Somatic evolution in cancer
The earliest ideas about neoplastic evolution come from Boveri[8] who proposed that tumors originated in chromosomal abnormalities passed on to daughter cells.
Armitage and Doll explained the cancer incidence data, as a function of age, as a process of the sequential accumulation of somatic mutations (or other rate limiting steps).
[12] In 1971, Knudson published the 2-hit hypothesis for mutation and cancer based on statistical analysis of inherited and sporadic cases of retinoblastoma.
The essential predictions of this model have been confirmed although mutations in some tumor suppressor genes, including CDKN2A (p16), predispose to clonal expansions that encompass large numbers of crypts in some conditions such as Barrett's esophagus.
[1] Most of the alterations that occur are deleterious for the cell, and those clones will tend to go extinct, but occasional selectively advantageous mutations arise that lead to clonal expansions.
There are multiple levels of genetic heterogeneity associated with cancer, including single nucleotide polymorphism (SNP),[35] sequence mutations,[30] Microsatellite shifts[29] and instability,[36] loss of heterozygosity (LOH),[34] Copy number variation (detected both by comparative genomic hybridization (CGH),[31] and array CGH,[37]) and karyotypic variations including chromosome structural aberrations and aneuploidy.
Recent studies from both direct DNA sequencing and karyotype analysis illustrate the importance of the high level of heterogeneity in somatic evolution.
For example, epigenetic silencing of genes responsible for the repair of mispairs or damages in the DNA (e.g. MLH1 or MSH2) results in an increase of genetic mutations.
[55] In cancers, loss of expression of genes occurs about 10 times more frequently by transcription silencing (caused by somatically heritable promoter hypermethylation of CpG islands) than by mutations.
[57][58][59] Methylation of the cytosine of CpG dinucleotides is a somatically heritable and conserved regulatory mark that is generally associated with transcriptional repression.
[65] Further clonal expansions have been observed in the stomach,[66] bladder,[67] colon,[68] lung,[69] hematopoietic (blood) cells,[70] and prostate.
First, they generate a large target population of mutant cells and so increase the probability that the multiple mutations necessary to cause cancer will be acquired within that clone.
These neoplasms are also indicated, in the diagram below the photo, by 4 small tan circles (polyps) and a larger red area (cancer).
Wright's shifting balance theory of evolution combines genetic drift (random sampling error in the transmission of genes) and natural selection to explain how multiple peaks on a fitness landscape could be occupied or how a population can achieve a higher peak on this landscape.
[81] The flexibility of adaptive landscapes provide several ways for natural selection to cross valleys and occupy multiple peaks without having to make large changes in their strategies.
Within the context of differential or difference equation models for population dynamics, an adaptive landscape may actually be constructed using a fitness generating function.
A population at a global maximum on the adaptive landscape corresponds an evolutionarily stable strategy (ESS) and will become dominant, driving all others toward extinction.
Populations at a minimum or saddle point are not resistant to invasion, so that the introduction of a slightly different mutant strain may continue the evolutionary process toward unoccupied local maxima.
The adaptive landscape provides a useful tool for studying somatic evolution as it can describe the process of how a mutant cell evolves from a small tumor to an invasive cancer.
The authors describe how tumor progression proceeds via a process analogous to Darwinian evolution, where each genetic change confers a growth advantage to the cell.
The six hallmarks are: Genetic instability is defined as an "enabling characteristic" that facilitates the acquisition of other mutations due to defects in DNA repair.
[96] In the case of Gleevec (Imatinib), which targets the BCR-ABL fusion gene in chronic myeloid leukemia, resistance often develops through a mutation that changes the shape of the binding site of the drug.
It turns out that it targets other tyrosine kinase genes and can be used to control gastrointestinal stromal tumors (GISTs) that are driven by mutations in c-KIT.
However, patients with GIST sometimes relapse with additional mutations in c-KIT that make the cancer cells resistant to Gleevec.
Two major mechanisms of acquired resistance have been discovered in patients who have developed clinical resistance to Gefitinib or Erlotinib:[102] point mutations in the EGFR gene targeted by the drugs,[103] and amplification of MET, another receptor tyrosine kinase, which can bypass EGFR to activate downstream signaling in the cell.
Selective estrogen receptor modulators (SERMs) are a commonly used adjuvant therapy in estrogen-receptor positive (ERα+) breast cancer and a preventive treatment for women at high risk of the disease.
[111] Likewise, extra copies of the AR gene (amplification) have been observed in anti-androgen resistant prostate cancer.
[112] These additional copies of the gene are thought to make the cell hypersensitive to low levels of androgens and so allow them to proliferate under anti-androgen therapy.
However, to date, comparisons of malignant tissue before and after radiotherapy have not been done to identify genetic and epigenetic changes selected by exposure to radiation.
[115] By manipulating the tumor environment, it is possible to create favorable conditions for the cells with least resistance to chemotherapy drugs to become more fit and outcompete the rest of the population.
