Abstract B137: Oncogenic chromosomal blocks in cancer genomes.

Abstract

Abstract Our preliminary observations suggest that chromosome structure rearrangements in cancer genomes are a parsimonious strategy to activate or suppress the expression of blocks of genes that contribute to cancer sustenance. We hypothesize that these rearrangements exploit the natural organization of the human genome to promote tumor development and drug resistance. We believe that in the process of cancer evolution, genes are brought together by chromosome rearrangement and then subsequently co-selected for providing a survival advantage to the cancer. In this manner, chromosome structure represents a novel means for encoding information in cancer cells, beyond the enzymatic and protein-protein interactions defining biochemical pathways. Using public data from a large collection of human cancer cell lines, we uncovered blocks of genes on each chromosome that undergo copy number alterations as a unit, which we term Cancer Syntenic Blocks (CSBs). Similar to syntenic blocks in comparative evolution, these CSBs appear to engage in rearrangements as chromosomal blocks, suggesting they may function as systems modules in cancer biology. We developed quantitative measures to identify CSBs in individual cancer types using a multi-gene network clustering approach, and showed that CSBs are enriched for cancer relevant functions. We further demonstrated that some CSBs are conserved across multiple cancer types, suggesting they may function in pan-cancer modules. We hypothesize that the component genes within a CSB do not necessarily act in one biochemical pathway, but instead may represent the coordination of pathways that contribute to a common cellular physiologic function. We also identified co-occurring sets of intra- and inter-chromosomal CSBs (both undergoing copy number gain, loss, or gain paired with loss), suggesting that multiple CSBs can act coordinately. The CSB framework can be exploited to assess systems activation of oncogenic blocks of genes in cancer, which can be used in cancer classification and in genome-based diagnostics. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B137. Citation Format: Joel P. Wagner, Edison T. Liu. Oncogenic chromosomal blocks in cancer genomes. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B137.