Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation. (April 2016)

• Record Type: Journal Article
• Authors: Tinhofer, I.; Budach, V.; Saki, M.; Konschak, R.; Niehr, F.; Jöhrens, K.; Weichert, W.; Linge, A.; Lohaus, F.; Krause, M.; Neumann, K.; Endris, V.; Sak, A.; Stuschke, M.; Balermpas, P.; Rödel, C.; Avlar, M.; Grosu, A.L.; Abdollahi, A.; Debus, J.; Belka, C.; Pigorsch, S.; Combs, S.E.; Mönnich, D.; Zips, D.; Baumann, M.
• Is Part Of: European journal of cancer. Volume 57(2016)
• Page Start: 78
• Page End: 86
• Publication Date: 2016-04
• Subjects: Head and neck cancer -- Human papilloma virus -- Mutation profiles -- Adjuvant chemoradiation -- Cisplatin; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2016.01.003
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: 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. Highlights: SCCHN tumor sequencing is useful for outcome prediction of adjuvant chemoradiation Unfavourable subgroup of tobacco-related SCCHN displays hotspot TP53 mutations PIK3CA, KRAS and NRAS mutations in HPV+ SCCHN are associated with reduced survival. Mutant p53 and the phosphoinositide 3-kinase pathway represent druggable targets.