Melanoma Development and Progression

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Questions and Answers

What is the outcome of a single mutation in BRAF or NRAS?

Formation of a dysplastic naevus

Formation of a benign naevus (correct)

Formation of an invasive melanoma

Formation of a melanoma in situ

What is required for the formation of an invasive melanoma?

A single mutation in BRAF or NRAS

Multiple mutations including TERT or P53

A combination of multiple mutations and epigenetic mutations (correct)

Epigenetic mutations alone

What is the primary cause of mutations in most cancer cells?

Inherited mutations

Replication errors (correct)

Environmental factors

Hereditary factors

What is the primary function of the P16 protein in relation to melanoma susceptibility?

It inhibits the CDK4/6 proteins as a cell cycle checkpoint inhibitor Signup and view all the answers

What is the leading cause of familial melanoma?

Mutation in the CDKN2A gene Signup and view all the answers

What is the result of UV-B radiation on DNA?

It leads to the formation of pyrimidine dimers Signup and view all the answers

What is the definition of familial melanoma?

A family with 3 or more invasive melanoma cases with a first-degree relationship between 2 or more affected relatives Signup and view all the answers

What is the result of the CDK4/6 proteins binding to Cyclin D1?

It phosphorylates the Rb protein, initiating the S phase of the cell cycle Signup and view all the answers

What is the role of p14 protein in regulating p53?

Regulating p53 Signup and view all the answers

What is the result of CDKN2A mutation?

Loss of checkpoint inhibition Signup and view all the answers

What is the function of the BAP1 protein?

Deubiquitinase with diverse functions in apoptosis Signup and view all the answers

What is the effect of the TERT promoter mutation?

Increasing telomerase activity Signup and view all the answers

What is the function of the Shelterin complex?

Protecting telomeres Signup and view all the answers

What is the benefit of understanding the genetic basis of melanoma susceptibility?

All of the above Signup and view all the answers

What is the approach used to identify rare melanoma susceptibility genes?

Targeted gene panel approach Signup and view all the answers

Study Notes

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

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Description

This quiz covers the development and progression of melanoma, including the role of melanocytes, keratinocytes, and oncogenic mutations. It also discusses the formation of benign lesions and the progression to malignant melanoma.