In this issue of Genome Medicine, Sveen and colleagues  analyzed over 300 MSI-positive CRCs from several sources: two Norwegian studies, the British VICTOR trial, The Cancer Genome Atlas, and a multicenter French cohort. A comprehensive analysis was performed on the datasets, which included somatic mutational analysis, clonality analysis, neoantigen load analysis, and gene expression analysis for immune infiltration and consensus molecular subtypes (CMSs). Frequent mutations were identified in several relevant genes, including CRTC1 (CREB-regulated transcription coactivator 1), CCND1/BCL1 (G1/S-specific cyclin-D1), PTCH1 (protein patched homolog 1), and JAK1 (tyrosine-protein kinase JAK1), although many were subclonal (present in only a small fraction of cells), consistent with significant heterogeneity within the tumor. JAK1 loss-of-function mutations were found in several cohorts, with a prevalence in MSI-positive CRCs of 20%, although mutations were primarily heterozygous. Interestingly, mutated tumors were associated with upregulation of genes associated with resistance to anti-PD1 treatment. However, the heterozygous nature of these mutations and positive association with disease outcomes seen in this study are inconsistent with previous reports, including a recent study reporting association of JAK1 mutations with resistance to PD-1 blockade in a small cohort of patients . It is possible that, although heterozygous JAK1 mutations might impart a better prognosis in the absence of immune-checkpoint blockade therapy, homozygous JAK1 mutation results in a resistance to antibodies against PD1 in patients treated with immunotherapy. Further studies are thus required to resolve the ultimate biological effect of these mutations.
As expected, Sveen and colleagues observed increased neoantigen load accompanying increasing mutational load even within these MSI-positive tumors. Immune infiltration, as measured by gene expression, was associated with the CMS1 gene-expression subtype but was not associated with increased mutational burden. Here, it is possible that specific antigens are present in this group of tumors or they have a microenvironment that is more permissive to T-cell infiltration. JAK1 mutations and the CMS1 subtype were both significantly associated with improved survival.