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. 2013 Nov 18;1(4):1000124.
doi: 10.4172/2329-6917.1000124.

Genetic Heterogeneity and Clonal Evolution of Tumor Cells and their Impact on Precision Cancer Medicine

Hatem E Sabaawy  1
Affiliations

Genetic Heterogeneity and Clonal Evolution of Tumor Cells and their Impact on Precision Cancer Medicine

Hatem E Sabaawy. J Leuk (Los Angel). .

Abstract

The efficacy of targeted therapies in leukemias and solid tumors depends upon the accurate detection and sustained targeting of initial and evolving driver mutations and/or aberrations in cancer cells. Tumor clonal evolution of the diverse populations of cancer cells during cancer progression contributes to the longitudinal variations of clonal, morphological, anatomical, and molecular heterogeneity of tumors. Moreover, drug-resistant subclones present at initiation of therapy or emerging as a result of targeted therapies represent major challenges for achieving success of personalized therapies in providing meaningful improvement in cancer survival rates. Here, I briefly portray tumor cell clonal evolution at the cellular and molecular levels, and present the multiple types of genetic heterogeneity in tumors, with a focus on their impact on the implementation of personalized or precision cancer medicine.

Keywords: Clonal evolution; Genetic heterogeneity; Precision medicine.

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Figures

Figure 1
Figure 1. Tumor intiating cells, tumor cell clonal evolution, and tumor heterogeneity
A simplified diagram displaying the different tumor evolution processes under review. Within the tumor microenvironment, Tumor intiating cells (TICs) initiate premalignant clones through the interactions with the niche cells. The premalignant clones may generate frequent sublinical lesions such as carcinoma in situ (or preleukemic conditions) that are either in most cases repaired at the cellular levels through cell death mechanisms, and at the genetic levels through DNA repair of driver genetic mutations. The premalignant clones may alternatively remain harboring quiescent TICs that can then undergo tumor cell differentiation and/or plasticity within the competitive clonal evolution process to compete for space, nutrients, and proximity to vascular supply. Acquisition of secondary genetic and epigenetic changes in TICs or supportive tumor cells that favor enhanced self-renewal and clonal growth allows premalignant lesions to become a clinically diagnosed malignancy. This tumor evolution process can take from weeks to several years or even decades depending on the tumor type and the the host genetic and enviromental exposure factors. TICs are the units of clonal evolution and their diversity seed the recently identified tumor heterogeneity within each tumor (intratumor heterogeneity) (represented by a dominant clone in red, and three additional subclones in green, blue and yellow in the model). I proposed one dominat clone and three subclones for simplicity. Indeed, the frequency of subclones can be unlimited and dependes on the sensetivity of the detection assays. Neverthless, only detectable clones are thought to have clinical implications. Genetic and phenotypic variations are also detected between individuals with the same tumor type (Intertumor heterogeneity), and occur due to the diversity of clones generated during tumor cell clonal evolution. Upon treatment (Rx), relapse might occur from the diagnostic dominant clone that acquired more selective and drug resistance features, or from sublones that have acquired or inherited resistance to therapy. Therefore, detecting clonal heterogeneity and mechanisms of development of therapy resistant clones is critical for tailoring combination therapies for personalized cancer medicine. Solid arrows indicate defined pathways while dashed arrows indicate suggested mechanisms.
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