Intratumor heterogeneity: evolution through space and time

Abstract

Recent technologic advances have permitted higher resolution and more rapid analysis of individual cancer genomes at the single-nucleotide level. Such advances have shown bewildering intertumor heterogeneity with limited somatic alterations shared between tumors of the same histopathologic subtype. Exacerbating such complexity, increasing evidence of intratumor genetic heterogeneity (ITH) is emerging, both within individual tumor biopsies and spatially separated between biopsies of the same tumor. Sequential analysis of tumors has also revealed evidence that ITH temporally evolves during the disease course. ITH has implications for predictive or prognostic biomarker strategies, where the tumor subclone that may ultimately influence therapeutic outcome may evade detection because of its absence or presence at low frequency at diagnosis or because of its regional separation from the tumor biopsy site. In this review, the implications of "trunk and branch" tumor evolution for drug discovery approaches and emerging evidence that low-frequency somatic events may drive tumor growth through paracrine signaling fostering a tumor ecologic niche are discussed. The concept of an "actionable mutation" is considered within a model of clonal dominance and heterogeneous tumor cell dependencies. Evidence that cancer therapeutics may augment ITH and the need to track the tumor subclonal architecture through treatment are defined as key research areas. Finally, if combination therapeutic approaches to limit the consequences of ITH prove challenging, identification of drivers or suppressors of ITH may provide attractive therapeutic targets to limit tumor evolutionary rates and adaptation.

Figure 1. Trunk and Branch model representing intratumour heterogeneity

Common or ubiquitous events in the tumour found in every subclone and every tumour region are represented in the trunk of the tree. Diverse, heterogeneous somatic events are represented by the branches and the leaves. Tumour somatic events occurring in the trunk or branches may be driver or passenger events that may be dynamic during tumour evolution and adaptation to therapy (Adapted from Yap et al 2012). The figure illustrates key research areas and the need to identify how cancer therapeutics might influence intratumour heterogeneity.

Figure 2. Evolutionary Bottlenecking and Restriction of Diversity between primary and metastases

(A) Transient restriction of diversity through an evolutionary bottlenecking process, eg during clonal selection through therapy or during metastatic progression may lead to the requirement for alternative mechanisms to generate ITH. One such mechanism can be generated through structural and whole chromosomal instability (CIN). Tetraploidy is thought to be a precursor of chromosomal instability. (B/C) Multi-region analysis of a primary renal cell carcinoma and its metastatic sites revealed the metastatic lesions were most similar to Region 4 of the primary (adapted from Gerlinger et al 2012). Ploidy analysis revealed that the primary regions were all diploid with the exception of region 4 which was tetraploid. Metastatic sites were sub-tetraploid. (D) Allelic imbalance analysis revealed substantial heterogeneity in chromosome structure between two biopsies of the same metastatic site (M2a and M2b). Taken together with ploidy analysis, these data indicate the possible emergence of CIN at metastatic sites. Longitudinal studies will reveal to what extent metastatic sites represent outgrowth of multiple heterogeneous subclones from the primary tumour and genetic events that may be permissive for metastatic outgrowth during the bottlenecking process. Figure 2 Adapted from references and (Gerlinger et al NEJM 2012 and Gerlinger et al 2010 British Journal of Cancer).