Exploring the Evolution of Melanoma

Melanoma, one of the most dangerous skin cancers in recent years (1), occurs when melanocytes start to multiply uncontrollably. Melanocytes are the cells in charge of the production of melanin, the pigment responsible for the darkening of our skin when we are exposed to UV radiation. This type of radiation may damage our DNA, resulting in pathogenic alterations (mutations) in the melanocytes genes, thus leading to an uncontrollable cellular growth (2).


When mutations accumulate, melanocytes begin to transform, passing through a series of changes until they reach a malignant form (neoplasm). We can classify the different types of lesions starting from a harmless nevus (commonly known as mole) to an intermediate lesion, which may further evolve until it reaches the stage of invasive melanoma (3). Throughout this evolutionary course, a number of alterations have been found in genes that affect different aspects of the melanocytes physiological state, like mutations disrupting cell differentiation, proliferation, migration and metabolism.



Assisted by technological breakthroughs, scientists have been able to acquire new perspectives regarding melanomagenesis. To be more specific, in pathways related to cell differentiation and survival, combinations of mutations were found to be present simultaneously and are acquired in a continual manner throughout the progress of melanoma (4). In addition, it was revealed that the mechanism regulating the passage from the stage of cell growth to the stage of DNA replication in a melanocyte’s life cycle, is gradually lost as a result of an accumulation of mutations in major genes of this cascade (5,6).


Although mutations related to environmental factors (like UV radiation) are a major cause of melanomagenesis, we should also consider other elements associated with an elevated risk of melanoma. The most prominent ones are the existence of many abnormal moles (medically known as dysplastic nevi syndrome), a lesser concentration of melanin, a common characteristic in fair-skinned people and a positive family history. In this case, for example, researchers were able to identify genes susceptible to mutations that can be passed down from parents to children, causing the transference of the disease to the next generation (7).


Overall, we can say with certainty that the underlying mechanism of melanomagenesis is very complex and not fully understood yet. Nevertheless, scientists should keep investigating this disease with an open mind, as novel advances in technology may unravel more mysteries about the melanoma evolution and eventually pave the way for new therapeutic interventions.




References:

(1) World Cancer Report; Stewart, B. W., Kleihues, P., International Agency for Research on Cancer, Eds.; IARC Press: Lyon, 2003.

(2) Melanoma. The Skin Cancer Foundation., https://skincancer.org/skin-cancer-information/melanoma/ (Last access: November 20th, 2019)

(3) Zeng, H.; Judson-Torres, R. L.; Shain, A. H. The Evolution of Melanoma – Moving beyond Binary Models of Genetic Progression. J. Invest. Dermatol. 2019, S0022202X19326995. https://doi.org/10.1016/j.jid.2019.08.002.

(4) Shain, A. H.; Joseph, N. M.; Yu, R.; Benhamida, J.; Liu, S.; Prow, T.; Ruben, B.; North, J.; Pincus, L.; Yeh, I.; et al. Genomic and Transcriptomic Analysis Reveals Incremental Disruption of Key Signaling Pathways during Melanoma Evolution. Cancer Cell 2018, 34 (1), 45-55.e4. https://doi.org/10.1016/j.ccell.2018.06.005.

(5) Akbani, R.; Akdemir, K. C.; Aksoy, B. A.; Albert, M.; Ally, A.; Amin, S. B.; Arachchi, H.; Arora, A.; Auman, J. T.; Ayala, B.; et al. Genomic Classification of Cutaneous Melanoma. Cell 2015, 161 (7), 1681–1696. https://doi.org/10.1016/j.cell.2015.05.044.

(6) Zeng, H.; Jorapur, A.; Shain, A. H.; Lang, U. E.; Torres, R.; Zhang, Y.; McNeal, A. S.; Botton, T.; Lin, J.; Donne, M.; et al. Bi-Allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation. Cancer Cell 2018, 34 (1), 56-68.e9. https://doi.org/10.1016/j.ccell.2018.05.014.

(7) Hill, V. K.; Gartner, J. J.; Samuels, Y.; Goldstein, A. M. The Genetics of Melanoma: Recent Advances. Annu. Rev. Genomics Hum. Genet. 2013, 14 (1), 257–279. https://doi.org/10.1146/annurev-genom-091212-153429.

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