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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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
18 February 2016
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| In: |
European journal of cancer
Year: 2016, Jahrgang: 57, Pages: 78-86 |
| ISSN: | 1879-0852 |
| DOI: | 10.1016/j.ejca.2016.01.003 |
| Online-Zugang: | 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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| Verfasserangaben: | 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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| 245 | 1 | 0 | |a Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation |c 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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| 520 | |a 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. | ||
| 650 | 4 | |a Adjuvant chemoradiation | |
| 650 | 4 | |a Cisplatin | |
| 650 | 4 | |a Head and neck cancer | |
| 650 | 4 | |a Human papilloma virus | |
| 650 | 4 | |a Mutation profiles | |
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