Therapy-Related Transcriptional Subtypes in Matched Primary and Recurrent Head and Neck Cancer.

Abstract

PURPOSE:

The genetic relatedness between primary and recurrent head and neck squamous cell carcinomas (HNSCC) reflects the extent of heterogeneity and therapy-driven selection of tumor subpopulations. Yet, current treatment of recurrent HNSCC ignores the molecular characteristics of therapy-resistant tumor populations.

EXPERIMENTAL DESIGN:

From 150 tumors, 74 primary HNSCCs were RNA sequenced and 38 matched primary/recurrent tumor pairs were both whole-exome and RNA sequenced. Transcriptome analysis determined the predominant classical (CL), basal (BA), and inflamed-mesenchymal (IMS) transcriptional subtypes according to an established classification. Genomic alterations and clonal compositions of tumors were evaluated from whole-exome data.

RESULTS:

Although CL and IMS subtypes were more common in primary HNSCC with low recurrence rates, the BA subtype was more prevalent and stable in recurrent tumors. The BA subtype was associated with a transcriptional signature of partial epithelial-to-mesenchymal transition (p-EMT) and early recurrence. In 44% of matched cases, the dominant subtype changed from primary to recurrent tumors, preferably from IMS to BA or CL. Expression analysis of prognostic gene sets identified upregulation of hypoxia, p-emt, and radiotherapy resistance signatures and downregulation of tumor inflammation in recurrences compared with index tumors. A relevant subset of primary/recurrent tumor pairs presented no evidence for a common clonal origin.

CONCLUSIONS:

Our study showed a high degree of genetic and transcriptional heterogeneity between primary/recurrent tumors, suggesting therapy-related selection of a transcriptional subtype with characteristics unfavorable for therapy. We conclude that therapy decisions should be based on genetic and transcriptional characteristics of recurrences rather than primary tumors to enable optimally tailored treatment strategies.

• Authors: Peter Weber, Axel Künstner, Julia Hess, Kristian Unger, Sebastian Marschner, Christian Idel, Julika Ribbat-Idel, Philipp Baumeister, Olivier Gires, Christoph Walz, Sibylle Rietzler, Laura Valeanu, Timm Herkommer, Lisa Kreutzer, Olena Klymenko, Guido Drexler, Thomas Kirchner, Cornelius Maihöfer, Ute Ganswindt, Axel Walch, Michael Sterr, Heiko Lickert, Martin Canis, Dirk Rades, Sven Perner, Mauricio Berriel Diaz, Stefan Herzig, Kirsten Lauber, Barbara Wollenberg, Hauke Busch, Claus Belka, Horst Zitzelsberger
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 5 Pg. 1038-1052 (Mar 01 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 34965946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• RNA

Topics

• Carcinoma, Squamous Cell (genetics, pathology)
• Head and Neck Neoplasms (genetics)
• Humans
• Neoplasm Recurrence, Local (genetics)
• RNA
• Squamous Cell Carcinoma of Head and Neck (genetics)