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.
Highlights
The cancer cell genome acquires genetic alterations differing from the germline of the host [1].Somatic mutation rates can be affected by exposure to exogenous factors, such as ultraviolet light or tobacco smoke [2], or by compounding genetic defects, such as DNA mismatch repair deficiency, microsatellite instability, or replicative DNA polymerase mutations [1,2,3]
We have evaluated how the sequencing region (WES vs. the gene set used in MSK-IMPACT vs. the gene set used in F1CDx) and method for Tumor mutational burden (TMB) calculation affect the final TMB and potential immune checkpoint inhibitors (ICIs) indication when various hypothetical cut-off values are applied
Patients with a higher TMB are more likely to respond to ICI in various settings, including PD-(L)1 blockade in non–small-cell lung cancer (NSCLC) [10], cytotoxicT-lymphocyte-associated protein 4 (CTLA-4) blockade in malignant melanoma [11], and combined PD(L)-1 and CTLA-4 blockade in NSCLC [17]
Summary
Somatic mutation rates can be affected by exposure to exogenous factors, such as ultraviolet light or tobacco smoke [2], or by compounding genetic defects, such as DNA mismatch repair deficiency, microsatellite instability, or replicative DNA polymerase mutations [1,2,3]. The genomic landscape of smoking-induced NSCLC and UV light-induced melanoma is often characterized by a high number of acquired alterations, while leukemias and pediatric tumors show the lowest mutations counts. We evaluated the extent to which potential ICI indication could be affected by variability in techniques and bioinformatic pipelines used for TMB assessment.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
