Abstract IA15: Genetic and functional tumor heterogeneity

Abstract

Abstract Despite advances in genomic technologies, most advanced solid tumors remain incurable and drug resistance is almost inevitable with limited biomarkers available to personalize therapy. Two important lessons have emerged from the comprehensive genomic analyses of cancers, which may provide an explanation for difficulties that have been encountered in biomarker development. First, each tumor contains an individual assortment of multiple genomic aberrations, few of which are shared between patients with the same histopathological tumor subtype. Second, emerging evidence suggests that these anomalies appear to vary within the tumor, indicating substantial intratumor heterogeneity. Increasingly, molecular evidence suggests that intratumor heterogeneity may contribute to tumor growth through a branched (polytypic) rather than a linear pattern of tumor evolution. Branched evolutionary growth and intratumor heterogeneity results in coexisting cancer cell subclones with variegated genotypes and associated phenotypes that may be regionally separated within the same tumor and alter in dominance over time. Variegated phenotypes, resulting from intratumoral genetic heterogeneity and the emergence of new subclones at relapse, are likely to have important implications for developing novel targeted therapies and for preventing the emergence of drug resistance. Intratumor heterogeneity and sampling bias may also contribute to the recently reported failures in implementation of robust biomarkers in the clinical setting. In this talk, evidence for genetic, epigenetic and transcriptomic intratumour heterogeneity, impacting upon signal transduction pathway phenotypic heterogeneity, will be reviewed. Darwinian models for biomarker discovery will be discussed based on trunk and branched tumor growth models that may improve drug discovery and clinical outcome prediction. Citation Format: Charles Swanton. Genetic and functional tumor heterogeneity. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA15.