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Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation

Background - Despite clear differences in clinical presentation and outcome, squamous cell carcinomas of the head and neck (SCCHN) arising from human papilloma virus (HPV) infection or heavy tobacco/alcohol consumption are treated equally. Next-generation sequencing is expected to reveal novel targe...

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Main Authors: Tinhofer, Ingeborg (Author) , Budach, V. (Author) , Saki, M. (Author) , Konschak, R. (Author) , Niehr, F. (Author) , Jöhrens, K. (Author) , Weichert, Wilko (Author) , Linge, A. (Author) , Lohaus, F. (Author) , Krause, M. (Author) , Neumann, K. (Author) , Endris, Volker (Author) , Sak, A. (Author) , Stuschke, M. (Author) , Balermpas, P. (Author) , Rödel, C. (Author) , Avlar, M. (Author) , Grosu, A. L. (Author) , Abdollahi, Amir (Author) , Debus, Jürgen (Author) , Belka, C. (Author) , Pigorsch, S. (Author) , Combs, S. E. (Author) , Mönnich, D. (Author) , Zips, D. (Author) , Baumann, M. (Author)
Format: Article (Journal)
Language:English
Published: 18 February 2016
In: European journal of cancer
Year: 2016, Volume: 57, Pages: 78-86
ISSN:1879-0852
DOI:10.1016/j.ejca.2016.01.003
Online Access:Verlag, Volltext: https://doi.org/10.1016/j.ejca.2016.01.003
Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0959804916000393
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Author Notes:I. Tinhofer, V. Budach, M. Saki, R. Konschak, F. Niehr, K. Jöhrens, W. Weichert, A. Linge, F. Lohaus, M. Krause, K. Neumann, V. Endris, A. Sak, M. Stuschke, P. Balermpas, C. Rödel, M. Avlar, A.L. Grosu, A. Abdollahi, J. Debus, C. Belka, S. Pigorsch, S.E. Combs, D. Mönnich, D. Zips, M. Baumann, for the DKTK-ROG
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Summary:Background - Despite clear differences in clinical presentation and outcome, squamous cell carcinomas of the head and neck (SCCHN) arising from human papilloma virus (HPV) infection or heavy tobacco/alcohol consumption are treated equally. Next-generation sequencing is expected to reveal novel targets for more individualised treatment. - Patients and methods - Tumour specimens from 208 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity, all uniformly treated with adjuvant cisplatin-based chemoradiation, were included. A customised panel covering 211 exons from 45 genes frequently altered in SCCHN was used for detection of non-synonymous point and frameshift mutations. Mutations were correlated with HPV status and treatment outcome. - Results - Mutational profiles and HPV status were successfully established for 179 cases. HPV- tumours showed an increased frequency of alterations in tumour suppressor genes compared to HPV+ cases (TP53 67% versus 4%, CDKN2A 18% versus 0%). Conversely, HPV+ carcinomas were enriched for activating mutations in driver genes compared to HPV- cases (PIK3CA 30% versus 12%, KRAS 6% versus 1%, and NRAS 4% versus 0%). Hotspot TP53 missense mutations in HPV- carcinomas correlated with an increased risk of locoregional recurrence (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.5-12.1, P=0.006) and death (HR 2.2, 95% CI 1.1-4.4, P=0.021). In HPV+ SCCHN, driver gene mutations were associated per trend with a higher risk of death (HR 3.9, 95% CI 0.7-21.1, P=0.11). - Conclusions - Distinct mutation profiles in HPV- and HPV+ SCCHN identify subgroups with poor outcome after adjuvant chemoradiation. Mutant p53 and the phosphoinositide 3-kinase pathway were identified as potential druggable targets for subgroup-specific treatment optimisation.
Item Description:Gesehen am 11.02.2020
Physical Description:Online Resource
ISSN:1879-0852
DOI:10.1016/j.ejca.2016.01.003

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