Microsatellite instability (MSI) defines a small subgroup of approximately 15% of colorectal cancers (CRC) which currently receives much attention due to its overall good response to immune-checkpoint inhibition. In the latest issue of Genome Medicine, scientist Anita Sveen and colleagues publish the largest multilevel genetic analysis of this tumor type reported to date, describing substantial inter- and intra-tumor heterogeneity. The clinical importance of these results, in particular with respect to the optimized use of immunotherapeutics for treatment of human cancers, was emphasized in a Research Highlight in the same issue of the journal.
The study is a collaboration between the Lothe and Skotheim groups, as part of the Norwegian Cancer Genomics Consortium. Exome sequencing revealed JAK1 as a new frequently mutated gene in MSI+ primary CRC, validated with a 20% mutation frequency in independent patient series. These truncating mutations were associated with gene expression-changes predicting a poor response to immune-checkpoint inhibition, consistent with a recent report of JAK1-associated treatment resistance in metastatic disease (Shin et al., Cancer Discov 2017;7:188-201). However, the mutations were also a marker of a good patient prognosis, predicting a low mutation frequency in metastatic disease and highlighting the need to uncover additional resistance mechanisms.
The indication of immunotherapy in MSI+ tumors is a result of their large mutation burden and subsequent infiltration of cytotoxic lymphocytes. Sveen and colleagues describe that the mutation load is indeed associated with the predicted neoantigen load also specifically among these tumors, but is not proportional with the level of immune cell infiltration. Tumor immunity was more closely associated with the gene expression-based consensus molecular subtypes (CMS), identifying the immunogenic subgroup CMS1 as an independent marker of a good patient prognosis and reinforcing the potential also for prognostic stratification of MSI+ CRC.
The article in Genome Medicine:
Multilevel genomics of colorectal cancers with microsatellite instability-clinical impact of JAK1 mutations and consensus molecular subtype 1.
Sveen A, Johannessen B, Tengs T, Danielsen SA, Eilertsen IA, Lind GE, Berg KCG, Leithe E, Meza-Zepeda LA, Domingo E, Myklebost O, Kerr D, Tomlinson I, Nesbakken A, Skotheim RI, Lothe RA.
Genome Med. 2017 May 24;9(1):46. doi: 10.1186/s13073-017-0434-0.
Research highlight article:
Dissecting microsatellite instability in colorectal cancer: one size does not fit all.
Samstein RM, Chan TA.
Genome Med. 2017 May 24;9(1):45. doi: 10.1186/s13073-017-0438-9.