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-tomesenchymal 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.
| Original language | English |
|---|---|
| Journal | Clinical Cancer Research |
| Volume | 28 |
| Issue number | 5 |
| Pages (from-to) | 1038-1052 |
| Number of pages | 15 |
| ISSN | 1078-0432 |
| DOIs | |
| Publication status | Published - 01.03.2022 |
Funding
We thank all patients who have donated their samples for this study. We also thank Ines Kunze for technical assistance with scRNA-seq analysis, Ulrike Pflugradt for patient data collection, Laura Holler and Claire Innerlohinger for technical assistance with DNA and RNA isolation from tissues samples, and Steffen Heuer for technical assistance with library preparations for sequencing. H. Busch and A. Ku€nstner acknowledge computational support from the OMICS compute cluster at the University of Lu€beck. This work was supported by the BMBF (ZiSS 02NUK024B and ZiSStrans 02NUK047A to J. Hess, K. Unger, and H. Zitzelsberger), by the Helmholtz Initiative on Personalized Medicine (iMed; project “Integrative Molecular Landscape of HNSCC” to H. Zitzelsberger, C. Belka, and S. Herzig), and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC 22167-390884018 (to H. Busch). P. Weber reports grants from BMBF (German Federal Ministry of Education and Research) and Helmholtz Initiative on Personalized Medicine during the conduct of the study. T. Kirchner reports personal fees from Amgen, AstraZeneca, Bristol Myers Squibb, Merck KGaA, Merck Sharp & Dohme, Novartis, and Pfizer, as well as grants from Definiens from outside the submitted work. U. Ganswindt reports personal fees from Merck, MSD, AstraZeneca, and Roche outside the submitted work. D. Rades reports grants from Merck Serono and Interreg (European Regional Development Fund), as well as personal fees from Elsevier outside the submitted work. C. Belka reports grants from DKTK and BMBF during the conduct of the study; C. Belka also reports personal fees from BMS, Merck Darmstadt, MSD, Amgen, and AstraZeneca, as well as grants and personal fees from Elekta and Brainlab outside the submitted work. H. Zitzelsberger reports grants and personal fees from BMBF and Helmholtz Initiative on Personalized Medicine during the conduct of the study. No disclosures were reported by the other authors.
