Noskova Hana, Kyr Michal, Pal Karol, Merta Tomas, Mudry Peter, Polaskova Kristyna, Ivkovic Tina Catela, Adamcova Sona, Hornakova Tekla, Jezova Marta, Kren Leos, Sterba Jaroslav, Slaby Ondrej
Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic.
Department of Pediatric Oncology, University Hospital Brno, 613 00 Brno, Czech Republic.
Cancers (Basel). 2020 Jan 17;12(1):230. doi: 10.3390/cancers12010230.
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.
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.
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.
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.
肿瘤突变负荷（TMB）是癌症中一种新兴的基因组生物标志物，与成人癌症中免疫检查点抑制剂（ICI）疗效的改善相关。据描述，不同的实验室技术和生物信息学流程的各种设置会导致TMB评估的变异性。在儿科肿瘤学中，目前尚未发表描述这种变异性的研究。
在我们的研究中，我们对106例患有28种不同癌症类型的高危/复发性儿科实体瘤患者进行了全外显子组测序（WES，包括种系和体细胞）并计算了TMB。随后，我们使用WES数据，通过计算机模拟两种美国食品药品监督管理局（FDA）批准/授权的癌症综合基因组检测板的方法来计算TMB。
我们描述了基于WES的TMB和基于检测板的TMB之间存在强相关性；然而，我们表明，仅纳入少数高突变病例会显著影响这种高相关性。在9例病例系列中，我们在两个连续采集的肿瘤组织标本中测定了TMB，并观察到TMB随肿瘤进展而增加。此外，我们评估了用于TMB评估的技术和生物信息学流程的变异性可能对潜在ICI适应证产生影响的程度。我们证实，这种技术变异性可能会显著影响儿科癌症患者的ICI适应证；然而，随着临界值的增加，这种显著性会降低。
在儿科肿瘤学中，我们首次使用实际的WES以及对两个主要靶向基因检测板进行计算机分析，评估了多种儿科癌症类型中TMB估计的可靠性，并证实不同的实验室技术和生物信息学流程的各种设置会引入显著的技术变异性。
