CDKN2A

CDKN2A, also known as cyclin-dependent kinase Inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. The gene codes for two proteins, including p16 (or p16INK4a) and p14arf. Both act as tumor suppressors by regulating the cell cycle. p16 inhibits cyclin dependent kinases 4 and 6 (CDK4 and CDK6) and thereby activates the retinoblastoma (Rb) family of proteins, which block traversal from G1 to S-phase. p14ARF (also known as p19ARF in the mouse) activates the p53 tumor suppressor. Somatic mutations of CDKN2A are common in the majority of human cancers, with estimates that CDKN2a is the second most commonly inactivated gene in cancer after p53. Germline mutations of CDKN2a are associated with familial melanoma, glioblastoma and pancreatic cancer.

Familial melanoma

CDKN2A is made up of four sections of exons – exon 1β, exon 1α,exon 2, and exon 3. These exons are used to create two proteins named p16 and p14ARF. Protein p16, created by exon 1α and exon 2, is responsible for tumor creation of genetic melanoma. When working normally, p16 binds to the cyclic dependent kinases CDK4 to inhibit their ability to create tumors, but when inactivated the suppression no longer occurs. When a mutation occurs in protein p16, it prevents the protein kinase of CDK4, which results in the inactivation of the tumor suppressor gene. Thus, kick starting the development of melanoma.

Melanoma only occurs in a small proportion of the population. Only 10% of those who have melanoma acquired it genetically. This disease is an autosomal dominant gene. If only two family members have melanoma, there is a 5 % chance somebody in the next generation will acquire the mutated gene. Also, there is a 20-40% chance of getting hereditary melanoma in a family if 3 or more people in the past generation had melanoma. For those who carry the hereditary mutated gene CDKN2A, acquiring skin cancer is a lot easier. Those who have the gene are far more likely to get melanoma a second or third time compared to those who don’t genetically have this gene. The population that is affected by this mutation has a high familial history of melanoma or atypical moles and birth marks in large numbers, a history of primary melanoma/cancers in general, immunosuppression, skin that burns easily and doesn't tan, freckling, blue eyes, red hair, or a history of blistering. People with these high risk factors are more likely to carry inherited mutations in CDKN2A. For those who have a gene mutation, the severity is also dependent on the environmental surroundings. Out of those who carry the gene, those who express the phenotype and actually developed melanoma have a history of more sun exposure, and light skin compared to those who also had the gene but never actually developed melanoma. This suggests that this gene co-works with ones surrounding environment. If two individuals are selected who carry the CDKN2A mutation, and both genetically have the same probability of acquiring skin cancer, but one is from Australia and the other is from Europe, there is a 58% the European will acquire cancer compared to a 91% chance the Australian will get it. This is because the factors mentioned earlier pertaining to those who are more susceptible to the disease and also dependent on the amount of sunscreen one wears and the UV radiation potency in their environment.

Therapeutic potential of BRAF kinase inhibitors

RAS-RAF-MEK-ERK MAP kinase pathway plays an important role in melanocytes, where melanoma arises. Stimulation of membrane bound receptors including tyrosine kinases and G-proteins receptors promote activation of RAS then activates Raf kinases which in turn promotes MEK then ERK activation. All of these proteins work together to help cell survival. A BRAF mutation in this activation chain triggers maligant transformation in melanoma cells. Melanoma relies on this BRAF mutation to grow and multiply as a tumor cell.

RNA interference of BRAF stops the multiplication of melanoma tumor cells. This suggests that BRAF inhibitors such as sorafenib, PLX4720, PLX4032, GDC-0879,GSK2118436, or AZ628 may be affective in treating melanoma. These have been tested and proven to slow down the production of melanoma due to BRAF mutation but PLX4032 and GSK2118436 show the most promise because they worked the most aggressively in early stages of cell development. Although this drug helps slow down or shrink the tumors, there are many serious side affects to using these drugs that were found in the trials including arthralgia, rash, nausea, phosphosensitivity], fatigue, pruritus and palmo-plantar dysesthesia.

Aging

Activation of the CDKN2a locus promotes the cellular senescence tumor suppressor mechanism, which is a permanent form of growth arrest. As senescent cells accumulate with aging, expression of CDKN2a increases exponentially with aging in all mammalian species tested to date, and has been argued to serve as a biomarker of physiological age.