Dr. David Fisher discusses the biology related to melanoma risk in the red hair background, including detection challenges and clinical implications.
David E. Fisher, MD, PhD, Professor and Chair of Dermatology at Massachusetts General Hospital and Director of the Melanoma Program at MGH Cancer Center
“The red hair gene in humans in virtually every case is attributed to nonfunctional variants of the melanocortin-1 receptor. The melanocortin-1 receptor …transduces signals that activate the pigmentation pathway—the pigmentation response in the melanocyte,” said David E. Fisher, MD, PhD, who presented “The Red Hair Background: Insights, Challenges, and Opportunities,” at Masterclasses in Dermatology in Sarasota, Florida.
Keratinocytes in the skin respond to DNA damage from ultraviolet (UV) radiation by producing melanocyte stimulating hormone (MSH), which is released and binds to the melanocortin-1 receptor. If that receptor is capable of responding, it produces a surge in cyclic adenosine monophosphate (AMP), which activates the pigmentary response to produce eumelanin in melanocytes, said Dr. Fisher.
“That melanin is packaged in …melanosomes, which are exported back out to the keratinocytes. So, the vast majority of pigment in our skin is not in melanocytes; it’s made by melanocytes but is exported back out and smoothly distributed into the keratinocytes.”
But when the melanocortin-1 receptor contains genetic variants that are unable to respond to MSH binding after UV radiation, there is no transduction of the signal, no pigmentary response, and no tanning response, he said.
It’s What’s Unseen
Recent data looked more carefully at the pigment that is made in the red hair background, according to Dr. Fisher.
“Red hair individuals are not albinos. They don’t have dark eumelanin pigment, but they have the red-blonde pheomelanin reddish pigment, which we don’t see that well in the skin but can easily see it in the hair.”
Many studies, including one in mice and at least two in humans, strongly suggest that not only does red pigment fail to protect skin from UV radiation, but it may directly contribute to carcinogenesis of melanocytes, said Dr. Fisher.
As one goes through the Fitzpatrick phototypes, the darker the skin, the better the ability to tan, the lower the risk of sunburns and of melanoma formation.
And as one gets to the lighter and lighter skin types, there typically are more benign nevi, he said.
“That tends to correlate with melanoma risk, with one striking exception.”
The exception is that with the lightest phototype—red hair background—the number of nevi plummets, said Dr. Fisher.
“Red haired individuals of course frequently have many freckles, but routine nevi that are pigmented and visible to the eye are strikingly rare on the red hair background.”
That, according to Dr. Fisher, led to the question: Could it be that the red hair background does, in fact, have more nevi, but they’re not visible to the human eye?
He described a study from his lab in which the researchers generated a mouse model of red-haired mice, where they could carry out a genetic trick to activate the BRAFV600E oncogene, which is responsible for more than 70% of benign nevi in humans, said Dr. Fisher.
“When you [activate BRAFV600E] on a black genetic background in mice they get nevi. You can see the nevi, and they have pigment in them. But … in red hair mice that are genetically identical except for that melanocortin-1 receptor variant that cannot make the pigment and is unable to make any darker melanin, we see no nevi.”
The study’s author carried out another trick, which was to activate formation of a green florescent protein by the same genetic switch that would turn on BRAF. As a result, every cell that had been activating BRAF would activate the expression of green florescent protein, said Dr. Fisher.
“Now when he looked at the skin, the red-haired mice had numerous nevi. These were a large clonal expansion of melanocytes that were by and large benign, except once in a while they would transform into melanoma.”
Albino red haired mice, on the other hand, did not develop melanomas, he said.
Clinical Implications
These mouse data suggest that nevi are probably much more abundant in the red hair background than what can be observed in the clinic, said Dr. Fisher.
“There have been studies that looked at the survival of patients with amelanotic melanoma, where we don’t see dark pigment, and, in fact, amelanotic melanoma is more lethal than melanotic melanoma.”
There are ongoing studies to validate this in human specimens, said Dr. Fisher.
UVA: Highly Carcinogenic
Animals have helped researchers to further study the influence of UV radiation, in particular, separating UVA from UVB radiation, said Dr. Fisher.
“We know UVB is highly carcinogenic. These findings suggest that UVB is carcinogenic whether on a black pigmented genetic background or red or albino genetic background. UVB is highly mutagenic when it hits DNA.”
Interestingly, it appears that UVA, which has a different oxidative damage mechanism of carcinogenesis, is highly dangerous in causing a transition to melanoma risk from benign nevi on a red hair background. But the UVA effect is completely gone with an albino red background, he said.
“There is something about the red pigment interacting with UVA wavelengths that is severely exacerbating the risk of melanoma formation.”
“This, we think, will be terribly important for the clinical community because unfortunately many sunscreen ingredients these days are good at UVB (what the SPF represents) but UVA is not encompassed within the SPF quantitative endpoint.”
These data suggest that if UVA is not being prevented from hitting the skin, it may be interacting in people with fair skin to exacerbate the risk of melanoma. It is important that UVA-directed sun filters be made available to people along with other forms of sun protection, he said.
Disclosures: Dr. Fisher is cofounder of Soltego, a biopharmaceutical innovator focused on pigmentation, and is a consultant or on the scientific advisory board of Tasca, Pierre Fabre, Escient, and Ventus.
