Because mole melanocytes have high levels of p15 while it’s depleted in melanomas, knowing P15 status may in the future help clinicians better diagnose ambiguous biopsies.
Researchers have identified a largely overlooked genetic factor which seems to be an important component in the progression of benign melanocytic nevus to melanoma. The finding could lead to more accurate diagnoses of histologically ambiguous mole biopsies, as well as to more medically relevant preclinical melanoma models.
University of Pennsylvania scientists reported tumor suppressor protein, p15, acts as a powerful brake on cell division in melanoma and, possibly, other cancers, in a study published online.1
Senior author Todd W. Ridky, M.D., Ph.D., assistant professor of dermatology at the University of Pennsylvania, says that the science study’s aim was to understand the mechanisms that normally restrain oncogene signaling in benign moles.
“The vast majority of common moles have an activating mutation in the BRAF oncogene. And this is the same exact BRAF oncogene that drives the majority of melanoma in people,” Dr. Ridky says. “What’s curious is that despite the fact that there is this activated oncogene, most moles don’t turn into cancer, although some of them do. The exact numbers are not available, but [it is thought that] around a third of all melanoma start in a pre-existing benign mole that loses that ability to restrain the oncogene.”
Dr. Ridky says he and other dermatology researchers wondered why most moles on people generally are the same size-about the size of a pencil eraser, give or take. They start off smaller and typically stop growing after 1-2 years.
“You get a BRAF mutation and that causes the melanocyte cells to proliferate. It’s like a mitogenic gas pedal for cell division. Cells divide and divide and build up. That’s what a mole is. It’s an accumulation of these melanocytes,” he says.
Finding out why moles eventually cease to proliferate is important because it may suggest critical points that fail when a mole progresses to melanoma.
“… the fact that some melanoma does start in moles means that whatever mechanism that normally restrains them is not perfect and can fail,” Dr. Ridky says.
That’s where p15 comes in.
The researchers developed a new model of human melanoma, using tissue engineering to make skin grafts containing human mole cells in which p15 was removed. When combined with other mutations known to be important for the development of melanoma, and transplanted into mice, the p15 depleted cells progressed into melanoma.
“One of the major factors that had previously been overlooked, is this protein called p15. I think p15 explains why moles are generally all a similar size range, across all people, and also potentially explains why some moles to eventually turn into melanoma when p15 is lost,” he says.
P15 is the protein product of the CDKN2B gene. CDKN2B gene is right next to another important tumor suppressor gene called p16, which is the CDKN2A gene.
“Among the most common genetic events of all human cancer is loss of the region of DNA containing CDKN2A (p16). And p16 has a role to play in cancer evolution. But 95% to 100% of the time when the CDKN2A is deleted, CDKN2B is deleted too,” Dr. Ridky says.
To date, most of the tumorigenic, or cancer-causing effects, of that deletion have been attributed to p16, which is clearly important. This study, however, found that p15 is important too.
“Prior melanoma research has not utilized the naturally occurring precursor cells from human benign moles on people,” he says. “Traditionally functional cancer biology experiments utilize mice or tumor cell lines. Mice don’t get moles so you can’t do this experiment in mice. So for this study we just started asking my patients if they would be willing to donate their benign moles. One of the great things about skin is patients usually don’t mind parting with a little mole. Much harder to get someone to part with a piece of their pancreas.”
They found that there was about 140 times more p15 in the mole melanocytes than in the melanocytes from normal skin.
“Then we did a series of genetic studies to show that p15 was a necessary and sufficient component of the brake mechanism that keeps the BRAF gene in check. Every single mole we looked at from people had huge amounts of p15. And a large percentage of melanomas had either diminished or no p15 at all,” he says. “It’s probably not only important for melanoma, but for other cancers. In the last few months, there was a paper implicating the important role of p15 in kidney cancer. …p15 is clearly bringing something extra to the table and doing something that p16 is not. It probably has something to do with unique amino acid sequences at one end of p15, and ongoing studies are looking at that.”
According to Dr. Ridky, if one takes normal melanocytes-not from a mole-and engineers them to overexpress the p16 protein, the melanocytes won’t grow as fast, but don’t completely stop growing. If one engineers the same amount, (or less) of the p15 protein, the cells stop proliferating completely.
“They don’t die. They just stop-just like moles on your body. We think p15 is a major brake pedal for that,” Dr. Ridky says.
Loss of p15 in a tissue section is an ominous sign, according to Dr. Ridky.
A potential utility for p15 status would be to help dermatologists best treat histologically ambiguous mole biopsies. Clearly benign moles have huge amounts of p15, according to Dr. Ridky.
“This isn’t something that dermatopathologists look for now. But we’re conducting studies on expanded numbers of tumors, and we think it will likely have a useful role in these histologically ambiguous cases,” he says.
Measuring p15 in melanoma could help dermatologists who encounter histologically ambiguous mole biopsies, according to Tucson, Ariz., dermatologist Norman Levine, M.D.
“In our practice, we occasionally find troublesome moles clinically which also have ambiguous histologic features. These are the lesions which are usually treated like a melanoma because of our concern about this potentially serious neoplasm. If a method was to be developed that would help to clarify the biologic potential of these types of lesions, it could be a very valuable addition to our diagnostic toolbox,” Dr. Levine says.
In the big oncology picture, this is part of the trend in research to understand how normal cells turn into cancer cells, according to Dr. Ridky.
“We’re now looking at the potential role of p15 in other cancers. Really the central question is what is p15 doing that p16 is not?” he says.
Drs. Ridky and Levine report no relevant disclosures.
1. McNeal AS, Liu K, Nakhate V, Natale CA, Duperret EK, Capell BC, Dentchev T,
Berger SL, Herlyn M, Seykora JT, Ridky TW. CDKN2B Loss Promotes Progression from
Benign Melanocytic Nevus to Melanoma. Cancer Discov. 2015 Oct;5(10):1072-85.