Genetic Factor Preventing Moles From Turning Into Melanoma Identified

Genetic Factor Preventing Moles From Turning Into Melanoma Identified
Moles are benign tumors found on the skin of almost every adult. Scientists have known for years that a mutation in the BRAF gene makes them start growing, but until now haven't understood why they stop. Now, researchers have identified a major genetic factor that keeps moles in their usual non-cancerous, no-growth state. The study was published in the journal Cancer Discovery.
Both moles and melanomas originate from melanin-producing cells (melanocytes) within the skin. Scientists have known for more than a decade that one particular mutation is responsible for the abnormal melanocyte growth that creates the majority of both benign moles and cancerous melanomas. The mutation, in a cell-growth gene called BRAF, causes BRAF to be in an "always on" state, continuously promoting cell division.
In moles, however, cell proliferation typically stops after the cluster of melanocytes has reached the few millimeters (or roughly the size of a pencil eraser). Why moles stop growing, despite all that BRAF activity, has been a long-standing question. To answer that question, the researchers studied mole cells isolated directly from normal benign moles removed from patients, and compared them to melanocytes isolated from normal (non-mole) skin. The mole melanocytes had 140 times more p15 than the normal skin melanocytes.
Comparing cells from patient melanomas that had originated from previously benign moles, the researchers found generally high p15 levels in the mole tissue, and very low or undetectable p15 in the melanomas. This suggested that p15 is important for holding regular moles in a benign state, and that any subsequent loss of p15 would promote the transition to melanoma. The researchers showed that the BRAF over-activation that drives the mole growth also causes the mole cells to secrete a signaling molecule called TGF-β, which in turn, signals back to the mole cells to make p15. These findings hinted at a possible explanation for the curious fact that most moles have to reach a diameter of at least a few millimeters before they stop growing - TGFB has to build up to a sufficient level first, and small collections of mole cells don't lead to enough local TGFB production in the mole to stop cell division.
The importance of p15 has been largely underappreciated up to now, because many researchers have assumed that a different, but related, tumor suppressor protein, p16, does the main work of growth-inhibition in moles. The gene for p16 is physically close to p15 in the nuclear DNA, is present in moles, and is also lost in melanomas and many other cancers. While the two tumor suppressors normally work together to keep the brakes on cell proliferation in moles, the researchers found evidence suggesting that p15 has unique functions. For example, inserting p15 into normal cells was enough to halt proliferation completely, whereas inserting p16 only slowed proliferation.
The researchers now plans to experiment extensively to provide insights into how melanoma develops, and how it might be targeted with new therapies. They will also study p15's possible roles in other cancers.
Based on material originally posted by University of Pennsylvania School of Medicine.