Washington University in St. Louis

New Publication for Michael Onken

Congratulations to Mike Onken and his collaborators on their recently published news-making paper in Clinical Cancer Research.  

Read the full WU news story published online June 25, 2014 at https://news.wustl.edu/news/Pages/27052.aspx.

Onken, MD, Winkler, AE, Kanchi, KL, Chalivendra, V, Law, JH, Rickert, CG, Kallogjieri, D, Judd, NP, Dunn, GP, Piccirillo, JF, Lewis, JS Jr, Mardis, and Uppaluri, R.  (2014) A surprising cross-species conservation in the genomic landscape of mouse and human oral cancer identifies a transcriptional signature predicting metastic disease.  Clin. Cancer Res. 20(11):2873-2884.

Purpose:  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.
Experimental Design:  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.
Results:  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.
Conclusions:  These data demonstrate surprising cross-species genomic conservation that has translational relevance for human oral squamous cell cancer. 

To access the complete journal article, click here.


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