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Published on: April 11, 2016
Tumor mutational burden measurement using comprehensive genomic profiling assay
Hidenori Kage1, Shinji Kohsaka2, Kenji Tatsuno3
1Next-Generation Precision Medicine Development Laboratory, Graduate School of Medicine, The University Tokyo, Tokyo, Japan.
Background:
Tumors with a high number of mutations in the genome, or tumor mutational burden, are presumed to be more likely to respond to immune checkpoint inhibitors. However, the optimal method to calculate tumor mutational burden using comprehensive genomic profiling assays is unknown.
Methods:
Todai OncoPanel is a dual panel of a deoxyribonucleic acid panel and a ribonucleic acid panel. Todai OncoPanel deoxyribonucleic acid panel version 6 is an improvement over version 3 with increased number of targeted genes and limited targeting of intronic regions. We calculated tumor mutational burden measured by Todai OncoPanel deoxyribonucleic acid panel versions 3 and 6 using three different calculation methods: all mutations within the targeted region (target tumor mutational burden), all mutations within the coding region (all coding tumor mutational burden) and non-synonymous mutations (non-synonymous coding tumor mutational burden). We then compared them with whole exosome sequencing tumor mutational burden. In addition, 16 lung cancer patients whose samples were analyzed using Todai OncoPanel deoxyribonucleic acid version 3 were treated with anti-PD-1 or PD-L1 antibody monotherapy.
Results:
When compared with whole exosome sequencing tumor mutational burden as the standard, tumor mutational burden measured by Todai OncoPanel deoxyribonucleic acid version 3 resulted in accuracy of 71% for all three calculation methods. In version 6, accuracy was 96% for target tumor mutational burden and all coding tumor mutational burden and 91% for non-synonymous coding tumor mutational burden. Patients with either partial response or stable disease had higher non-synonymous coding tumor mutational burden (6.7/Mb vs. 1.6/Mb, P = 0.02) and higher PD-L1 expression (40% vs. 3%, P = 0.01) and a trend toward higher target tumor mutational burden (9.2/Mb vs. 2.4/Mb, P = 0.09) compared with patients with progressive disease.
Conclusions:
Increase in targeted gene number and limiting intronic regions improved tumor mutational burden measurement by Todai OncoPanel when compared with whole exosome sequencing tumor mutational burden. Target tumor mutational burden may be the method of choice to measure tumor mutational burden.
Insights
High tumor mutational burden (TMB) predicts response to immunotherapy. The Todai OncoPanel assay, particularly version 6, accurately measures TMB, with target TMB showing promise for clinical use.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- High tumor mutational burden (TMB) is associated with better response to immune checkpoint inhibitors.
- Optimal methods for calculating TMB using comprehensive genomic profiling (CGP) assays are not well-established.
Purpose of the Study:
- To evaluate the accuracy of TMB calculation using two versions of the Todai OncoPanel DNA assay.
- To compare TMB measurements with whole exome sequencing (WES) and assess their correlation with clinical response in lung cancer patients.
Main Methods:
- Todai OncoPanel DNA versions 3 and 6 were used to calculate TMB via three methods: target TMB, all coding TMB, and non-synonymous coding TMB.
- TMB values were compared against WES-derived TMB.
- Lung cancer patients treated with anti-PD-1/PD-L1 therapy were analyzed for TMB and PD-L1 expression.
Main Results:
- Todai OncoPanel v6 demonstrated higher accuracy (91-96%) compared to v3 (71%) when correlated with WES TMB.
- Patients with partial response or stable disease exhibited significantly higher non-synonymous coding TMB and PD-L1 expression than those with progressive disease.
- A trend towards higher target TMB was observed in patients with better clinical outcomes.
Conclusions:
- Improvements in Todai OncoPanel (v6), including increased gene targets and limited intronic regions, enhance TMB measurement accuracy.
- Target TMB calculation may be the preferred method for assessing TMB in clinical settings.
- Accurate TMB assessment is crucial for predicting immunotherapy response.
