Melanoma: the chiken and egg story once more!

If you read about Melanoma pathophysiology, the emphasis is clearly on p16/CDK2A and on p14ARF.  Other will emphasize the BRAF and PTENand BRCA2.  But when you think about this, These are important modulator of cell division processes which in this disease are gone awry.

Transforming growth factor beta stabilizes p15INK4B protein, increases p15INK4B-cdk4 complexes, and inhibits cyclin D1-cdk4 association in human mammary epithelial cells.

C Sandhu, J Garbe,
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 wikipedia:
"The protein (p16) is a cyclin-dependent kinase (CDK) inhibitor that slows down the progression of the cell cycle by inactivating the Cyclin dependent kinase that phosphorylates the retinoblastoma protein (pRb). Both p16 and retinoblastoma (pRb) are important tumor suppressors that regulate the cell cycle. In addition to protein p16, pRB there are many other important tumor suppressors that regulate the cell cycle and one of them is protein p53. Cyclin D1 promotes the progression of the cell cycle to the S phase by cyclin D-dependent kinases (CDK4/CDK6). However, the activities of CDK4/CDK6 are restricted by protein p16 since protein p16 is a potent inhibitor of CDKs. Protein Rb, p16 and cyclin D1 are major restriction factors of the cell cycle restriction check points. The progression of cells from G1 phase to S phase is blocked by protein p16, which is a potential tumor suppressor that acts to disrupt the complex cyclin D1 and CDK 4 or 6. The most critical point in cell cycle regulation is the G1 checkpoint and it is at this checkpoint, that the complex cyclin D1 interactions take place to determine whether the cell cycle goes back into a quiescent state (G0) phase or enter into the S phase, where cells are destined to divide. when cells enter into the S phase the cells divide uncontrollably and that leads to cancer. It is important to note that Cyclin D1 is not a kinase but it activates kinases and it also appears to be most strongly implicated in human carcinogenesis."

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The point  is that by the time these regulators of cell cycle enter the game, and their role magnified, TUMOR GROWTH factor amplification is already in effect driving this madness neoplastic process.  and the lack of breaks due to mutations in these named genes become a critical failure to stop cell division.  One should therefore ask what started the the growth factor in the first place.
Growth cycle amplification result from high activity of Epigenetic phenomena. UV light perturbs not the necessarily the p16 molecules, but membrane structures including WNT and NOTCH and various Receptors.  At the receptors, stress will induce response including HSP-90, NK-kB, c-JUN which will start epigenetic phenomena including TGF and c-MYC (remember c-MYC is a "critical mediator of the NOTCH").

Interferon at high dose is the only therapeutic intervention in adjuvant setting because it affect cytokines and the TGF of the cellular world.
Failure to repair cellular damage will exacerbate the FAK, NOTCH and the WNT.  Cellular loss of polarization,and deformation leading to warts and Nevi clearly involve membranous phenomena.
========================= The involvement of the GNAQ gene in Uveal Melanoma further re-enforces the notion that the initial insult is at the membrane.

you tell me what comes first, the chicken or the egg or p16 or the TGF and epigenetic disturbances?
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"Guanine nucleotide-binding protein G(q) subunit alpha is a protein that in humans is encoded by the GNAQ gene.^[1]
Guanine nucleotide-binding proteins are a family of heterotrimeric proteins that couple cell surface, 7-transmembrane domain receptors to intracellular signaling pathways".(wikipedia)