Cancer as the Disintegration of Robustness: Population-Level Variance in Gene Expression Identifies Key Differences Between Tobacco- and HPV-Associated Oropharyngeal Carcinogenesis

Abstract

Context Oropharyngeal squamous cell carcinoma (OPSCC) is associated both with tobacco use and human papillomavirus (HPV) infection. It is argued that carcinogen-driven tumorigenesis is a distinct disease from its virally-driven counterpart. We hypothesized that tumorigenesis is the result of a loss of genotypic robustness resulting in an increase in phenotypic variation in tumors compared to adjacent histologically normal tissues, and that carcinogen-driven tumorigenesis results in greater variation than their virally-driven counterparts. Objective To examine the loss of robustness in carcinogen- and virally-driven OPSCC samples, and to identify potential pathways involved. Design We used coefficients of variation (CVs) for mRNA and microRNA expression to measure the loss of robustness in OPSCC samples. Tumors were compared to matched normal tissues, and were further categorized by HPV and patient smoking status. Weighted gene co-expression networks were constructed for genes with highly variable expression among the HPV- tumors from smokers. Results We observed more genes with variable mRNA expression in tumors compared to normal tissues, regardless of HPV and smoking status, and more microRNAs with variable expression in HPV− and HPV+ tumors from smoking patients than from non-smokers. For both the mRNA and microRNA data, we observed more variance among HPV− tumors from smokers compared to HPV+ tumors from non-smokers. The gene co-expression network construction highlighted pathways that have lost robustness in carcinogen-induced tumors but appear stable in virally-induced tumors. Conclusions Using CVs and co-expression networks, we identified multiple altered pathways that may play a role in carcinogen-driven tumorigenesis.

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