Measurement of tumor mutational burden (TMB) in routine molecular diagnostics: in silico and real-life analysis of three larger gene panels

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Volker Endris - , Universität Heidelberg (Autor:in)
  • Ivo Buchhalter - , Universität Heidelberg, Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)
  • Michael Allgäuer - , Universität Heidelberg (Autor:in)
  • Eugen Rempel - , Universität Heidelberg (Autor:in)
  • Amelie Lier - , Universität Heidelberg (Autor:in)
  • Anna Lena Volckmar - , Universität Heidelberg (Autor:in)
  • Martina Kirchner - , Universität Heidelberg (Autor:in)
  • Moritz von Winterfeld - , Universität Heidelberg (Autor:in)
  • Jonas Leichsenring - , Universität Heidelberg (Autor:in)
  • Olaf Neumann - , Universität Heidelberg (Autor:in)
  • Roland Penzel - , Universität Heidelberg (Autor:in)
  • Wilko Weichert - , Technische Universität München, Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)
  • Hanno Glimm - , Nationales Centrum für Tumorerkrankungen Dresden, Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)
  • Stefan Fröhling - , Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)
  • Hauke Winter - , Universität Heidelberg, Translational Lung Research Center Heidelberg (TLRC) - DZL-Standort Heidelberg (Autor:in)
  • Felix Herth - , Translational Lung Research Center Heidelberg (TLRC) - DZL-Standort Heidelberg, Universität Heidelberg (Autor:in)
  • Michael Thomas - , Translational Lung Research Center Heidelberg (TLRC) - DZL-Standort Heidelberg, Universität Heidelberg (Autor:in)
  • Peter Schirmacher - , Universität Heidelberg, Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)
  • Jan Budczies - , Universität Heidelberg, Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)
  • Albrecht Stenzinger - , Universität Heidelberg, Deutsches Krebsforschungszentrum (DKFZ) (Autor:in)

Abstract

Assessment of Tumor Mutational Burden (TMB) for response stratification of cancer patients treated with immune checkpoint inhibitors is emerging as a new biomarker. Commonly defined as the total number of exonic somatic mutations, TMB approximates the amount of neoantigens that potentially are recognized by the immune system. While whole exome sequencing (WES) is an unbiased approach to quantify TMB, implementation in diagnostics is hampered by tissue availability as well as time and cost constrains. Conversely, panel-based targeted sequencing is nowadays widely used in routine molecular diagnostics, but only very limited data are available on its performance for TMB estimation. Here, we evaluated three commercially available larger gene panels with covered genomic regions of 0.39 Megabase pairs (Mbp), 0.53 Mbp and 1.7 Mbp using i) in silico analysis of TCGA (The Cancer Genome Atlas) data and ii) wet-lab sequencing of a total of 92 formalin-fixed and paraffin-embedded (FFPE) cancer samples grouped in three independent cohorts (non-small cell lung cancer, NSCLC; colorectal cancer, CRC; and mixed cancer types) for which matching WES data were available. We observed a strong correlation of the panel data with WES mutation counts especially for the gene panel >1Mbp. Sensitivity and specificity related to TMB cutpoints for checkpoint inhibitor response in NSCLC determined by wet-lab experiments well reflected the in silico data. Additionally, we highlight potential pitfalls in bioinformatics pipelines and provide recommendations for variant filtering. In summary, our study is a valuable data source for researchers working in the field of immuno-oncology as well as for diagnostic laboratories planning TMB testing.

Details

OriginalspracheEnglisch
Seiten (von - bis)2303-2312
Seitenumfang10
FachzeitschriftInternational journal of cancer
Jahrgang144
Ausgabenummer9
PublikationsstatusVeröffentlicht - 1 Mai 2019
Peer-Review-StatusJa

Externe IDs

PubMed 30446996

Schlagworte

Ziele für nachhaltige Entwicklung

ASJC Scopus Sachgebiete

Schlagwörter

  • mutational load, NGS, panel sequencing, TMB, tumor mutational burden