期刊
CLINICAL CANCER RESEARCH
卷 20, 期 11, 页码 2873-2884出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-0205
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类别
资金
- Genome Institute at Washington University [NIH/NHGRI 5U54HG003079]
- NIH [P30DC04665]
- biostatistics cores
- Siteman Cancer Frontier Fund, Tissue Procurement (NCI Cancer Center) [P30 CA91842]
- GTAC (NCCR ICTS/CTSA) [UL1TR000448, NCI-CA91842]
- NIGMS [R01GM38542]
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. (C) 2014 AACR.
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