Gene Expression Subtype Predicts Nodal Metastasis and Survival in Human Papillomavirus–Negative Head and Neck Cancer

Abstract

Objective/Hypothesis Gene expression analyses of head and neck cancer have revealed four molecular subtypes: basal (BA), mesenchymal (MS), atypical (AT), and classical (CL). We evaluate whether gene expression subtypes in oral cavity (OCSCC) and laryngeal (LSCC) can be used to predict nodal metastasis and prognosticate survival. Level of Evidence 2b Study Design Retrospective cohort study and genomic analysis Methods OCSCC and LSCC cases were identified from the TCGA head and neck cancer cohort. RNA-Seq by Expected Maximization (RSEM) was used to quantify gene expression levels from TCGA RNA-seq data and to assign each case to one of four subtypes. Descriptive statistics were used to describe patient, disease and treatment characteristics in each subtype. Cox regression and Kaplan Meier analyses were used to determine associations with survival. Results OCSCC cases were comprised primarily of the MS and BA subtypes, while LSCC was comprised primarily of CL and AT subtypes. In OCSCC, the MS subtype was significantly associated with higher risk of nodal metastasis. In a subset analysis of clinically T1-2N0M0 OCSCC, we demonstrate that the MS subtype was predictive of occult nodal metastasis (RR=3.38, 95% CI 1.08–10.69). In LSCC, the CL subtype was associated with significantly worse overall survival (HR=4.32, 95% CI 1.77–10.54, p=0.001). Conclusions Gene expression analysis reveals potential novel markers of nodal metastasis and survival in HPV (−) head and neck cancer. Future studies will continue to refine and validate these markers, with the goal of providing molecular risk assessments that guide therapy and improve patient outcomes.

Single-Cell Analysis of Different Stages of Oral Cancer Carcinogenesis in a Mouse Model

“…Head and neck cancer studies have used numerous cancer cells to explore gene expression and regulation [4,5]. However, human tumor cells are composed of malignant, immune, and stromal cells.…”

Recurrent human papillomavirus-related head and neck cancer undergoes metabolic re-programming and is driven by oxidative phosphorylation

“…Previous research identified a predilection for alteration of oxidative stress genes (KEAP1, NFE2L2, or CUL3) among head and neck cancers of the classical subtype(7) and an association with poor survival in laryngeal SCC(21). The mesenchymal subtype has been associated with increased expression of innate immunity genes and a higher risk of nodal metastasis in oral cavity SCC(21). We found that 8/10 of the rOPSCCs were of the classical or mesenchymal subtype.…”

“…Thus, targeting OXPHOS in Nrf2-mediated recurrent HPVrelated HNSC in conjunction with cisplatin therapy may provide a synergistic precision target for improving oncologic outcomes in this devastating disease.Recurrent HPV-related HNSC portends a poor prognosis(2). Previous research identified a predilection for alteration of oxidative stress genes (KEAP1, NFE2L2, or CUL3) among head and neck cancers of the classical subtype(7) and an association with poor survival in laryngeal SCC(21). The mesenchymal subtype has been associated with increased expression of innate immunity genes and a higher risk of nodal metastasis in oral cavity SCC(21).…”

Predicting salvage laryngectomy in patients treated with primary nonsurgical therapy for laryngeal squamous cell carcinoma using machine learning

“…The NCDB does not offer unique patient information, such as gene expression patterns or genomic sequence data, that may be predictive of patients' response to treatment. [65][66][67] The NCDB data also lacks information about treatment "quality" such as adequacy of RT given. The current literature points to the reality that drivers of survival in head and neck cancer are complex and multifactorial in nature and may be affected by treatment quality 68 in addition to socioeconomic factors and inherent disease biology.…”