An integrative in-silico analysis discloses a novel molecular subset of colorectal cancer possibly eligible for immune checkpoint immunotherapy

• DOI: 10.1186/s13062-022-00324-y
• Publication Date: 2022-05-09T06:03:33Z
• Authors: Pasquale Sibilio; Francesca Belardi...; Valerio Licursi; Paola Paci; Giuseppe Giannini
• Keywords: Microsatellite Instability; Chromosome instability; Immune checkpoint

Abstract Background Historically, the molecular classification of colorectal cancer (CRC) was based on global genomic status, which identified microsatellite instability in mismatch repair (MMR) deficient CRC, and chromosomal MMR proficient CRC. With introduction immune checkpoint inhibitors, regained momentum as condition predicted sensitivity to possibly due both high tumor mutation burden (TMB) levels infiltrating lymphocytes. Conversely, CRC are mostly resistant immunotherapy. To better understand relationship between classification, eventually discover additional subgroups relevant for therapeutic decisions, we developed a computational pipeline that include integrative analysis genomic, epigenomic transcriptomic data. Results The first step unsupervised hierarchical clustering copy number variations (CNVs) versus hypermutation status cluster with few CNVs enriched Hypermutated samples, second including non-HM stable third (7.8% entire dataset) low TMB, shared clinical-pathological features CRCs thus defined Hypermutated-like CRCs. mutational features, DNA methylation profile base substitution fingerprints these tumors revealed patients molecularly distinct from non-Hypermutated likely develop progress through different genetic events. Transcriptomic highlighted further differences amongst three groups an inflamed microenvironment modulation Immune Checkpoint Genes Conclusion Therefore, our work highlights previously unidentified subgroup responsive inhibitors. If validated, findings can lead expanding fraction eligible