Cancer heterogeneity: converting a limitation into a source of biologic information

Abstract

Analysis of spatial and temporal genetic heterogeneity in human cancers has revealed that somatic cancer evolution in most cancers is not a simple linear process composed of a few sequential steps of mutation acquisitions and clonal expansions. Parallel evolution has been observed in many early human cancers resulting in genetic heterogeneity as well as multilineage progression. Moreover, aneuploidy as well as structural chromosomal aberrations seems to be acquired in a non-linear, punctuated mode where most aberrations occur at early stages of somatic cancer evolution. At later stages, the cancer genomes seem to get stabilized and acquire only few additional rearrangements. While parallel evolution suggests positive selection of driver mutations at early stages of somatic cancer evolution, stabilization of structural aberrations at later stages suggests that negative selection takes effect when cancer cells progressively lose their tolerance towards additional mutation acquisition. Mixing of genetically heterogeneous subclones in cancer samples reduces sensitivity of mutation detection. Moreover, driver mutations present only in a fraction of cancer cells are more likely to be mistaken for passenger mutations. Therefore, genetic heterogeneity may be considered a limitation negatively affecting detection sensitivity of driver mutations. On the other hand, identification of subclones and subclone lineages in human cancers may lead to a more profound understanding of the selective forces which shape somatic cancer evolution in human cancers. Identification of parallel evolution by analyzing spatial heterogeneity may hint to driver mutations which might represent additional therapeutic targets besides driver mutations present in a monoclonal state. Likewise, stabilization of cancer genomes which can be identified by analyzing temporal genetic heterogeneity might hint to genes and pathways which have become essential for survival of cancer cell lineages at later stages of cancer evolution. These genes and pathways might also constitute patient specific therapeutic targets.

Keywords: Genetic heterogeneity; Parallel evolution; Punctuated evolution; Somatic cancer evolution.

Fig. 1

Schematic representation of somatic cancer evolution as a phylogenetic tree with early parallel evolution and strong negative selection at later stages of cancer progression. This results in a strong early rise of mutation load and structural rearrangements followed by limited further increase of mutation load after cancer cells have reached a point of maximum tolerable disorder of the genome. Ω indicates extinction of a subclone lineage due to lethal mutations

Fig. 2

Schematic representation of somatic cancer evolution as a phylogenetic tree. Different colors represent subclones and indicate genetic heterogeneity in the primary tumor and its metastases. a, b, c, d indicate sampling of cancer specimens. Spatial heterogeneity is detected by sampling and analyzing either a and b or c and d and will result in an enhanced sensitivity for detection of subclones and mutations. Analyzing a or b together with c or d will reveal temporal heterogeneity. X indicates extinction of a subclone

Fig. 3

Temporal course of serum tumor marker levels and radiologic tumor mass measuring in a BRAF V600E-mutated malignant melanoma during targeted therapy with a BRAF-inhibitor and a PD1-checkpoint-inhibitor (90% PDL1-positivity of tumor cells). A rise in serum marker levels indicates emerging resistance to therapy and is confirmed by CT-scan measurement of metastasis volume. S actual surgery of recurrent tumor, LB potential time points for early liquid biopsy analysis of temporal genetic heterogeneity