Health ·

Melanoma, Melanin & Molecular Biology

Melanoma, Melanin & Molecular Biology: A Deeper Look at Skin Cancer Risk Across Demographics


Melanoma, a highly aggressive form of skin cancer, exhibits significant variations in prevalence and prognosis across global populations. This disparity is intricately linked to genetic factors, skin pigmentation, and environmental exposure to ultraviolet (UV) radiation. While melanin offers protective photobiological functions, it also alters the dynamics of vitamin D synthesis, adding complexity to public health strategies. This article explores the epidemiology of melanoma, the biological distinctions between UVA, UVB, and UVC rays, the physiology of melanin production, and the influence of genetics and skin tone on vitamin D metabolism.

1. Introduction

Skin cancer is one of the most prevalent malignancies worldwide, with cutaneous melanoma accounting for a disproportionate share of skin cancer–related deaths. While early detection has improved survival in light-skinned populations, delayed diagnoses in darker-skinned individuals have contributed to poorer prognoses despite lower overall incidence. Understanding the biological, genetic, and sociocultural factors that modulate risk is critical for equitable healthcare interventions.

2. Global Prevalence and Demographics

Melanoma is most prevalent among fair-skinned individuals of European ancestry, particularly in regions with high UV exposure such as Australia, New Zealand, and parts of North America. According to the World Health Organization (WHO), melanoma incidence rates can be over 20 times higher in White populations compared to Black or Asian populations.

However, darker-skinned populations tend to present with acral lentiginous melanoma, a rarer and often deadlier form, typically found on the soles of the feet, palms, or under nails. The delayed detection in these populations is often due to underrepresentation in awareness campaigns and a persistent myth that melanin offers complete protection.

3. Ultraviolet Radiation: UVA, UVB, UVC

UV radiation from the sun is divided into three major categories based on wavelength:

  • UVA (315–400 nm): Penetrates deeper into the dermis; contributes to photoaging and indirect DNA damage via reactive oxygen species.

  • UVB (280–315 nm): Causes direct DNA damage and is primarily responsible for sunburn and carcinogenesis; critical for vitamin D synthesis.

  • UVC (100–280 nm): Largely absorbed by the ozone layer and does not typically reach the earth’s surface.

Both UVA and UVB are implicated in melanomagenesis, but UVB has a more direct mutagenic effect, often causing cyclobutane pyrimidine dimers that result in signature mutations in the p53 tumor suppressor gene.

4. The Biology of Melanin

Melanin is produced by melanocytes through a complex process known as melanogenesis, regulated by tyrosinase and transcription factor MITF (Microphthalmia-associated transcription factor). The two primary forms are:

  • Eumelanin: Brown-black pigment offering strong UV protection.

  • Pheomelanin: Red-yellow pigment found in lighter skin tones, less photoprotective and can even generate free radicals under UV exposure.

Increased melanin in darker skin acts as a natural photoprotectant, absorbing and scattering harmful UV rays, thus reducing the risk of UV-induced DNA damage.

5. Vitamin D Synthesis & Skin Tone

Vitamin D3 (cholecalciferol) is synthesized in the skin upon exposure to UVB radiation, making cutaneous synthesis the primary source of vitamin D for most individuals. However, higher melanin concentration in the skin acts as a natural sunscreen, reducing vitamin D production efficiency by 50–95% in darker-skinned individuals compared to lighter-skinned counterparts.

This contributes to higher rates of vitamin D deficiency in people with richly pigmented skin, particularly in northern latitudes with limited UVB exposure.

6. Genetics, Diagnostics & Treatment

Several genes influence melanoma risk:

  • CDKN2A: Mutations here are the most common cause of familial melanoma.

  • MC1R (Melanocortin 1 Receptor): Variants are strongly linked to red hair, freckling, and increased pheomelanin production — elevating melanoma risk.

  • BRAF and NRAS: Frequently mutated in cutaneous melanomas and associated with tumor aggressiveness.

These genetic factors interact with environmental exposure to define individual melanoma risk, with some genetic variants contributing more significantly in fair-skinned populations due to the synergistic effect with UV damage.

Diagnosis of Melanoma

Early diagnosis is the most critical factor in reducing melanoma mortality. Clinicians use a combination of visual inspection, dermoscopic analysis, and biopsy techniques to confirm malignancy. The most well-known screening tool remains the ABCDE rule:

  • Asymmetry

  • Border irregularity

  • Color variation

  • Diameter >6 mm

  • Evolving lesion

Dermoscopy improves diagnostic accuracy by allowing visualization of pigmentation structures beneath the epidermis, distinguishing melanomas from benign nevi.

When suspicion is high, an excisional biopsy is performed — removing the entire lesion with a narrow margin to assess histopathological characteristics. Key features include Breslow thickness (tumor depth), ulceration status, and mitotic rate, all of which are used for staging according to the AJCC TNM system.

Advanced diagnostic methods include confocal microscopy, molecular assays (e.g., BRAF mutation testing), and sentinel lymph node biopsy for high-risk lesions to determine regional metastasis.

Public health strategies increasingly encourage self-exams and digital monitoring apps, though accessibility and education gaps remain, particularly among communities of color where atypical presentations may delay diagnosis.

Treatment of Melanoma

Melanoma treatment depends on the stage, tumor location, genetic profile, and patient health status.

  • Surgical Excision

For localized melanoma, the gold standard remains wide local excision with margins based on tumor depth. This is often curative in Stage 0–IIA melanomas. Sentinel lymph node biopsy may accompany surgery if invasive characteristics are present.

  • Immunotherapy

Revolutionizing metastatic melanoma care, checkpoint inhibitors like:

  1. Anti-PD-1 (nivolumab, pembrolizumab)
  2. Anti-CTLA-4 (ipilimumab)
    have shown durable responses by activating the immune system against cancer cells.
  3. Targeted Therapy

For melanomas harboring BRAF V600 mutations, combination therapy with BRAF inhibitors (dabrafenib, vemurafenib) and MEK inhibitors (trametinib, cobimetinib) significantly improves progression-free survival. These are often used in Stage III/IV melanoma.

  • Radiation Therapy

Less commonly used as a primary treatment, radiation may help in palliative care or when surgical margins are positive or nodal involvement is high.

  • Clinical Trials & Emerging Therapies

Ongoing research includes personalized mRNA vaccines, oncolytic viruses, and T-cell therapies — offering hope for immunoresistant or relapsed cases.

Multidisciplinary care involving dermatology, surgical oncology, pathology, and genetics is vital for optimal outcomes. Importantly, access to advanced therapies remains limited in underserved regions, highlighting the need for global equity in melanoma care.

7. The Path Forward

Equity in melanoma prevention and treatment will require:

  • Increased public health outreach to underserved communities

  • Greater representation of skin of color in dermatology education and visual diagnostics

  • Research into vitamin D supplementation guidelines based on melanin levels and geography

  • Personalized medicine approaches integrating genetic profiling and UV exposure patterns

References

  1. Leiter, U., & Garbe, C. (2008). Epidemiology of melanoma and nonmelanoma skin cancer—the role of sunlight. Advances in Experimental Medicine and Biology, 624, 89–103.

  2. Brenner, M., & Hearing, V. J. (2008). The protective role of melanin against UV damage in human skin. Photochemistry and Photobiology, 84(3), 539–549.

  3. Holick, M. F. (2007). Vitamin D deficiency. New England Journal of Medicine, 357(3), 266–281.

  4. Bastiaens, M. et al. (2001). The melanocortin-1-receptor gene is the major freckle gene. Human Molecular Genetics, 10(16), 1701–1708.

  5. Gloster, H. M., & Neal, K. (2006). Skin cancer in skin of color. Journal of the American Academy of Dermatology, 55(5), 741–760.

  6. Narayanan, D. L., Saladi, R. N., & Fox, J. L. (2010). Ultraviolet radiation and skin cancer. International Journal of Dermatology, 49(9), 978–986.

Back to Everything but Anchovies