Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.
Level 4 - case-series / case-control
Cross-sectional genomic profiling and observational cohort study across tumor samples without clinical intervention.
PubMed 28420421 · doi:10.1186/s13073-017-0424-2
What was done
Researchers compared tumor mutational burden (TMB) assessed by a targeted comprehensive genomic profiling (CGP) assay targeting ~1.1 Mb of coding genome to whole exome sequencing, simulating measurement variance when sequencing less than the whole exome. They then mapped TMB distributions, microsatellite instability, age associations, and somatic alterations across 100,000 human cancer cases across more than 100 tumor types.
What was found
CGP measurements strongly mirrored whole exome sequencing, with measurement variance increasing significantly below 0.5 Mb. A subset of patients showed high TMB across almost all analyzed cancer types. TMB increased significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Additionally, a cluster of somatic promoter mutations in PMS2 was identified in 10% of skin cancers and was strongly associated with increased TMB.
Why it matters
The findings show that targeted gene panels can accurately quantify TMB compared to whole exome sequencing. This provides a comprehensive landscape of which tumor types contain high-TMB patient subsets that may benefit from immune checkpoint inhibitor therapies.
Limits
The abstract does not define the numerical cutoff used to classify high TMB. No clinical outcomes or direct response rates to immunotherapy are reported for this cohort. Patient selection criteria and potential referral biases in the 100,000 sequenced samples are not stated.
Cited by
- supports There are over 100 distinct types of cancer.