Family history and genetic factors relating to the development of malignant melanoma

Family history of melanoma is considered to be a strong risk factor in MM (1)

• a patient with a first degree relative with melanoma has twice the risk of developing melanoma than those without a family history (1)
  
  
• approximately 5 -10% of patients with MM have a family history (2)
  
  
• some families have high-risk genes that are inherited as autosomal dominants, and these may manifest as multiple primary tumours in an individual and/or clustering in families
  • genetic mutation in the CDKN2A (or p16) gene is seen commonly in these families
  • a second mutation in CDK4 can occur rarely (1)

In the general UK population, individuals with multiple moles (the atypical mole syndrome (AMS); also known as dysplastic nevus syndrome) are at increased risk of MM and this is thought to be genetic, probably due to low-penetrance susceptibility genes

• phenotype is common and patients with the AMS require education about prevention, both primary (sun avoidance) and secondary (signs and symptoms)
  
  
• patients with AMS have a relative risk of MM of around 10 compared with those who have very few moles (lifetime risk of MM in the UK is approximately 1 in 150; patients with AMS have an estimated 1 in 20 lifetime risk compared with a person with an average number of moles. Their risk is lower when compared, for example, with those with xeroderma pigmentosum, but as 2% of the general population have the AMS these patients 'explain' a significant proportion of the disease (2)

In some families with melanoma there is an increased susceptibility to some other cancers e.g. - pancreas, brain and breast cancer. Hence in a melanoma patient, obtaining a thorough family history of cancers is important (1).

The following suggest an underlying genetic predisposition in a melanoma patient:

• occurrence at a younger age (<40 years)
• multiple primary melanomas
• a history of precursor lesions such as dysplastic nevi (1)

Patients who are genetically predisposed to melanoma tend to have tumours which are superficially invasive and have a better prognosis (1).

A genetic predisposition to melanoma may be seen in patients without a family history of melanoma. New mutations in the CDKN2A gene or CDK4 gene may occur in these patients which can be passed on to offsprings in an autosomal dominant fashion (1)

Reference:

• 1. Markovic SN et al. Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis. Mayo Clin Proc. 2007;82(3):364-80
• 2. Bataille V, de Vries E. Melanoma--Part 1: epidemiology, risk factors, and prevention. BMJ. 2008;337:a2249.