Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden

By Z. Chalmers, Caitlin F. Connelly, D. Fabrizio, L. Gay, Siraj M. Ali, Riley Ennis, A. Schrock, B. Campbell, A. Shlien, J. Chmielecki and 14 more. Genome Medicine, 2017

3,045 citations recorded by the source corpus.

BackgroundHigh tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types.MethodsIn this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types.ResultsWe demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB.ConclusionsThese results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis.

Subfields: Cancer Research, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/f50e5cbee9e73931672a93151a52749a49d2b408

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Citations in the corpus

Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. (2018, background): “5 Mb, the accuracy of TMB determined by targeted NGS diminishes.(35)”
Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic (2018, background): “Recent efforts have begun to validate targeted NGS panels against WES data as these panels are already being used routinely in clinic for oncogenic mutation detection [37, 68].”
ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. (2019, background): “Notably, an estimation of TMB can also be made with targeted panels, avoiding the costs of whole-exome or of whole-genome sequencing [99, 100].”
STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma (2018, methodology): “TMB was measured by Foundation Medicine as described previously (53).”
Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers (2017, background): “TMB levels were divided into three groups based off the Foundation Medicine official reports: low (1–5 mutations/mb), intermediate (6–19 mutations/mb), and high ( 20 mutations/mb), which in a large cohort divided approximately 50% of patients to low TMB, 40% intermediate TMB, and 10% high TMB (34).”
Genomic features of response to combination immunotherapy in patients with advanced non-small cell lung cancer (2018, background): “Additionally, to explore the applicability of targeted next-generation sequencing as an estimate of exonic mutation burden (Chalmers et al., 2017; Zehir et al., 2017), we found that limiting variants to the 468 genes represented in our institutional MSKIMPACT panel (Zehir et al.”