The lack of melanin in people with light skin-and the resulting increased vulnerability to UV damage-may not be enough to explain why risk of melanoma is as much as 30 times higher for people with light skin compared to individuals with dark skin. That is the key finding from researchers who have investigated why melanoma risk is so much higher in people with light skin (Sci Adv 2022; doi: 10.1126/sciadv.abn4007). In a series of lab experiments using human melanocytes, they found there are intrinsic differences between melanocytes in both light and dark skin samples that affect cells' abilities to grow and replicate, as well as their susceptibility to malignant transformation. The melanin precursor dihydroxyphenylalanine (DOPA) was involved and the results suggest that CHRM1 and FOXM1 may be new therapeutic targets for melanoma. Todd W. Ridky, MD, PhD, Associate Professor of Dermatology at the Perelman School of Medicine at the University of Pennsylvania and attending physician at the Hospital of the University of Pennsylvania, explained the findings and implications for future melanoma treatment and care.
1 What led your research of melanoma risk in different skin types?
"The classical teaching is that light-skinned people are more prone to melanoma and other skin cancers because they're more vulnerable to UV damage from the sun. Light skin is relatively deficient in melanin pigment, which serves as a physical shield against UV rays from the sun. So, if the melanin absorbs the UV, then that protects the DNA. But if you don't have as much melanin in the skin, then the UV goes right through, hits the DNA in your cells, and causes damage, which then turns into mutations that drive cancer.
"But we thought that explanation was not sufficient to explain the huge gap in the difference in the cancer incidence between dark-skinned and light-skinned people with regards to melanoma. There are a few different lines of reason that suggest this to be the case. The first is anal-rectal melanoma. It's not super common, but that cancer appears to be 13 times more common in light-skinned people than dark-skinned people. You can't really invoke a UV sun-shielding explanation for a cancer in that location. So we thought there must be other factors involved.
"Second, in the course of our research, we routinely isolate and study melanocytes. If you isolate [them] out of light skin and dark skin on the same day and grow them in identical conditions, the light ones always proliferate much faster than the dark ones. We thought it not coincidental; the cells that proliferate much faster are also the ones that are much more prone to give rise to cancer. "
2 How did you show there's something going on besides more UV shielding in people with dark skin?
"We took a set of four oncogenic proteins that are associated among the most common changes in melanoma in people. These include BRAF mutations, which drive half of all melanoma; CDK4; dominant-negative p53; and hTERT. We did some tissue engineering to generate composite human skin tissues in a dish. And then we took those pieces of skin-some had the melanocytes with the oncogenes from the light skin and some [were] from the dark skin-and we grafted them onto the backs of host mice. After 100 days, the skin grafts with the light melanocytes expressing the four oncoproteins turned into melanomas. However the dark cells, engineered with the same oncoproteins, did not turn into melanoma.
"So, yes, there is probably...some sun-shielding activity from the UV, which likely helps prevent the dark melanocytes from getting the mutations in the first place. But this experiment showed that, even if dark melanocytes get the mutations and express those oncoproteins, they are still very resistant to making melanoma compared to light melanocytes.
"The fact that they were growing different in the dish, and the fact that even when they got the oncogenes in them they still did not progress to melanoma, told us there are clearly factors beyond simply UV damage that are underlying this huge difference in melanoma between dark skin and light skin, and it's not simply about UV shielding. There are other genetic determinants in the cells that correlate with pigment type, but that are independent of UV. This is paradigm-shifting. This is something that's been missed by the field."
3 What were other key findings?
"Miriam Doepner, a PhD candidate in the Department of Dermatology at Perelman, had the idea that this was maybe due to an upstream synthetic intermediate in the melanin pathway, rather than melanin itself. And that's what led us to DOPA. The melanin synthetic pathway starts with tyrosine, an amino acid. Then the first step in that process, the rate-limiting step in making melanin, is conversion of tyrosine to DOPA. And DOPA turned out to be critical.
"DOPA, we discovered, has this previously unrecognized signaling activity that is anti-melanoma and has nothing to do with UV. Dark melanocytes have a lot more DOPA than light melanocytes. We found that, if you add DOPA to dark melanocytes, nothing happens. If you add it to light melanocytes, they slow down and get darker. That was also true of melanoma cells; DOPA makes them proliferate more slowly and also get darker. You can even treat mice with melanoma with DOPA; their tumors grow more slowly and they live longer.
"This is very interesting because DOPA is actually an FDA-approved agent, which is DOPA combined with a stabilizer as treatment for Parkinson's disease. It works in mice; whether it works in people is yet to be determined. It's potentially easier to do a new drug trial with an already-approved agent rather than a brand new one. This is also really interesting because we know there's an association between melanoma and Parkinson's disease.
"The bottom line for the oncology community to know right now is to have this fundamental awareness that there's a lot of heterogeneity in people and a lot of heterogeneity in cancer. In exploring the mechanisms underlying the heterogeneity, you can learn things about diseases and cancer you would not have learned otherwise. There are groups of people that do much better or much worse with the same disease."