Melanoma Development and Progression

Melanoma in the Netherlands

• Common in 40-60 year old individuals
• Stage 1 has a good prognosis

Melanoma Development and Progression

• Melanocytes produce melanin, which absorbs radiation and prevents DNA damage
• Mutations in BRAF or NRAS lead to naevus (moedervlek) formation
• Additional mutations in TERT or P53 lead to dysplastic naevus formation
• Multiple mutations are needed to form a melanoma in situ
• Even more mutations are needed to form an invasive melanoma

Disease Course

• UV radiation, hereditary factors, nevi, skin type, and immunity contribute to disease development
• Cancer is caused by mutations: inherited (H), due to DNA replication errors (R), or environmental factors (E)
• Melanomas are often due to environmental factors, but hereditary mutations are dominant in familial cancers

Heritable Cancer Predisposition

• Sporadic melanoma: 90%, familial melanoma: 10%
• Familial melanoma is defined by 3 or more melanoma cases in one family
• Sporadic melanoma risk factors: environmental (UV radiation, 50-100 mutations/s exposed skin) and genetic (50 SNPs enriched for in melanoma cases)

Familial Melanoma

• Different terms: familial melanoma, FAMMM syndrome, hereditary melanoma
• Leading cause is mutation in CDKN2A (p16-leiden), other mutations: CDK4, BAP1, TERT, POT1, ACD, TERF2IP, MITF, MEK11
• CDKN2A mutation: hereditary melanoma and pancreatic cancer, autosomal dominant, cancer at early age, multiple tumors, benign precursor lesions

CDKN2A Mutation

• Encodes two different proteins: p14 and p16, with different sequences and functions
• P16 is a cell cycle checkpoint inhibitor, inhibiting CDK4/6 proteins
• P14 protein plays a role in regulating p53
• CDKN2A mutation is an inactivating mutation, leading to loss of checkpoint inhibition and loss of p14 function

Identification of More Cancer Susceptibility Genes

• With Next-generation sequencing, 120 cancer susceptibility genes have been identified
• Role in DNA repair, cell cycle regulation, and various other functions

BAP1-Associated Tumor Syndromes

• Carriers of BAP1 have an increased risk for skin lesions, uveal melanoma, melanoma, mesothelioma, basal cell carcinoma, and renal cancer

MITF-Associated Familial Melanoma

• Germline mutation in MITF predisposes to melanoma and renal cancer
• MITF E318K mutation disrupts MITF sumoylation site, leading to altered MITF activity

TERT and Shelterin Complex Gene Mutations

• TERT promoter mutation: activates transcription of RT subunit of telomerase, increases telomere length and stability
• POT1, TERF2IP, ACD mutations: inactivating mutation leads to increased telomere length and stability, predisposition to multiple tumors

Rare Melanoma Susceptibility Mutations

• Targeted gene panel approach: 30 melanoma susceptibility genes, 451 melanoma families, 488 samples
• Non-CDKN2A, non-CDK4 mutations: rare melanoma susceptibility mutations

Diagnosis and Therapy

• Genetic testing for diagnosis
• Surveillance: skin and internal organs based on gene defect
• New therapies: targeted and immune checkpoint inhibitors, BRAF and MEK inhibitors, immunotherapies