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Basic science and translational research

3720 - Assessment and comparison of tumor mutational burden and microsatellite instability status in >40,000 cancer genomes


08 Oct 2016


Basic science and translational research


David Fabrizio


Annals of Oncology (2016) 27 (6): 15-42. 10.1093/annonc/mdw363


D.A. Fabrizio1, D.A. Fabrizio1, Z.R. Chalmers1, J.X. Sun1, V.A. Miller2, P.J. Stephens1

Author affiliations

  • 1 Research And Development, Foundation Medicine, 02141 - Cambridge/US
  • 2 Medical Affairs, Foundation Medicine, 02141 - Cambridge/US


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Abstract 3720


The overall quantity of mutations in a cancer genome, termed tumor mutational burden (TMB), is an emerging biomarker for response to immunotherapy. Mutations occur in cancer genomes by a number of different processes, each of which is associated with a distinct mutational signature. Microsatellite instability (MSI) is one common mechanism by which cancer cells can acquire high TMB. We sought to explore the relationship of TMB and MSI in a large cohort of advanced cancer cases from a wide array of tumor types.


CGP targeting >500x sequencing coverage (non-PCR duplicate reads) for the full coding regions of 315 genes was performed on >40,000 cancer specimens from unique patients, in >400 cancer disease sub-types. MSI status was determined by assessing the indel alterations occurring at 114 microsatellites covered by the CGP test. TMB was determined by evaluating the number of somatic, coding, base substitution and indel mutations occurring per megabase of coding genome targeted on the test. Tumors with ≥ 20 mutations per megabase were considered to have high TMB.


Overall, 1.4% of cases were found to be MSI-High while 7.1% of cases had high TMB. The vast majority (85%) of MSI-High cases also had high TMB, but the converse was not true. Numerous cases with high TMB were observed that did not show evidence of MSI. These results were highly disease specific. In some tumor types very few high TMB cases (75%) were MSI-High. In all tumor types, there was a meaningful fraction of cases with high TMB and no evidence of MSI. The full landscape of TMB and MSI across 40,000 cases and hundreds of cancer sub-types will be presented.


As expected, these results support the understanding that TMB and MSI status in cancer genomes are correlated and that the majority of MSI-High cases also had high overall TMB. These data also demonstrate that a large portion of cancers with high TMB are microsatellite stable. This indicates that assessment of both TMB and MSI will be valuable for identifying patients most likely to benefit from immunotherapy.

Clinical trial identification

Legal entity responsible for the study

Foundation Medicine


Foundation Medicine Inc.


G.M. Frampton, D.A. Fabrizio, Z.R. Chalmers, J.X. Sun, V.A. Miller, P.J. Stephens: Employee and stockholder of Foundation Medicine Inc.

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