.; Fakhro, K.A.; Zoppoli, G.; Ballestrero, A.; Tollenaar, R.A.E.M.; Marincola, F.M.; Galon, J.; Khodor, S. al; Ceccarelli, M.; Hendrickx, W.; Bedognetti, D.

doi:doi:10.1038/s41591-023-02324-5

The lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications. Quantification of genetic immunoediting, defined as a lower number of neoantigens than expected, further refined its prognostic value. We identified...Show moreThe lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications. Quantification of genetic immunoediting, defined as a lower number of neoantigens than expected, further refined its prognostic value. We identified a microbiome signature, driven by Ruminococcus bromii, associated with a favorable outcome. By combining microbiome signature and Immunologic Constant of Rejection, we developed and validated a composite score (mICRoScore), which identifies a group of patients with excellent survival probability. The publicly available multi-omics dataset provides a resource for better understanding colon cancer biology that could facilitate the discovery of personalized therapeutic approaches.
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An integrated tumor, immune and microbiome atlas of colon cancer