Spatial and Temporal Heterogeneity of Panel-Based Tumor Mutational Burden in Pulmonary Adenocarcinoma: Separating Biology From Technical Artifacts.

Détails

ID Serval
serval:BIB_E1CA5C54D324
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Spatial and Temporal Heterogeneity of Panel-Based Tumor Mutational Burden in Pulmonary Adenocarcinoma: Separating Biology From Technical Artifacts.
Périodique
Journal of thoracic oncology
Auteur⸱e⸱s
Kazdal D., Endris V., Allgäuer M., Kriegsmann M., Leichsenring J., Volckmar A.L., Harms A., Kirchner M., Kriegsmann K., Neumann O., Brandt R., Talla S.B., Rempel E., Ploeger C., von Winterfeld M., Christopoulos P., Merino D.M., Stewart M., Allen J., Bischoff H., Meister M., Muley T., Herth F., Penzel R., Warth A., Winter H., Fröhling S., Peters S., Swanton C., Thomas M., Schirmacher P., Budczies J., Stenzinger A.
ISSN
1556-1380 (Electronic)
ISSN-L
1556-0864
Statut éditorial
Publié
Date de publication
11/2019
Peer-reviewed
Oui
Volume
14
Numéro
11
Pages
1935-1947
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Tumor mutational burden (TMB) is an emerging biomarker used to identify patients who are more likely to benefit from immuno-oncology therapy. Aside from various unsettled technical aspects, biological variables such as tumor cell content and intratumor heterogeneity may play an important role in determining TMB.
TMB estimates were determined applying the TruSight Oncology 500 targeted sequencing panel. Spatial and temporal heterogeneity was analyzed by multiregion sequencing (two to six samples) of 24 pulmonary adenocarcinomas and by sequencing a set of matched primary tumors, locoregional lymph node metastases, and distant metastases in five patients.
On average, a coding region of 1.28 Mbp was covered with a mean read depth of 609x. Manual validation of the mutation-calls confirmed a good performance, but revealed noticeable misclassification during germline filtering. Different regions within a tumor showed considerable spatial TMB variance in 30% (7 of 24) of the cases (maximum difference, 14.13 mut/Mbp). Lymph node-derived TMB was significantly lower (p = 0.016). In 13 cases, distinct mutational profiles were exclusive to different regions of a tumor, leading to higher values for simulated aggregated TMB. Combined, intratumor heterogeneity and the aggregated TMB could result in divergent TMB designation in 17% of the analyzed patients. TMB variation between primary tumor and distant metastases existed but was not profound.
Our data show that, in addition to technical aspects such as germline filtering, the tumor content and spatially divergent mutational profiles within a tumor are relevant factors influencing TMB estimation, revealing limitations of single-sample-based TMB estimations in a clinical context.
Mots-clé
ITH, TMB, intratumor heterogeneity, lung adenocarcinoma, tumor mutational burden, Intratumor heterogeneity, Lung adenocarcinoma, Tumor mutational burden
Pubmed
Web of science
Création de la notice
06/08/2019 17:33
Dernière modification de la notice
05/01/2020 7:18
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