Clinical advantage of targeted sequencing for unbiased tumor mutational burden estimation in samples with low tumor purity

BackgroundTumor mutational burden (TMB) measurement is limited by low tumor purity of samples, which can influence prediction of the immunotherapy response, particularly when using whole-exome sequencing-based TMB (wTMB). This issue could be overcome by targeted panel sequencing-based TMB (pTMB) wit...

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Published in:Journal for immunotherapy of cancer 2020-10, Vol.8 (2), p.e001199
Main Authors: Hong, Tae Hee, Cha, Hongui, Shim, Joon Ho, Lee, Boram, Chung, Jongsuk, Lee, Chung, Kim, Nayoung K D, Choi, Yoon-La, Hwang, Soohyun, Lee, Yoomi, Park, Sehhoon, Jung, Hyun Ae, Kim, Ji-Yeon, Park, Yeon Hee, Sun, Jong-Mu, Ahn, Jin Seok, Ahn, Myung-Ju, Park, Keunchil, Lee, Se-Hoon, Park, Woong-Yang
Format: Article
Language:English
Subjects:
Algorithms
Biomarkers
Breast cancer
Cancer
Clinical/Translational Cancer Immunotherapy
computational biology
Datasets
Estimates
Genomes
Genomics
Immunotherapy
Lung cancer
Mutation
tumor
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Summary:BackgroundTumor mutational burden (TMB) measurement is limited by low tumor purity of samples, which can influence prediction of the immunotherapy response, particularly when using whole-exome sequencing-based TMB (wTMB). This issue could be overcome by targeted panel sequencing-based TMB (pTMB) with higher depth of coverage, which remains unexplored.MethodsWe comprehensively reanalyzed four public datasets of immune checkpoint inhibitor (ICI)-treated cohorts (adopting pTMB or wTMB) to test each biomarker’s predictive ability for low purity samples (cut-off: 30%). For validation, paired genomic profiling with the same tumor specimens was performed to directly compare wTMB and pTMB in patients with breast cancer (paired-BRCA, n=165) and ICI-treated patients with advanced non-small-cell lung cancer (paired-NSCLC, n=156).ResultsLow tumor purity was common (range 30%–45%) in real-world samples from ICI-treated patients. In the survival analyzes of public cohorts, wTMB could not predict the clinical benefit of immunotherapy when tumor purity was low (log-rank p=0.874), whereas pTMB could effectively stratify the survival outcome (log-rank p=0.020). In the paired-BRCA and paired-NSCLC cohorts, pTMB was less affected by tumor purity, with significantly more somatic variants identified at low allele frequency (p
ISSN:2051-1426
2051-1426
DOI:10.1136/jitc-2020-001199