Malignant Melanoma: Causes

Pathogenesis (disease development)

The factors leading to the development of malignant melanoma (MM) are unclear. It is thought that UV exposure causes mutations in the pigment system to accumulate. This is also seen in the development of melanocytic nevi (liver spots).Note: The risk of melanoma increases almost linearly with the number of melanocytic nevi. See also under “Disease-related causes”.However, only about one-third of melanomas develop on preexisting (“pre-existing”) melanocytic nevi. Thus, the majority of melanomas develop de novo (“from scratch”) on inconspicuous skin.

Etiology (causes)

Biographic causes

  • Genetic burden from parents, grandparents, as well:
    • Familial atypical multiple birthmark and melanoma syndrome (FAMMM); this is fulfilled if two first-degree relatives or three relatives of any degree have melanoma; nevi larger than 5 mm in diameter on the buttocks (hazard ratio (HR) 9.4) were found to be a characteristic risk factor in childhood, especially if they were atypical (HR 14.0)
    • Genetic risk dependent on gene polymorphisms:
      • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
        • Genes: ATM, MC1R, PIGU
        • SNP: rs1805007 in gene MC1R (red hair gene).
          • Allele constellation: CT (2.2-fold).
          • Allele constellation: TT (5.0-fold)
        • SNP: rs1805008 in gene MC1R (red hair gene).
          • Allele constellation: CT (2.2-fold).
          • Allele constellation: TT (5.0-fold)
        • SNP: rs1805009 in gene MC1R (red hair gene).
          • Allele constellation: CG (2.2-fold).
          • Allele constellation: CC (5.0-fold)
        • SNP: rs910873 in the gene PIGU
          • Allele constellation: AG (1.7-fold).
          • Allele constellation: AA (3.0-fold)
        • SNP: rs1801516 in the gene ATM
          • Allele constellation: AA (0.86-fold).
  • Skin type
    • Fair-skinned population (Fitzpatrick I-II)
    • Redheads – The fair skin of red-haired people, often covered with freckles, is caused by a gene variant in the so-called melanocortin receptor. As a result, a particularly large amount of pheomelanin (red-yellow pigment) is produced. Phaeomelanin seems to play a key role in the tendency to develop malignant melanoma even without ultraviolet rays
  • Occupations
    • Occupations with high UV exposure
    • Pilots and cabin crew – 2.22-fold increased risk of disease for pilots and a 2.09-fold increased risk for cabin crew compared with the average population

Behavioral causes

  • UV exposure (esp. : UV-B radiation; UV-A radiation e.g. solariums?) [major risk factor for the development of malignant melanoma].
    • Sun exposure in childhood and adolescence is crucial; this is shown by immigration studies e.g. from Australia and Israel; individuals who immigrated to these countries after the age of 20 had no increased risk of melanoma compared to the white population who had spent their childhood there.
    • UV-A exposure from artificial sources: e.g., tanning beds or light therapy.
      • Moderate tanning bed use should not lead to an increased risk of melanoma.
      • According to a case-control study, tanning in tanning beds is not only associated with an increased risk of melanoma (depending on the frequency of use: 20-75%), but also increases the risk of multiple melanomas by 2.8 times.
  • In men: overweight (BMI ≥ 25; obesity).

Disease-related causes

  • Hypertension (high blood pressure)
  • Melanocytic nevi; number on total body surface (definition: nevus with a melanocytic change ≥ 2 millimeters in diameter):
    • > 50 nevi: melanoma risk: increased 4 to 5 times.
    • > 100 nevi: melanoma risk: 8- to 10-fold increased
    • The number of nevi correlated best with the number of nevi on the right arm in terms of predicting the number of nevi on the total body surface: women with more than 11 nevi on the arm were 9-fold more likely to have at least 100 nevi on the total body surface (adjusted odds ratio [OR]: 9.38; 95% confidence interval: 6.71-13.11)

Medications

  • Angiotensin receptor blockers (possibly wg.photosensitizing effect)
  • Hydrochlorothiazide (HCT) – increased risk of developing nodular or lentiginous melanoma).
  • Sildenafil (PDE-5 inhibitor).

Environmental pollution – intoxications (poisonings).

  • Herbicides (for occupational exposure; risk increase about 85% for any exposure; no significant risk increase, however, compared with insecticides or pesticides) Note: risk of bias due to UV radiation.
  • Radon
  • UV light

Other causes