Abstract B70: Conexic: A Bayesian framework to detect drivers and their function uncovers an endosomal signature in melanoma

Genomics is revolutionizing our understanding of cancer biology. Tumor samples assayed for comprehensive chromosomal and gene expression data are accumulating at a staggering rate. A major challenge involves the development of analysis methods to uncover biological insights from these data, including the identification of the key mutations that drive cancer and how these events alter cellular regulation. We have developed Conexic, a novel computational framework to integrate chromosomal copy number and gene expression data to detect genetic alterations in tumors that drive proliferation, and to model how these alterations perturb normal cell growth/survival. The underlying assumption to our approach is that significantly recurring copy number change, coinciding with its ability to predict the expression patterns varying across tumors, strengthens the evidence of a gene9s causative role in cancer. This method not only pinpoints specific regulators within an a large region of copy number variation, but can shed light on the way in which gene regulation is altered We applyed our Conexic framework to a melanoma dataset (Lin et al, Cancer Research, 2007) comprising 65 paired measurements of gene expression and copy number, with interesting results. Our analysis correctly identified many known ‘driver’ events, while also connecting these to many of their known targets (e.g. MITF). Our global integrative analysis reveals insight into how the drivers alter transcriptional programs. An interesting recurring characteristic is that there are a number of different ways by which drivers can be altered; e.g., the expression of a driver may be altered through copy number variation or other mechanisms, but its influence downstream remains the same. In addition to confirming the role of known drivers in melanoma, our analysis suggests a number of novel drivers. Most strikingly, these point to a major role in regulation of protein trafficking and endosome biology in this malignancy. These results have linked endosomal processing and sorting to adhesion and survival. Preliminary experimental validation supports three novel drivers including TBC1D16, RAB7A and RAB27A. Together, these results affirm the potential of Conexic to elaborate novel driver modules with biological and possibly therapeutic importance in melanoma and other cancers. Citation Information: Cancer Res 2009;69(23 Suppl):B70.