Familial cutaneous melanoma is responsible for 3-5% of melanoma diagnoses
Germline mutations in CDKN2A/p14 or CDK4 are responsible for the syndrome.
- CDKN2A gives rise to two proteins:
- p16INK4A binds to cyclin dependent kinase 4, preventing the binding of cyclin-D1 which is required for progression through the cell cycle G1 checkpoint. Mutations in CDKN2A limit the production of this protein and allow unregulated activation of CDK4
- p14ARF interacts with TP53, MDM2 and E2F1 and encourages cell cycle arrest. It shares some of the same gene sequence as p16INK4A and therefore may be 'knocked out' by the same mutation as in p16INK4A
- CDK4 mutations lead to ineffective binding of p16INK4A, causing a similar effect to mutations in CDKN2A.
Patients are at elevated risk for cutaneous melanoma; about 1/4 will develop melanoma during their lifetime. Melanomas are more likely to be earlier in life.
There is a suggestion that breast and pancreatic cancers may also be more common.
The detection of CDKN2A is complicated due to low incidence, even in patients with a strong family history or multiple melanomas. This is due to a heavy environmental influence on the development of the disease as well as other genetic factors (e.g. fair skin, red hair) that increase risk within families. The absence of CDKN2A does not significantly diminish the risk for a patient, who might go on to undertake high risk activities more frequently.
Genetic counselling is essential.
D: Familial Cancer
- BRCA 1 & 2
- Cowden Syndrome
- Familial Adenomatous Polyposis (FAP)
- Familial Cutaneous Melanoma
- Li Fraumeni Syndrome
- Lynch Syndrome (Hereditary Non-Polyposis Colon Cancer)
- MEN 1 and MEN 2
- Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome)
- Peutz-Jeghers Syndrome
- Tuberous Sclerosis Complex (TSC)