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Familial melanoma
This condition significantly raises the risk of melanoma for affected individuals and their family members. It is typically caused by genetic changes passed down through generations, making early detection and surveillance crucial.
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Overview
Familial melanoma refers to a pattern of melanoma within a family that suggests an inherited genetic predisposition. Melanoma is a severe form of skin cancer that develops from pigment-producing cells called melanocytes. In families with familial melanoma, individuals often develop multiple melanomas, or melanoma appears at a younger age than is typical in the general population [PMID:33675091].
While most melanomas are not hereditary, familial melanoma accounts for a smaller but significant proportion of cases. Identifying families with this condition allows for targeted screening and prevention strategies, which can be vital for early detection and improving outcomes.
Symptoms & clinical features
The primary 'symptom' of familial melanoma is the development of melanoma itself. Melanomas can appear as new moles or as changes in existing moles. Careful attention to skin changes is important, especially for those with a family history of melanoma.
Key features that might suggest a mole is a melanoma include the 'ABCDE' criteria: Asymmetry (one half doesn't match the other), Border irregularity (edges are ragged, notched, or blurred), Colour variation (uneven colour, shades of black, brown, and tan, or patches of pink, red, white, or blue), Diameter (larger than 6mm), and Evolving (changes in size, shape, colour, or elevation, or any new symptoms like bleeding, itching, or crusting) [PMID:30138927]. Individuals with familial melanoma may also have a larger number of moles (naevi) compared to the general population, some of which may be atypical.
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Affected organs
Familial melanoma primarily affects the skin, as this is where melanocytes are located. Melanoma can develop anywhere on the skin, including areas not typically exposed to the sun. Although less common, melanoma can also originate in other parts of the body where melanocytes are present, such as the eyes (uveal melanoma), or mucous membranes lining the nose, mouth, oesophagus, gut, and genital or anal regions.
Risks & severity
Individuals with familial melanoma have a significantly increased lifetime risk of developing melanoma compared to the general population. The risk can vary between families and depends on the specific genetic change involved. Some studies suggest families with germline pathogenic variants in certain genes may have a lifetime melanoma risk ranging from 28% to 92% [PMID:24602160].
Melanoma can be a very serious cancer, with the potential to spread (metastasise) to other parts of the body if not detected and treated early. The typical age of onset for melanoma in familial cases is often younger, sometimes in the 30s or even earlier, compared to sporadic cases. The severity of familial melanoma relates directly to the aggressiveness of the specific tumour and the stage at which it is diagnosed; early detection is critical for better prognosis.
Genetic causes
Familial melanoma is often caused by inherited changes in specific genes that play a role in controlling cell growth and division. The most commonly identified genes associated with familial melanoma are CDKN2A and CDK4.
CDKN2A (cyclin dependent kinase inhibitor 2A) is a tumour suppressor gene. Its job is to help regulate the cell cycle, acting as a brake on cell proliferation to prevent uncontrolled growth. Pathogenic changes in CDKN2A can disrupt this crucial function, leading to an increased risk of melanoma and other cancers, such as pancreatic cancer [PMID:33675091]. CDK4 (cyclin dependent kinase 4) also plays a vital role in cell cycle control. Pathogenic variants in CDK4 can affect its normal interaction with other proteins, contributing to the development of melanoma.
- CDK4 cyclin dependent kinase 4
- CDKN2A cyclin dependent kinase inhibitor 2AThe CDKN2A gene provides instructions for producing proteins that act as tumour suppressors, playing a crucial role in preventing uncontrolled cell growth.
Inheritance pattern
Familial melanoma typically follows an autosomal dominant inheritance pattern. This means that a person only needs to inherit one copy of an altered gene from one parent to have an increased risk of developing the condition. If a parent has a pathogenic variant linked to familial melanoma, each of their children has a 50% chance of inheriting that variant.
Individuals who inherit the genetic change may not necessarily develop melanoma, as other genetic and environmental factors also influence risk; this concept is known as reduced penetrance. However, those who inherit the variant will have a significantly higher lifetime risk. They also have a 50% chance of passing the variant on to each of their children, regardless of whether they themselves develop melanoma.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
The diagnosis of familial melanoma is typically suspected based on a strong family history of melanoma, especially if there are multiple affected individuals, early onset of melanoma, or multiple primary melanomas in one individual. Clinical suspicion often leads to referral to a dermatology or clinical genetics service.
Confirmation of familial melanoma involves genetic testing to identify specific pathogenic variants in genes like CDKN2A or CDK4. This testing is usually arranged through the NHS Genomic Medicine Service (GMS) after a clinical genetics referral. Relevant R-codes for genetic testing for inherited melanoma predisposition include R190 Inherited melanoma (CDKN2A) and R217 Inherited melanoma (CDK4), which can be requested by specialist clinicians.
Management & lifestyle
Due to the increased risk, management for individuals with familial melanoma or those at high risk because of a family history focuses on early detection and prevention. This typically involves regular, lifelong skin surveillance by a dermatologist, often including full-body skin examinations and sometimes mole mapping (photographs of moles to track changes over time).
Individuals are also advised on sun protection measures, such as using high-factor sunscreen, wearing protective clothing, and avoiding peak sun exposure. Regular self-skin checks are encouraged, and individuals are taught how to recognise suspicious changes. Where a genetic cause has been identified, genetic counselling is available to discuss the implications for the individual and their wider family.
UK care pathway
In the UK, suspected cases of familial melanoma are usually referred by a GP or dermatologist to a clinical genetics service. This service can provide a comprehensive assessment, including detailed family history analysis, and discuss the appropriateness of genetic testing. Genetic testing for familial melanoma falls under the NHS Genomic Medicine Service (GMS) and is typically requested using specific R-codes for genes such as CDKN2A and CDK4.
Genetic counsellors play a vital role in explaining the inheritance patterns, risk implications, and potential psychological impact of a genetic diagnosis, both for the individual tested and their relatives. They can also help coordinate screening for at-risk family members.
Frequently asked questions
What does it mean to have 'familial' melanoma?
Familial melanoma means that melanoma occurs in several members of a family, often at an earlier age or with multiple occurrences in one person, suggesting an inherited genetic cause. This differs from sporadic melanoma, which is not linked to a strong family history.
How is familial melanoma passed down through families?
Familial melanoma typically follows an autosomal dominant inheritance pattern. This means if one parent carries a specific genetic change linked to the condition, each child has a 50% chance of inheriting that change and therefore an increased risk of developing melanoma.
What genes are associated with familial melanoma?
The primary genes associated with familial melanoma are CDKN2A and, less commonly, CDK4. Changes in these genes affect how cells grow and divide, leading to a higher risk of developing melanoma.
If I have familial melanoma, what should I do to manage my risk?
If you have familial melanoma, or are at high risk due to family history and genetic testing, regular skin surveillance by a dermatologist is recommended. Practising strict sun protection and performing regular self-skin checks are also crucial to detect any changes early.
Can genetic testing help my family?
Yes, if a specific genetic cause for familial melanoma is identified in your family, genetic testing can then be offered to other at-risk relatives. This allows those who have inherited the genetic change to begin early surveillance and risk management strategies.
References
- Swetter SM, Tsao H, Bichakjian CK. Guidelines of care for the management of primary cutaneous melanoma. Journal of the American Academy of Dermatology. 2019. PMID: 30392755
- Newton JA. Familial melanoma. Clinical and experimental dermatology. 1993. PMID: 8440053
- Serra S, Chetty R. p16. Journal of clinical pathology. 2018. PMID: 30076191
- Newton-Bishop J, Bishop DT, Harland M. Melanoma Genomics. Acta dermato-venereologica. 2020. PMID: 32346746
- Read J, Wadt KA, Hayward NK. Melanoma genetics. Journal of medical genetics. 2016. PMID: 26337759
- Stahl S, Bar-Meir E, Friedman E. Genetics in melanoma. The Israel Medical Association journal : IMAJ. 2004. PMID: 15609895
- Hansson J. Familial melanoma. The Surgical clinics of North America. 2008. PMID: 18672145
- Miller PJ, Duraisamy S, Newell JA. Classifying variants of CDKN2A using computational and laboratory studies. Human mutation. 2011. PMID: 21462282