Describe How The Development Of Colorectal Cancer Can Be Seen As A Form Of Darwinian Evolution

Describe how the development of colorectal cancer can be as a form of Darwinian Evolution.

Darwinian Evolution describes the process by which organisms that are better suited to the environment tend to become more prevalent in a population over time. Darwinian Evolution can be observed in the progression of colorectal cancer as Tumorigenesis itself begins when a particular mutation in a normal cell allows it to overcome growth restraints which typically allow tissue homeostasis. Having overcome these restraints, it can outcompete surrounding cells and thus continue to divide at an increasingly faster rate compared to its competitors and achieve limitless replicative potential. How was evolution theorized? Darwin observed that differences in physical characteristics of finches on the Galapagos Island such as their beak shape and size were suited to their own unique surroundings.

It is estimated that 4-5 mutations are required for a normal cell to transform into a malignant cell the evolution of colorectal cancer occurs in stages as described by the. Clonal expansion occurs when a particular cell with a particular set of mutations that results in peak fitness and this results in linear evolution or a clonal sweep as this particular clone outcompetes all other competitors. This is synonymous with Darwin famous statement Survival of the fittest .

Truncal Mutations are mutations that are present in every clone in the tumour. These are inevitably sourced from the dominant clone initiating the most recent clonal sweep at any point in time during the progression of the tumour. Further subclones may arise in different area of the tumour (ie different tumour microenvironments) This can be due to varying degrees of hypoxia or exposure to the immune system. Increased Branching of cell lineages occurs with microsatellite instability. ^1

Such a rapid production of subclones also results in incredibly rare mutations that may be clinically significant towards a patient s treatment but are unable to be detected by standard clinical care biopsies. An example of such a mutation is KRAS Q22K. ^2

In the case of metastatic colorectal cancer, sub-clones within the primary tumour have been postulated to initiate metastasis. While it is generally concluded that most metastases are single seeded, they can also arise from multiple clones originating from the primary tumour (i.e. are polyclonal). ^2

The immense variety and sheer number of possible subclones results in the heterogeneity of tumour. In regard to Darwinian Evolution, the heterogeneity of tumours is reminiscent of the variation observed between both members of a species and between species. Tumour heterogeneity poses an issue for cancer therapy as it is difficult for a drug to tackle cells of so many different mutational profiles.

Selection of cells based on their evolutionary viability can be divided into three types positive selection, neutral selection and negative selection. Mutations that occur in oncodriver genes result in growth of a tumour and will be positively selected for. Positive Selection can promote resistance to chemotherapy amongst tumours. For example, a KRAS mutation confers resistance to Anti EGFR Therapy such as cexitumab amongst metastatic colorectal cancer patients. Thus, cells with a KRAS mutation within the tumour are selected for and those that are not against. Neutral Selection occurs when a mutation does not offer any selective advantage nor disadvantage. These mutations are called passenger mutations. How are passenger mutations and oncodriver mutations differentiated? We can compare the mutational profiles of both normal and tumour cells though use of PCR and identify the mutations present in the tumour cell and absent in the normal cells. While less common, negative selection occurs when a mutation offers a selective disadvantage to tumour growth.

It is estimated that 4-5 mutations are required for a normal cell to transform into a malignant cell. The sequence of mutations correlated with the development of colorectal cancer or the adenoma- carcinoma sequence was first accurately described by the Feron Volgenstein model. The histological progression of colorectal cancer closely follows this sequence of mutations.

APC > KRAS > q19 >p53.

APC acts as a tumour suppressor, by regulating a multitude of genes related to the cell cycle. A mutant KRAS allele codes for an overacting GTPase with increased affinity for GTP. Q19 is then mutated and finally p53 (guardian of the genome). The wild type form of these proteins are essential for establishing growth restraints. This sequence of mutations seems to be crucial and both conserved amongst all different cases of colorectal cancer.

Such a rapid production of subclones also results in incredibly rare mutations that may be clinically significant towards a patient s treatment but are unable to be detected by standard clinical care biopsies. An example of such a mutation is KRAS Q22K. ^3

In the case of metastatic colorectal cancer, sub-clones within the primary tumour have been postulated to initiate metastasis. While it is generally concluded that most metastases are single seeded, they can also arise from multiple clones originating from the primary tumour (i.e. are polyclonal). ^4

This ultimately results in the heterogeneity of tumours. In regard to Darwinian Evolution, the heterogeneity of tumours is reminiscent of the variation observed between both members of a species and between species. Tumour heterogeneity poses an issue for cancer therapy as it is difficult for a drug to tackle cells of so many different mutational profiles.

Delivering chemotherapy mimics a bottleneck . A proportion of cells within a tumour are killed, but a significant number are left behind. These leftover cells are hypothesized to be the culprit for relapses amongst cancer patients. In this study, there was a significant association between the rate of primary colorectal cancer recurrence and number of subclones, suggesting that recurrence is also correlated to high tumour heterogeneity. A genetic bottleneck describes the phenomenon in which a random event results in a shrinkage of the genetic population and thus its genetic diversity. The genetic composition of the remaining survivors is left up to chance. Bottlenecks are observed in ecological systems when an environmental hazard results in a sudden shrinkage of a population.

Ultimately, the Darwinian Evolution of colorectal cancer poses the greatest challenge for cancer scientists and drug development as it results in tumour cells that are constantly adapting their genetic profile to survive novel therapies.