Translational implications of tumor heterogeneity

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 prospectively 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.

Figure 1

Different types of tumor heterogeneity. (A) Intratumor heterogeneity: the presence of multiple subclones within a primary tumor resulting in heterogeneity among tumor cells. (B) Interpatient heterogeneity: the presence of unique subclones in the tumor of each patient. (C) Intermetastatic heterogeneity: the presence of different subclones in different metastatic lesions of the same patient; some subclones may have been derived from the primary tumor and some may have emerged as a result of acquired alterations within each metastatic lesion. (D) Intrametastatic heterogeneity: the presence of multiple subclones within a single metastatic lesion.

Figure 2

Phylogenetic tree analyses. Primary tumors consist of different subclones with shared and private somatic alterations. Alterations shared by all tumor cells (‘A’) occur early in tumorigenesis represented by the blue trunk of the phylogenetic tree, alterations shared by tumor cells present in some regions of the tumor but not all (‘B’ and ‘C’) occur later in tumorigenesis represented by the yellow branches of the tree, and private alterations (‘D’, ‘E’ and ‘F’) present in only one region of the tumor also occur later in tumorigenesis represented by the red branches of the tree.

Figure 3

Intratumor heterogeneity and clonal evolution. Primary tumors consisting of different subclones may be subjected to various selection pressures including chemotherapy and microenvironmental factors such as hypoxia, infiltrating stromal and immune cells. Under the influence of such selection pressures, subclones with intrinsic resistance (green subclone) can outgrow a tumor mass potentially leading to disease progression, and/or subclones can acquire somatic alterations (purple subclone) promoting cell survival, proliferation and metastatic tumor formation. The outgrowth of some subclones (red subclone) may be constrained by selection pressures that they are sensitive to, for example, targeted therapy against a tumor subclone with a somatic alteration sensitive to therapy. Tumour infiltrating lymphocytes may recognize neo-antigens presented on the surface of tumor cells as non-self, promoting enhanced T-cell activation and immune cell tumor infiltration.