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.
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.
Somatic cancer evolution Genetic heterogeneity Parallel evolution Punctuated evolution Background
Malignant tumors can display a high degree of spatial and temporal genetic heterogeneity [1, 2]. Genetic heterogeneity is the result of multilineage somatic evolution of genetically unstable cancer cells and it is regarded as the main reason for failure of classic cytotoxic drugs, as well as modern targeted therapy . In this review, we would like to present evidence for the assumption that analyzing spatial and temporal genetic heterogeneity enhances the information content of molecular cancer profiling, key to identifying suitable patient-specific therapeutic targets.
Characteristics of human cancer evolution
Mutation load does not increase linearly with cancer progression The identification of only a few and specific mutations in colon cancer has suggested that malignant progression proceeds with the continuous accumulation of a limited number of oncogenic mutations followed by clonal expansion of the mutated subclones resulting in a linear multistep process of cancer evolution . Subsequent research on somatic cancer evolution which analyzed primary tumors and metastases in individual patients [4, 5], complex chromosome rearrangement events in single cancers [1, 6, 7, 8] or multiple single cells within one malignant tumor [1, 2, 9, 10, 11] could not confirm this assumption. In contrast, most data suggest a non-linear accumulation of structural and numeric chromosomal aberrations as well as of gene mutations. This has been denominated punctuated evolution .
Chromosome aberrations such as aneuploidy, more complex chromosomal rearrangement as well as abundant gene copy number variations can be found in early stages of malignant progression and these structural mutations seem to get stabilized at later stages of somatic cancer evolution and clinical progression. This has been demonstrated in many tumors such as malignant melanoma, breast cancer, pancreatic cancer and prostate cancer [1, 2, 4, 5, 6, 7, 8, 9, 10, 11].
Point mutations seem to be acquired more steadily but at least in melanoma, more advanced tumors do not always display higher mutation loads [12, 13].
This insight into somatic cancer evolution raises two major questions: Why do cancer cells acquire most structural mutations (aneuploidy, rearrangements, translocations, gene copy number variations) and probably most driving point mutations during early stages of carcinogenesis where molecular and histologic signs of genome destabilization such as atypical mitoses are less apparent compared to metastasized cancer cells? What are the mechanisms responsible for the apparent stabilization of the cancer genomes at later stages of malignant progression? Aneuploidy is pseudo-stabilized under constant selective pressure Aneuploidy has fascinated generations of pathologists as atypical mitoses, a key process leading to unequal distribution of chromosomes are visible under the microscope in cancer samples . In addition, aneuploidy may be directly visible as the presence of gigantic nuclei, of multinucleate cells as well as of cancer cell nuclei which strongly vary in size. There has been a long debate on whether aneuploidy is one driver or the only driver of carcinogenesis  but most scientists would agree that under the concept of carcinogenesis and cancer progression as an evolutionary process, aneuploidy represents one form of genetic instability which accelerates somatic cancer evolution. An inherent feature of aneuploidy is that one missegregation event during a cancer cell division results in the duplication or loss of thousands of genes which profoundly alters the genetic composition of the progenitor cells [15, 16, 17]. It has been speculated that this feature of aneuploidy allows cancer cells to respond much faster towards environmental changes than by acquisition of point mutations. It has to be mentioned that aneuploidy is not the only mechanism leading to multiple gene dosage changes through one rearrangement event. The same effect will be achieved by other complex structural rearrangements of chromosomes or chromosome parts such as chromotripsis and chromoplexy [5, 18, 19]. It might be expected that aneuploid cancer cells constantly change their chromosome composition, but the genomes of aneuploidy cancers remain remarkably stable at later stages of cancer progression . This behavior of aneuploidy cells has been replicated in cell culture. It could be demonstrated that the chromosome composition of aneuploidy cancer cell lines is not by itself stable, but that it may oscillate for many passages around a predominant karyotype .
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