Abstract
Improved understanding of the molecular basis underlying oral squamous cell carcinoma (OSCC) aggressive growth has significant clinical implications. Herein, cross-species genomic comparison of carcinogen-induced murine and human OSCCs with indolent or metastatic growth yielded results with surprising translational relevance. Murine OSCC cell lines were subjected to next-generation sequencing (NGS) to define their mutational landscape, to define novel candidate cancer genes, and to assess for parallels with known drivers in human OSCC. Expression arrays identified a mouse metastasis signature, and we assessed its representation in four independent human datasets comprising 324 patients using weighted voting and gene set enrichment analysis. Kaplan-Meier analysis and multivariate Cox proportional hazards modeling were used to stratify outcomes. A quantitative real-time PCR assay based on the mouse signature coupled to a machine-learning algorithm was developed and used to stratify an independent set of 31 patients with respect to metastatic lymphadenopathy. NGS revealed conservation of human driver pathway mutations in mouse OSCC, including in Trp53, mitogen-activated protein kinase, phosphoinositide 3-kinase, NOTCH, JAK/STAT, and Fat1-4. Moreover, comparative analysis between The Cancer Genome Atlas and mouse samples defined AKAP9, MED12L, and MYH6 as novel putative cancer genes. Expression analysis identified a transcriptional signature predicting aggressiveness and clinical outcomes, which were validated in four independent human OSCC datasets. Finally, we harnessed the translational potential of this signature by creating a clinically feasible assay that stratified patients with OSCC with a 93.5% accuracy. These data demonstrate surprising cross-species genomic conservation that has translational relevance for human oral squamous cell cancer. Clin Cancer Res; 20(11); 2873-84. ©2014 AACR.
Highlights
Aggressive carcinogen-induced oral squamous cell carcinomas (OSCC) are difficult to treat due to locoregional recurrences
Expression analysis identified a transcriptional signature predicting aggressiveness and clinical outcomes, which were validated in four independent human OSCC datasets
We present our genomic analysis of a carcinogen-induced mouse model of oral squamous cell carcinoma (OSCC) that has surprising conservation with human OSCC with significant translational implications
Summary
Aggressive carcinogen-induced oral squamous cell carcinomas (OSCC) are difficult to treat due to locoregional recurrences. More indolent lesions can be treated with single-modality surgical intervention with low morbidity and favorable outcomes Histologic criteria, such as perineural or lymphovascular invasion and Authors' Affiliations: Departments of 1Cell Biology and Physiology, 2Otolaryngology, 3Genetics, 4Pathology and Immunology, and 5Neurosurgery; 6The Genome Institute, Washington University School of Medicine; and 7John Cochran VA Medical Center, St. Louis, Missouri. Among clinical staging criteria, metastatic lymphadenopathy is one of the best predictors of a poor prognosis as it likely reflects aggressive primary tumor biology (3–5; seer.cancer.gov/statfacts/html/oralcav.html). This staging is especially challenging in early disease as 20% of these patients have pathologically identifiable disease that is clinically undetectable. The molecular underpinnings of aggressive OSCC growth and metastasis remain largely undefined [5, 8]
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