Subtyping of microsatellite instability-high colorectal cancer

Wangxiong Hu,Lina Qi,Weiting Ge,Shu Zheng,Jiani Chen,Yanmei Yang

doi:10.1186/s12964-019-0397-4

Abstract

BackgroundPatients with microsatellite instability-high (MSI-H) colorectal cancer (CRC) generally have a better prognosis than patients with microsatellite stable (MSS) CRC. However, some MSI-H CRC patients do not gain overall survival benefits from immune checkpoint-blockade treatment. In other words, heterogeneity within the subgroup of MSI-H tumors remains poorly understood. Thus, an in-depth molecular characterization of MSI-H tumors is urgently required.MethodsHere, we use nonnegative matrix factorization (NMF)-based consensus clustering to define CRC MSI-H subtypes in The Cancer Genome Atlas and a French multicenter cohort GSE39582. CIBERSORT was used to calculate the proportions of 22 lymphocytes in tumor tissue in MSI-H subtypes.ResultsMSI-H CRC samples basically clustered into two subgroups (MSI-H1 and MSI-H2). MSI-H1 was characterized by a lower BRAF mutational status, higher frequency of chromosomal instability, global hypomethylation, and worse survival than MSI-H2. Further examination of the immune landscape showed that macrophages of the M2 phenotype were enriched in MSI-H1, which may be associated with poor prognosis in this subgroup.ConclusionsOur results illustrate the genetic heterogeneity in MSI-H CRCs and macrophages may serve as good targets for anticancer therapy in MSI-H1.Graphical abstract

Highlights

Patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC) generally have a better prognosis than patients with microsatellite stable (MSS) CRC
MSI-H CRC clusters into two distinct subtypes A stochastic nonnegative matrix factorization (NMF) algorithm was used to assess whether any clusters were present in the MSI-H CRC cases
Of the 59 MSI-H samples annotated in The Cancer Genome Atlas (TCGA), 11 were classified into MSI-H group 1 (MSI-H1) and 48 were classified into MSI-H group 2 (MSI-H2)

Summary

Introduction

Patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC) generally have a better prognosis than patients with microsatellite stable (MSS) CRC. An in-depth molecular characterization of MSI-H tumors is urgently required. Much effort has been devoted to the molecular subtyping of colorectal cancer (CRC) based on gene expression profiles [1,2,3]. According to the current widely accepted consensus molecular subtype (CMS) classification system, microsatellite instability-high (MSI-H) samples belong to the CMS1 subtype and are characterized by hypermutation and CpG island methylator phenotype (CIMP). MSI-H tumors generally respond well to immunotherapy by anti-PD-1 immune checkpoint inhibition [7]. JAK1 loss-of-function mutations, with a prevalence of 20% in MSI-positive CRC are associated with the upregulation of genes associated with resistance to anti-PD-1 treatment [8]. The MSI-H population may display different expression patterns that are masked by higher variations relative to other subtypes, such as CMS2–4

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