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Genome Med. 2017 May 24;9(1):46. doi: 10.1186/s13073-017-0434-0.

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

Sveen A1,2,3,4, Johannessen B1,2,3,4, Tengs T1,2,3,4, Danielsen SA1,2,3,4, Eilertsen IA1,2,4, Lind GE1,2,4, Berg KCG1,2,4, Leithe E1,2,4, Meza-Zepeda LA3,5,6, Domingo E7, Myklebost O3,5, Kerr D8, Tomlinson I7, Nesbakken A2,3,4,9, Skotheim RI1,2,3,4, Lothe RA10,11,12,13.

Author information

1
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway.
2
K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway.
3
Norwegian Cancer Genomics Consortium, Oslo University Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway.
4
Centre for Cancer Biomedicine, Institute for Clinical Medicine, University of Oslo, P.O. Box 4950, Nydalen, NO-0424, Oslo, Norway.
5
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway.
6
Genomics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway.
7
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
8
Department of Oncology, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK.
9
Department of Gastrointestinal Surgery, Oslo University Hospital, P.O. Box 4950, Nydalen, NO-0424, Oslo, Norway.
10
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway. rlothe@rr-research.no.
11
K. G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway. rlothe@rr-research.no.
12
Norwegian Cancer Genomics Consortium, Oslo University Hospital, P.O. Box 4953, Nydalen, NO-0424, Oslo, Norway. rlothe@rr-research.no.
13
Centre for Cancer Biomedicine, Institute for Clinical Medicine, University of Oslo, P.O. Box 4950, Nydalen, NO-0424, Oslo, Norway. rlothe@rr-research.no.

Abstract

BACKGROUND:

Approximately 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.

METHODS:

A 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.

RESULTS:

Novel, 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).

CONCLUSIONS:

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. See related research highlight by Samstein and Chan 10.1186/s13073-017-0438-9.

KEYWORDS:

Colorectal cancer; Consensus molecular subtypes; Immunogenicity; Immunotherapy resistance; JAK1; Microsatellite instability; Mutation; Neoantigen; Prognosis

PMID:
28539123
PMCID:
PMC5442873
DOI:
10.1186/s13073-017-0434-0
[Indexed for MEDLINE]
Free PMC Article

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