Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation.
Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation.
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DOI：
10.1016/j.ejca.2016.01.003
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发表时间：
2016-04
影响因子：
8.4
通讯作者：
I. Tinhofer;I. Tinhofer;V. Budach;V. Budach;Mohammad Saki;Mohammad Saki;R. Konschak;R. Konschak-R.-Ko
中科院分区：
文献类型：
--
作者：
I. Tinhofer;I. Tinhofer;V. Budach;V. Budach;Mohammad Saki;Mohammad Saki;R. Konschak;R. Konschak-R.-Ko
背景：尽管临床表现和结果存在明显差异，但由人乳头状瘤病毒（HPV）感染或大量吸烟/饮酒引起的头颈部鳞状细胞癌（SCCHN）的治疗是平等的。下一代测序有望揭示更多个体化治疗的新靶点。患者和方法纳入208例局部晚期下咽、口咽或口腔鳞状细胞癌患者的标本，所有患者均接受顺铂辅助放化疗。定制的面板覆盖了45个SCCHN中经常改变的基因的211个外显子，用于检测非同义点和移码突变。突变与HPV状态和治疗结果相关。结果179例成功建立了突变谱和HPV状态。与HPV+病例相比，HPV -肿瘤显示肿瘤抑制基因改变的频率增加（TP5367%对4%，CDKN2A18%对0%）。相反，与HPV -病例相比，HPV+癌在驱动基因的激活突变中富集（PIK3CA30%对12%，KRAS6%对1%，nras4%对0%）。HPV -癌hotspottp53错义突变与局部复发风险增加（风险比[HR] 4.3, 95%可信区间[CI] 1.5-12.1，P= 0.006）和死亡（风险比[HR] 2.2, 95% CI 1.1-4.4，P= 0.021）相关。在HPV+ SCCHN中，驱动基因突变与更高的死亡风险相关（HR 3.9, 95% CI 0.7-21.1，P= 0.11）。结论HPV -和HPV+ SCCHN的不同突变谱确定了辅助放化疗后预后不良的亚组。突变型p53和磷酸肌肽3激酶途径被确定为亚群特异性治疗优化的潜在药物靶点。
BackgroundDespite 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 methodsTumour 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.ResultsMutational 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 (TP5367% versus 4%,CDKN2A18% versus 0%). Conversely, HPV+ carcinomas were enriched for activating mutations in driver genes compared to HPV– cases (PIK3CA30% versus 12%,KRAS6% versus 1%, andNRAS4% versus 0%). HotspotTP53missense 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).ConclusionsDistinct 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.