Abstract Advances in next-generation sequencing and bioinformatics have led to an unprecedented view of the cancer genome and its evolution. Genomic studies have demonstrated the complex and heterogeneous clonal landscape of tumors of different origins and the potential impact of intratumor heterogeneity on treatment response and resistance, cancer progression, and the risk of disease relapse. However, the significance of subclonal mutations, in particular mutations in driver genes, and their evolution through time and their dynamics in response to cancer therapies, is yet to be determined. The necessary tools are now available to prospec-tively determine whether clonal heterogeneity can be used as a biomarker of clinical outcome and to what extent subclonal somatic alterations might influence clinical outcome. Studies that use longitudinal tissue sampling, integrating both genomic and clinical data, have the potential to reveal the subclonal composition and track the evolution of tumors to address these questions and to begin to define the breadth of genetic diversity in different tumor types and its relevance to patient outcome. Such studies may provide further evidence for drug-resistance mechanisms informing combinatorial, adaptive, and tumor immune therapies placed within the context of tumor evolution. Introduction Over the past few years, genomic studies have demonstrated the complex and heterogeneous landscape in cancer (1, 2) and its potential implications for treatment response and prognosis (2-4). Using whole-genome or whole-exome sequencing, these studies have demonstrated that tumors consist of somatic events, defined by mutations and copy number alterations (CNA), occurring early in tumor evolution, and somatic events present in some cells, but not all, occurring later in tumor evolution (5). In addition, these studies have shown spatial heterogeneity, branched evolution, and mutational patterns that can vary over time (6, 7) and in response to cancer therapies (8-10). Given the existence of such heterogeneity in tumors in advanced metastatic disease, the efficacy of therapies targeting somatic driver aberrations, even in combination, may be limited in terms of achieving disease cure and contribute in some health economies to a prohibitive health economic burden (11). The relevance of subclonal mutations to cancer outcome and therapeutic response requires further investigation (12). Although this review focuses on genetic intratumor heterogeneity, both stochastic and epigenetic factors are known to play a role in shaping the tumor landscape and are reviewed in-depth elsewhere (13).
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