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. 2020 Jan 17;12(1):230.
doi: 10.3390/cancers12010230.

Assessment of Tumor Mutational Burden in Pediatric Tumors by Real-Life Whole-Exome Sequencing and In Silico Simulation of Targeted Gene Panels: How the Choice of Method Could Affect the Clinical Decision?

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Free PMC article

Assessment of Tumor Mutational Burden in Pediatric Tumors by Real-Life Whole-Exome Sequencing and In Silico Simulation of Targeted Gene Panels: How the Choice of Method Could Affect the Clinical Decision?

Hana Noskova et al. Cancers (Basel). .
Free PMC article

Abstract

Background: Tumor mutational burden (TMB) is an emerging genomic biomarker in cancer that has been associated with improved response to immune checkpoint inhibitors (ICIs) in adult cancers. It was described that variability in TMB assessment is introduced by different laboratory techniques and various settings of bioinformatic pipelines. In pediatric oncology, no study has been published describing this variability so far.

Methods: In our study, we performed whole exome sequencing (WES, both germline and somatic) and calculated TMB in 106 patients with high-risk/recurrent pediatric solid tumors of 28 distinct cancer types. Subsequently, we used WES data for TMB calculation using an in silico approach simulating two The Food and Drug Administration (FDA)-approved/authorized comprehensive genomic panels for cancer.

Results: We describe a strong correlation between WES-based and panel-based TMBs; however, we show that this high correlation is significantly affected by inclusion of only a few hypermutated cases. In the series of nine cases, we determined TMB in two sequentially collected tumor tissue specimens and observed an increase in TMB along with tumor progression. Furthermore, we evaluated the extent to which potential ICI indication could be affected by variability in techniques and bioinformatic pipelines used for TMB assessment. We confirmed that this technological variability could significantly affect ICI indication in pediatric cancer patients; however, this significance decreases with the increasing cut-off values.

Conclusions: For the first time in pediatric oncology, we assessed the reliability of TMB estimation across multiple pediatric cancer types using real-life WES and in silico analysis of two major targeted gene panels and confirmed a significant technological variability to be introduced by different laboratory techniques and various settings of bioinformatic pipelines.

Keywords: TMB; gene panel sequencing; immune checkpoint inhibitors; pediatric tumors; tumor mutational burden; whole-exome sequencing.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Tumor mutational burden (TMB) values determined in our pediatric cancer patient cohort (WES—Method1) stratified by cancer type. Hypothetical TMB cut-off values are shown as dashed lines (green, TMB ≥ 5; blue, TMB ≥ 10, red, TMB ≥ 20).
Figure 2
Figure 2
Correlation of tumor mutational burden (TMB) determined by real-life WES and targeted gene panels: real-life WES vs. in silico MSK-IMPACT (A), in silico F1CDx vs. MSK-IMPACT (B), real-life WES vs. in silico F1CDx (C), real-life WES vs. real-life laboratory service F1Heme (D).
Figure 3
Figure 3
Workflow for tumor mutational burden (TMB) assessment by WES in this study.

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References

    1. Stratton M.R., Campbell P.J., Futreal P.A. The cancer genome. Nature. 2009;458:719–724. doi: 10.1038/nature07943. - DOI - PMC - PubMed
    1. Chalmers Z.R., Connelly C.F., Fabrizio D., Gay L., Ali S.M., Ennis R., Schrock A., Campbell B., Shlien A., Chmielecki J., et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9:34. doi: 10.1186/s13073-017-0424-2. - DOI - PMC - PubMed
    1. Chang H., Sasson A., Srinivasan S., Golhar R., Greenawalt D.M., Geese W.J., Green G., Zerba K., Kirov S., Szustakowski J. Bioinformatic Methods and Bridging of Assay Results for Reliable Tumor Mutational Burden Assessment in Non-Small-Cell Lung Cancer. Mol. Diagn. Ther. 2019;23:507–520. doi: 10.1007/s40291-019-00408-y. - DOI - PMC - PubMed
    1. Lawrence M.S., Stojanov P., Polak P., Kryukov G.V., Cibulskis K., Sivachenko A., Carter S.L., Stewart C., Mermel C.H., Roberts S.A., et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214–218. doi: 10.1038/nature12213. - DOI - PMC - PubMed
    1. Hodi F.S., O’Day S.J., McDermott D.F., Weber R.W., Sosman J.A., Haanen J.B., Gonzalez R., Robert C., Schadendorf D., Hassel J.C., et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010;363:711–723. doi: 10.1056/NEJMoa1003466. - DOI - PMC - PubMed
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