Multilevel genomics of colorectal cancers with microsatellite instability\u2014clinical impact of JAK1 mutations and consensus molecular subtype 1

Anita Sveen,Arild Nesbakken,Edward Leithe,Ina A Eilertsen,David Kerr,Ian Tomlinson,Leonardo A Meza-Zepeda,Ola Myklebost,Rolf I Skotheim,Stine A Danielsen,Torstein Tengs,Enric Domingo,Guro E Lind,Kaja C G Berg,Bjarne Johannessen,Ragnhild A Lothe

doi:10.1186/s13073-017-0434-0

Abstract

BackgroundApproximately 15% of primary colorectal cancers have DNA mismatch repair deficiency, causing a complex genome with thousands of small mutations—the microsatellite instability (MSI) phenotype. We investigated molecular heterogeneity and tumor immunogenicity in relation to clinical endpoints within this distinct subtype of colorectal cancers.MethodsA total of 333 primary MSI+ colorectal tumors from multiple cohorts were analyzed by multilevel genomics and computational modeling—including mutation profiling, clonality modeling, and neoantigen prediction in a subset of the tumors, as well as gene expression profiling for consensus molecular subtypes (CMS) and immune cell infiltration.ResultsNovel, frequent frameshift mutations in four cancer-critical genes were identified by deep exome sequencing, including in CRTC1, BCL9, JAK1, and PTCH1. JAK1 loss-of-function mutations were validated with an overall frequency of 20% in Norwegian and British patients, and mutated tumors had up-regulation of transcriptional signatures associated with resistance to anti-PD-1 treatment. Clonality analyses revealed a high level of intra-tumor heterogeneity; however, this was not associated with disease progression. Among the MSI+ tumors, the total mutation load correlated with the number of predicted neoantigens (P = 4 × 10−5), but not with immune cell infiltration—this was dependent on the CMS class; MSI+ tumors in CMS1 were highly immunogenic compared to MSI+ tumors in CMS2-4. Both JAK1 mutations and CMS1 were favorable prognostic factors (hazard ratios 0.2 [0.05–0.9] and 0.4 [0.2–0.9], respectively, P = 0.03 and 0.02).ConclusionsMultilevel genomic analyses of MSI+ colorectal cancer revealed molecular heterogeneity with clinical relevance, including tumor immunogenicity and a favorable patient outcome associated with JAK1 mutations and the transcriptomic subgroup CMS1, emphasizing the potential for prognostic stratification of this clinically important subtype.See related research highlight by Samstein and Chan 10.1186/s13073-017-0438-9

Highlights

15% of primary colorectal cancers have DNA mismatch repair deficiency, causing a complex genome with thousands of small mutations—the microsatellite instability (MSI) phenotype
Multilevel genomic analyses of MSI+ colorectal cancer revealed molecular heterogeneity with clinical relevance, including tumor immunogenicity and a favorable patient outcome associated with JAK1 mutations and the transcriptomic subgroup CMS1, emphasizing the potential for prognostic stratification of this clinically important subtype
Molecular overview of mismatch repair (MMR) deficiency in MSI+ Colorectal cancer (CRC) A total of 333 MSI+ CRCs were analyzed in the study; an overview of the genomic analyses and results is shown in Fig. 1

Summary

Introduction

15% of primary colorectal cancers have DNA mismatch repair deficiency, causing a complex genome with thousands of small mutations—the microsatellite instability (MSI) phenotype. Colorectal cancers (CRCs) with the microsatellite instability (MSI) phenotype are defined by high rates of insertions and deletions (indels) of nucleotides in short, repetitive sequences [1,2,3]. This is caused by a defective DNA mismatch repair (MMR) machinery, either by epigenetic silencing, primarily of MLH1 [4,5,6], or through somatic or germ line mutations [7,8,9,10,11]. Large-scale analysis of indel mutations has been challenging [25, 26], and a recent paper describing frameshift mutations in RNF43 in 80% of MSI+ CRCs clearly demonstrates that even highly prevalent indel mutations have gone unnoticed [27]

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Results

Discussion

Conclusion