Abstract
BackgroundCurrent management of head and neck squamous cell carcinoma (HNSCC) depends on tumor staging. Despite refinements in clinical staging algorithms, outcomes remain unchanged for the last two decades. In this study, we set out to identify a small, clinically applicable molecular panel to aid prognostication of patients with HNSCC.Materials and MethodsData from The Cancer Genome Atlas (TCGA) was used to derive copy number aberrations and expression changes to identify putative prognostic genes. To account for cross entity relevance of the biomarkers, HNSCC (n = 276), breast (n = 808) and lung cancer (n = 282) datasets were used to identify robust and reproducible markers with prognostic potential. Validation was performed using immunohistochemistry (IHC) on tissue microarrays of an independent cohort of HNSCC (n = 333).FindingsUsing GISTIC algorithm together with gene expression analysis, we identified six putative prognostic genes in at least two out of three cancers analyzed, of which four were successfully optimized for automated IHC. Of these, three were successfully validated; each molecular target being significantly prognostic on univariate analysis. Patients were differentially segregated into four prognostic groups based on the number of genes dysregulated (p < 0.001). The IHC panel remained an independent predictor of survival after adjusting for known survival covariates including clinical staging criteria in a multivariate Cox regression model (p < 0.001). InterpretationWe have identified and validated a clinically applicable IHC biomarker panel that is independently associated with overall survival. This panel is readily applicable, serving as a useful adjunct to current staging systems and provides novel targets for future therapeutic strategies.
Highlights
Apart from prognostication, tumor staging in head and neck squamous cell carcinoma (HNSCC) plays a major role in treatment decisions
Analysing the The Cancer Genome Atlas (TCGA) data, three amplicons (11q13, 3q22-29, 5p15) were associated with a number of genes for which expression data was prognostic in head and neck and in either breast or lung cancers
The final targets selected were: Anoctamin 1 (ANO 1) [11q13], Cortactin (CTTN) [11q13], Exocyst Complex Component 3 (EXOC 3) [5p15], Chaperonin Containing TCP1, Subunit 5 (CCT5) [5p15], Signal Sequence Receptor, Gamma (SSR3) [3q22-29] and ATPase Type 13A3 (ATP13A3) [3q22-29] The results for the prognostic significance of each target selected are shown in Supplementary Figure 1
Summary
Apart from prognostication, tumor staging in head and neck squamous cell carcinoma (HNSCC) plays a major role in treatment decisions. Patients with higher tumor stage benefit from the addition of adjuvant treatment which includes radiotherapy, chemotherapy (including cisplatin, 5-fluorouracil and/or taxol/taxanes) and biologic therapy (such as monoclonal antibodies against EGFR, e.g. cetuximab) [1,2,3]. Notwithstanding, overall outcomes have remained unchanged for the last two decades [4,5,6,7,8]. Even with the addition of a range of clinical data, there exists substantial variation within subgroups that are likely a reflection of the genetic and biologic make-up of the tumor itself. Current management of head and neck squamous cell carcinoma (HNSCC) depends on tumor staging. Despite refinements in clinical staging algorithms, outcomes remain unchanged for the last two decades. We set out to identify a small, clinically applicable molecular panel to aid prognostication of patients with HNSCC
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