Abstract 2404: Cumulative dosage effect of TSGs and OGs drives aneuploidy patterns in cancer

Since Boveri's postulates in 1914, aneuploidy has been recognized as a hallmark of human cancer. However, no comprehensive theory exists to explain the patterns of aneuploidy and its role in tumor evolution. Recurrent gains or losses of specific chromosomes have been observed in cancer, but it is not clear whether a recurrent pattern of aneuploidy exists among cancer karyotypes and whether the recurrent patterns just happen to occur more frequently or are specifically selected during tumor evolution. We have developed the Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method for the prediction of tumor suppressor genes (TSGs) and oncogenes (OGs) through the analysis of the pattern of somatic mutations in cancer (Davoli et al., Cell, 2013). By analyzing >8200 tumor-normal pairs from more than 20 tumor types we provide statistical evidence suggesting that many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. The TUSON Explorer analysis on the entire dataset has identified new potential TSGs such as RASA1, TP53BP1, USP28 and OGs such as PPP2R1A and PPP6C. The TUSON Explorer was also applied to individual tumor types, leading to the identification of new potential tissue-specific drivers. In addition, we have integrated our prediction of TSGs and OGs with information of copy number alterations. We found that the distribution on chromosome and the potency of TSGs and OGs can predict the frequency of arm-level and chromosome-level deletions and amplification. For example, the density and potency of TSGs strongly positively and negatively correlated with the frequency of arm and chromosome deletion and amplification, respectively (r value=∼0.6, p Citation Format: Teresa Davoli, Andrew Wei Xu, Kristen E. Mengwasser, Laura M. Sack, John C. Yoon, Peter J. Park, Stephen J. Elledge. Cumulative dosage effect of TSGs and OGs drives aneuploidy patterns in cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2404. doi:10.1158/1538-7445.AM2014-2404