Multi-omic characterization of consensus molecular subtype 1 (CMS1) colorectal cancer with dampened immune response improves precision medicine.

Abstract

Colorectal cancer (CRC) is a heterogenous disease with distinct biological and clinical subgroups, each with different prognoses and responses to therapy. In this case report, taking inspiration from a case of locally advanced CRC with serine/threonine-protein kinase B-raf (BRAF) V600E mutation, we highlight an atypical consensus molecular subtype 1 (CMS1). Deep multi-omic analyses showed a limited expression of programmed cell death protein 1 (PD-1) and reduced T-cell infiltration, including CD8⁺ and natural killer (NK) cells, in the analyzed CMS1 tumor. In parallel, a reduced activation of the JAK/STAT pathway was detected, suggesting a lack of clinical response to immunotherapy with checkpoint inhibitors. Furthermore, the finding of up-regulated expression of WEE1 G2 checkpoint kinase (WEE1), checkpoint kinase 1 (CHK1), and checkpoint kinase 2 (CHK2), poly(ADP-ribose) polymerase (PARP), and heat shock protein 90 (HSP90) suggests a potential alternative therapeutic approach using inhibitors of the cell cycle, HSP90, or PARP in combination with conventional chemotherapy, targeted agents, or immunotherapy. This paradigmatic case should stimulate a regular deep omics analysis to improve precision medicine. We therefore suggest that full mutational and expression profiling analyses of CRC subtypes should be undertaken to improve therapeutic strategies in CRC treatment.