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

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 Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0434-0) contains supplementary material, which is available to authorized users.

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“…Then, to calculate neoantigen load, they further analyzed the tumor genomes: they found a total of 578 potential mutation-associated neoantigens in tumors associated with MSI, but only 21 in tumors associated with MSS [32]. Another study found a similar number of mutation-associated neoantigens in the tumors associated with MSI [44]. Still, other studies found vastly different numbers of mutation-associated neoantigens in their MSI cohorts [43, 45].…”

“…These differences are due to inconsistencies in methodology. Some investigators evaluated exome mutation by comparing the entirety of the tumor exome sequence to a noncancerous sequence [32, 44], whereas others observed mutations from a selective gene panel [43, 45]. Before these genomic markers can be incorporated into clinical practice, a stable cutpoint must be established for high mutation load or high neoantigen number; the agreed-to evaluation procedure must standardize biopsy site positions, sample preparation, sequencing methods, read depth, and analysis algorithms.…”

“…In most clinical studies that measured the neoantigen load, it was proportional to the total overall mutation burden [49–51]. In patients with CRC associated with MSI (vs. MSS), the tumors have a higher number of total somatic mutations, as well as more neoantigens, on average [32, 43, 44]. …”

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“…CMS4 show mesenchymal‐like cancers, with high stromal infiltration and poor patient prognosis. In comparison with CMS2‐4, CMS1 is a particularly immunogenic subtype also specifically among MSI+ tumors, in which CMS1 has a significantly higher level of infiltration of cytotoxic lymphocytes and a higher immune score with robust PD‐1 signaling and JAK‐STAT signaling, independent of JAK1 mutation status . Fatty acid binding protein 1 (FABP1) plays a role in the CMS1 subgroup of colorectal carcinomas, and FABP1 is an intracellular protein responsible for the transportation of long chain fatty acids, as well as its functions in lipid metabolism and cellular differentiation.…”

“…In comparison with CMS2-4, CMS1 is a particularly immunogenic subtype also specifically among MSI+ tumors, in which CMS1 has a significantly higher level of infiltration of cytotoxic lymphocytes and a higher immune score with robust PD-1 signaling and JAK-STAT signaling, independent of JAK1 mutation status. 13,14 Fatty acid binding protein 1 (FABP1) plays a role in the CMS1 subgroup of colorectal carcinomas, and FABP1 is an intracellular protein responsible for the transportation of long chain fatty acids, as well as its functions in lipid metabolism and cellular differentiation. In addition, FABP1 has been linked to the regulation of inflammatory states via its interaction with PPARs, 15,16 which are nuclear transcription factors whose downstream effects manage lipid metabolism, inflammation, and cellular metabolism.…”