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?

J 2020

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?

PÁLOVÁ, Hana, Michal KÝR, Karol PÁL, Tomáš MERTA, Peter MÚDRY et. al.

Basic information

Original name

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?

Authors

PÁLOVÁ, Hana (203 Czech Republic, belonging to the institution), Michal KÝR (203 Czech Republic, belonging to the institution), Karol PÁL (703 Slovakia, belonging to the institution), Tomáš MERTA (203 Czech Republic, belonging to the institution), Peter MÚDRY (203 Czech Republic, belonging to the institution), Kristýna POLÁŠKOVÁ (203 Czech Republic, belonging to the institution), Tina CATELA IVKOVIĆ (191 Croatia, belonging to the institution), Soňa ADAMCOVÁ (703 Slovakia, belonging to the institution), Tekla HORNAKOVA, Marta JEŽOVÁ (203 Czech Republic), Leoš KŘEN (203 Czech Republic), Jaroslav ŠTĚRBA (203 Czech Republic, belonging to the institution) and Ondřej SLABÝ (203 Czech Republic, guarantor, belonging to the institution)

Edition

Cancers, BASEL, MDPI, 2020, 2072-6694

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 6.639

RIV identification code

RIV/00216224:14740/20:00118224

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.3390/cancers12010230

UT WoS

000516826700230

Keywords in English

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

Abstract

V originále

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.

Links

MUNI/A/1409/2019, interní kód MU

Name: Personalizovaná léčba v dětské onkologii: na cestě k "liquid dynamic medicine" a "N-of-1 clinical trials"

Investor: Masaryk University, Category A

NV16-33209A, research and development project

Name: Sekvenování nové generace a expresní profilování jako diagnostický podklad pro návrhy individualizovaných léčebných plánů pro děti se solidními nádory

Citovat

PÁLOVÁ, Hana, Michal KÝR, Karol PÁL, Tomáš MERTA, Peter MÚDRY, Kristýna POLÁŠKOVÁ, Tina CATELA IVKOVIĆ, Soňa ADAMCOVÁ, Tekla HORNAKOVA, Marta JEŽOVÁ, Leoš KŘEN, Jaroslav ŠTĚRBA and Ondřej SLABÝ. 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? Cancers. BASEL: MDPI, 2020, vol. 12, No 1, p. 1-14. ISSN 2072-6694. Available from: https://dx.doi.org/10.3390/cancers12010230.

@article{1744844,
   author = {Pálová, Hana and Kýr, Michal and Pál, Karol and Merta, Tomáš and Múdry, Peter and Polášková, Kristýna and Catela Ivković, Tina and Adamcová, Soňa and Hornakova, Tekla and Ježová, Marta and Křen, Leoš and Štěrba, Jaroslav and Slabý, Ondřej},
   article_location = {BASEL},
   article_number = {1},
   doi = {http://dx.doi.org/10.3390/cancers12010230},
   keywords = {pediatric tumors; tumor mutational burden; TMB; whole-exome sequencing; gene panel sequencing; immune checkpoint inhibitors},
   language = {eng},
   issn = {2072-6694},
   journal = {Cancers},
   title = {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?},
   url = {https://www.mdpi.com/2072-6694/12/1/230},
   volume = {12},
   year = {2020}
}

TY  - JOUR
ID  - 1744844
AU  - Pálová, Hana - Kýr, Michal - Pál, Karol - Merta, Tomáš - Múdry, Peter - Polášková, Kristýna - Catela Ivković, Tina - Adamcová, Soňa - Hornakova, Tekla - Ježová, Marta - Křen, Leoš - Štěrba, Jaroslav - Slabý, Ondřej
PY  - 2020
TI  - 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?
JF  - Cancers
VL  - 12
IS  - 1
SP  - 1-14
EP  - 1-14
PB  - MDPI
SN  - 20726694
KW  - pediatric tumors
KW  - tumor mutational burden
KW  - TMB
KW  - whole-exome sequencing
KW  - gene panel sequencing
KW  - immune checkpoint inhibitors
UR  - https://www.mdpi.com/2072-6694/12/1/230
N2  - 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.
ER  -

PÁLOVÁ, Hana, Michal KÝR, Karol PÁL, Tomáš MERTA, Peter MÚDRY, Kristýna POLÁŠKOVÁ, Tina CATELA IVKOVI$\backslash$'C, Soňa ADAMCOVÁ, Tekla HORNAKOVA, Marta JEŽOVÁ, Leoš KŘEN, Jaroslav ŠTĚRBA and Ondřej SLABÝ. 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? \textit{Cancers}. BASEL: MDPI, 2020, vol.~12, No~1, p.~1-14. ISSN~2072-6694. Available from: https://dx.doi.org/10.3390/cancers12010230.

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