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Weber, P. ; Künstner, A.* ; Hess J. ; Unger, K. ; Marschner, S. ; Idel, C.* ; Ribbat-Idel, J.* ; Walz, C.* ; Rietzler, S.* ; Valeanu, L.* ; Herkommer, T. ; Kreutzer, L. ; Klymenko, O.* ; Kirchner, T.* ; Ganswindt, U. ; Walch, A.K. ; Sterr, M. ; Lickert, H. ; Canis, M.* ; Rades, D.* ; Perner, S.* ; Berriel Diaz, M. ; Herzig, S. ; Wollenberg, B.* ; Busch, H.* ; Zitzelsberger, H.

Therapy-related transcriptional subtypes in matched primary and recurrent head and neck cancer.

Clin. Cancer Res. 28, 1038-1052 (2022)
Postprint DOI PMC
Open Access Green
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: While 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. Gene set enrichment analysis identified upregulation of Hypoxia, p-emt and radiation resistance signatures and downregulation of tumor inflammation in recurrences compared to 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Squamous-cell Carcinoma; Genetic-heterogeneity; Oropharyngeal Cancer; Local Recurrence; Open-label; Hpv; Multicenter; Evolution; Genomics; Insights
ISSN (print) / ISBN 1078-0432
e-ISSN 1557-3265
Journal Clinical Cancer Research
Quellenangaben Volume: 28, Issue: 5, Pages: 1038-1052 Article Number: , Supplement: ,
Publisher American Association for Cancer Research (AACR)
Publishing Place 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Translational Metabolic Oncology (TMO)
CCG Personalized Radiotherapy in Head and Neck Cancer (KKG-KRT)
Research Unit Analytical Pathology (AAP)
Institute of Diabetes and Regeneration Research (IDR)
Institute of Diabetes and Cancer (IDC)
Grants Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy
Helmholtz Initiative on Personalized Medicine (iMed; project "Integrative Molecular Landscape of HNSCC")
BMBF