Original ResearchTargeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation☆,☆☆
Introduction
It is generally acknowledged that human papilloma virus-negative (HPV–) and HPV+ squamous cell carcinomas of the head and neck (SCCHN) represent two distinct subgroups with significant differences in treatment outcome [1]. The dissimilarities are thought to result from distinct molecular patterns which have evolved during the pathogenesis of HPV– and HPV+ SCCHN. Recent studies designed to unravel the genomic landscape of SCCHN by next-generation sequencing (NGS) have discovered large differences between HPV– and HPV+ tumours [2], [3], [4], [5], [6]. Smoking-related patterns which mainly comprised loss-of-function mutations in tumour suppressor genes were predominantly detected in HPV– carcinomas. In contrast, a mutation signature associated with viral infection and resembling mutation patterns of HPV-associated cervical cancer [4], [7] were described for HPV+ tumours [2], [3], [4], [5], [6].
Although distinct mutation patterns were identified by the above-mentioned studies, their prognostic value and their interference with the efficacy of current state-of-the art treatment regimens remain largely unresolved. Since many of the affected genes have a role in cell cycle, DNA repair and cell survival under stress conditions, we hypothesised that the mutational profiles might influence the tumour cell response to chemoradiation. This multicentre study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG) was designed to test this hypothesis in a uniformly treated and well-characterised cohort of locally advanced SCCHN.
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Patients
Ethical approval for this retrospective biomarker study was obtained by the local ethics committees of all DKTK partner sites. Patients with histologically proven squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity were eligible for this study; all patients had undergone complete curative surgical procedure, and due to high risk of locoregional recurrence (i.e., stage pT4, more than three affected lymph nodes, positive microscopic resection margins and/or extracapsular spread)
Patient characteristics and genomic profiles
Patient characteristics according to the HPV status are presented in Supplementary Table 2. Median follow-up of patients for OS and LRC was 55 and 47 months, respectively. As reported previously [11], patients with HPV+ OPC (N = 47) had a significantly better OS (hazard ratio [HR] 0.3, 95% confidence interval [CI] 0.14–0.69, P = 0.004) and LRC (HR 0.09, 95% CI 0.01–0.65, P = 0.018) compared to the group of patients with non-HPV-driven SCCHN (N = 132).
After filtering against the NCBI dbSNP and COSMIC
Discussion
Our study provides first evidence that targeted NGS may be of clinical use for defining molecular subgroups of SCCHN patients with distinct outcome after adjuvant cisplatin-based chemoradiation. We also confirmed the previous data [4], [5], [6] that non-HPV-driven SCCHN and HPV+ OPC have distinct mutation profiles, with TP53 and CDKN2A mutations exclusively detected at high frequency in the former and activating driver mutations in PIK3CA accumulating in the latter group.
After recognition of
Role of the funding source
The sponsors of the study had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Conflict of interest statement
All authors have declared no conflict of interest.
Acknowledgement
The authors thank all pathologists, head and neck surgeons and maxillofacial surgeons at the eight treatment centres who provided tumour material and data for this study.
References (37)
- et al.
Genomic alterations in head and neck squamous cell carcinoma determined by cancer gene-targeted sequencing
Ann Oncol
(2015) - et al.
HPV16 DNA status is a strong prognosticator of loco-regional control after postoperative radiochemotherapy of locally advanced oropharyngeal carcinoma: results from a multicentre explorative study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG)
Radiother Oncol
(2014) - et al.
Mutant p53 in cancer: new functions and therapeutic opportunities
Cancer Cell
(2014) - et al.
The INK4a/ARF tumor suppressor: one gene–two products–two pathways
Trends Biochem Sci
(1998) - et al.
PIK3CA mutational status and overall survival in patients with cervical cancer treated with radical chemoradiotherapy
Gynecol Oncol
(2013) - et al.
Preoperative chemoradiation therapy with capecitabine/oxaliplatin and cetuximab in rectal cancer: long-term results of a prospective phase 1/2 study
Int J Radiat Oncol Biol Phys
(2013) - et al.
Different types of K-Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer
Ann Oncol
(2011) - et al.
HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity
Radiother Oncol
(2013) - et al.
Treatment response of HPV-positive and HPV-negative head and neck squamous cell carcinoma cell lines
Oral Oncol
(2013) - et al.
Combined TP53 mutation/3p loss correlates with decreased radiosensitivity and increased matrix-metalloproteinase activity in head and neck carcinoma
Oral Oncol
(2015)
Human papillomavirus in head and neck cancer: its role in pathogenesis and clinical implications
Clin Cancer Res
Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1
Science
The mutational landscape of head and neck squamous cell carcinoma
Science
Comprehensive genomic characterization of head and neck squamous cell carcinomas
Nature
Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas
Clin Cancer Res
Signatures of mutational processes in human cancer
Nature
Prognostic significance of truncating TP53 mutations in head and neck squamous cell carcinoma
Clin Cancer Res
TP53 mutations and survival in squamous-cell carcinoma of the head and neck
N Engl J Med
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Presented in part at the 51th ASCO Annual Meeting, Chicago, IL, May 29th to June 2nd 2015.
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The study was financed by a Joint Funding Grant within the German Cancer Consortium (DKTK) awarded to the DKTK-ROG (principle investigator: Michael Baumann). The DKTK is funded as one of the National German Health Centers by the Federal German Ministry of Education and Research.