Abstract
Head and neck squamous cell carcinomas (HNSCC) includes multiple subsites that exhibit differential treatment outcome, which is in turn reflective of tumor stage/histopathology and molecular profile. This study hypothesized that the molecular profile is an accurate prognostic adjunct in patients triaged based on clinico-pathological characteristics. Towards this effect, publically available micro-array datasets (n = 8), were downloaded, classified based on HPV association (n = 83) and site (tongue n = 88; laryngopharynx n = 53; oropharynx n = 51) and re-analyzed (Genespring; v13.1). The significant genes were validated in respective cohorts in The Cancer Genome Atlas (TCGA) for correlation with clinico-pathological parameters/survival. The gene entities (n = 3258) identified from HPV based analysis, when validated in TCGA identified the subset specifically altered in HPV+ HNSCC (n = 63), with three genes showing survival impact (RPP25, NUDCD2, NOVA1). Site-specific meta-analysis identified respective differentials (tongue: 3508, laryngopharynx: 4893, oropharynx: 2386); validation in TCGA revealed markers with high incidence (altered in >10% of patients) in tongue (n = 331), laryngopharynx (n = 701) and oropharynx (n = 404). Assessment of these genes in clinical sub-cohorts of TCGA indicated that early stage tongue (MTFR1, C8ORF33, OTUD6B) and laryngeal cancers (TWISTNB, KLHL13 and UBE2Q1) were defined by distinct prognosticators. Similarly, correlation with perineural/angiolymophatic invasion, identified discrete marker panels with survival impact (tongue: NUDCD1, PRKC1; laryngopharynx: SLC4A1AP, PIK3CA, AP2M1). Alterations in ANO1, NUDCD1, PIK3CA defined survival in tongue cancer patients with nodal metastasis (node+ECS-), while EPS8 is a significant differential in node+ECS- laryngopharyngeal cancers. In oropharynx, wherein HPV is a major etiological factor, distinct prognosticators were identified in HPV+ (ECHDC2, HERC5, GGT6) and HPV- (GRB10, EMILIN1, FNDC1). Meta-analysis in combination with TCGA validation carried out in this study emphasized on the molecular heterogeneity inherent within HNSCC; the feasibility of leveraging this information for improving prognostic efficacy is also established. Subject to large scale clinical validation, the marker panel identified in this study can prove to be valuable prognostic adjuncts.
Highlights
Accurate molecular prognosticators predictive of survival in patients diagnosed with cancer can be an invaluable adjunct to the existing clinical and pathological parameters
TNM staging is a primary parameter for triaging the patients based on prognosis, stage-independent prognostic impact attributed to the presence of pathological parameters such as PNI, angiolymphatic invasion (ALI) and LVI [5,6] indicates the need for a multi-parameter assessment
This study proposed that molecular markers can serve as accurate adjuncts to existing prognostic parameters in head and neck cancers
Summary
Accurate molecular prognosticators predictive of survival in patients diagnosed with cancer can be an invaluable adjunct to the existing clinical and pathological parameters. TNM staging is a primary parameter for triaging the patients based on prognosis, stage-independent prognostic impact attributed to the presence of pathological parameters such as PNI, angiolymphatic invasion (ALI) and LVI [5,6] indicates the need for a multi-parameter assessment. PNI was identified as a prognostic factor in early stage tongue cancer, while LVI was a significant parameter in late stage buccal mucosal cancers [3]. These studies point out to etiological/biology-driven differences in the survival impact of the existing clinical and pathological parameters; identifying the underlying biological parameters may be significant in improving their prognostic impact
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