Purpose: Chromosome 3q26-29 is a critical region of genomic amplification in lung squamous cell carcinomas (SCCs). Identification of candidate drivers in this region could help uncover new mechanisms in the pathogenesis and potentially new targets in SCC of the lung. Experimental Design: We performed a meta-analysis of seven independent data sets containing a total of 593 human primary SCC tumor samples to identify consensus candidate drivers in 3q26-29 amplicon. Through integrating protein-protein interaction network information, we further filtered for candidates that may function together in a network. Computationally predicted candidates were validated using RNAi knock down and cell viability assays. Clinical relevance of the experimentally supported drivers was evaluated in an independent cohort of 52 lung SCC tumors using survival analysis. Results: The meta-analysis identified 20 consensus candidates, among which four (SENP2, DCUN1D1, DVL3 and UBXN7) were involved in a small protein-protein interaction network. Knocking down any of the four proteins led to cell growth inhibition of the 3q26-29 amplified SCC. Moreover, knocking down of SENP2 resulted in the most significant cell growth inhibition and downregulation of DCUN1D1 and DVL3. Importantly, a gene expression signature composed of SENP2, DCUN1D1 and DVL3 stratified patients into subgroups with different response to adjuvant chemotherapy. Conclusion: Together, our findings show that SENP2, DCUN1D1 and DVL3 are candidate driver genes in the 3q26-29 amplicon of SCC, providing novel insights into the molecular mechanisms of disease progression and may have significant implication in the management of SCC of the lung.
- Received March 1, 2013.
- Revision received June 28, 2013.
- Accepted July 17, 2013.
- Copyright © 2013, American Association for Cancer Research.