On this page
Melanoma (polygenic risk)
Also known as Melanoma · Skin cancer
Understanding melanoma involves recognising how genetic susceptibility, combined with environmental factors like UV exposure, influences an individual's risk. It is a significant health concern in the UK, with varying lifetime risks for men and women.
Available at Jeen Health
Clinical tests that include this
Overview
Melanoma is a form of skin cancer that originates in melanocytes, which are the cells responsible for producing skin pigment [PMID:31700201]. Unlike some other skin cancers, melanoma has a higher potential to spread to other parts of the body if not detected and treated early. The development of melanoma often involves a combination of genetic factors and environmental exposures, particularly ultraviolet (UV) radiation from sunlight or sunbeds. Awareness of skin changes and regular skin checks are important for early detection.
Symptoms & clinical features
Melanoma can appear as a new mole or a change in an existing mole. Key characteristics to look out for are often summarised by the 'ABCDE' rule: Asymmetry (one half does not match the other), Border irregularity (edges are ragged, notched, or blurred), Colour variation (uneven colour, shades of brown, black, tan, red, white, or blue), Diameter (greater than 6mm, though melanomas can be smaller), and Evolving (changes in size, shape, colour, or elevation, or new symptoms like bleeding, itching, or crusting). Any suspicious skin changes should be promptly evaluated by a healthcare professional [PMID:31700201].
Video: Is cancer in your genes?
Affected organs
Melanoma primarily affects the skin. However, it can occasionally develop in other parts of the body where melanocytes are present, such as the eyes (ocular melanoma) or mucous membranes (mucosal melanoma), which include the lining of the nose, mouth, and genital areas. If melanoma spreads beyond its original site, it can affect nearby lymph nodes and eventually distant organs like the lungs, liver, or brain.
Risks & severity
The lifetime risk of developing melanoma in the UK is approximately 1 in 35 for men and 1 in 41 for women. The severity of melanoma largely depends on how early it is diagnosed and treated. Superficial melanomas caught in their early stages often have a very good prognosis. However, if melanoma progresses and spreads, it becomes more challenging to treat and can be life-threatening. Factors increasing risk include a history of severe sunburns, having many moles or atypical moles, a family history of melanoma, and certain genetic predispositions [PMID:31700201]. Age of onset is variable, but risk generally increases with age, particularly after 50 years.
Genetic causes
Melanoma development can be influenced by multiple genes acting together with environmental factors, a pattern known as polygenic or complex inheritance. Several genes have been identified that contribute to an individual's susceptibility. For example, *CDKN2A* plays a crucial role in regulating cell growth and preventing tumour formation. Pathogenic changes in *CDKN2A* are strongly linked to increased melanoma risk, particularly in families with a history of the disease [PMID:30541731]. Other genes, such as *IRF4*, *MC1R*, and *OCA2*, are also associated with melanoma risk. *MC1R* is notably involved in determining skin and hair colour, and certain variants are associated with red hair, fair skin, and an increased susceptibility to UV damage and melanoma [PMID:24107693]. These genes, individually and in combination, contribute to an overall genetic predisposition, interacting with lifestyle factors to influence risk.
Inheritance pattern
Melanoma risk is generally considered to follow a polygenic or complex inheritance pattern. This means that multiple genes, each contributing a small effect, combine with environmental factors to determine an individual's overall risk. Unlike single-gene disorders, it's not a simple case of inheriting one faulty copy of a gene. Instead, individuals may inherit a combination of common genetic variations that, together, increase their susceptibility. This also means that while genetic factors play a role, lifestyle choices, particularly regarding sun exposure, remain very important. Close relatives of someone with melanoma may have a slightly increased risk due to shared genetic predispositions and environmental factors.
Diagnosis & testing
Diagnosing melanoma typically begins with a clinical skin examination by a GP or dermatologist. If a suspicious lesion is identified, a skin biopsy will be performed. This involves removing part or all of the lesion for microscopic examination by a histopathologist. Genetic testing may be considered in specific circumstances, such as for individuals with a strong family history of melanoma, multiple primary melanomas, or melanoma diagnosed at a young age. This testing might identify pathogenic changes in genes like *CDKN2A*, which can significantly inform risk management for the individual and their family. Referrals for genetic testing within the NHS are typically made by clinical genetics services, and relevant R-codes for genetic testing may apply depending on the specific clinical scenario.
Management & lifestyle
Management of melanoma varies based on the stage of the disease. Early-stage melanoma is primarily treated with surgical removal of the tumour. For more advanced stages, treatment options may include further surgery, immunotherapy, targeted therapy, or radiation therapy. Following treatment, regular follow-up appointments and skin examinations are essential to monitor for recurrence or the development of new melanomas. Individuals with an increased genetic risk may be advised to undergo more frequent surveillance and to adopt strict sun protection measures. The NHS offers comprehensive care pathways for cancer patients, typically coordinated by multidisciplinary teams. Genetic counsellors can provide valuable support and information regarding hereditary cancer risks and family planning.
UK care pathway
In the UK, suspected melanoma typically leads to prompt referral to a dermatologist or skin cancer specialist within the NHS. If a hereditary predisposition is suspected, patients may be referred to a clinical genetics service. These services assess family history, discuss the availability of genetic testing (which may involve specific R-codes for genes like *CDKN2A*), and provide genetic counselling. Genetic counsellors offer support and information to individuals and families dealing with genetic conditions affecting melanoma risk.
Frequently asked questions
What is polygenic risk for melanoma?
Polygenic risk means that many different genes, each having a small effect, contribute to your overall likelihood of developing melanoma. It's not caused by a single gene, but rather a combination of genetic variations working together with environmental factors, like sun exposure.
Can I reduce my risk of melanoma if I have a genetic predisposition?
Yes, even with a genetic predisposition, you can significantly reduce your risk by adopting sun-safe behaviours. This includes using broad-spectrum sunscreen, wearing protective clothing, seeking shade, and avoiding sunbeds. Regular self-skin checks and professional skin examinations are also important.
Should my family members also be tested if I have a genetic risk factor for melanoma?
If a specific genetic risk factor, like a pathogenic variant in *CDKN2A*, is identified in you, your family members might also be at risk. Clinical genetics services can offer genetic counselling to discuss whether testing is appropriate for your relatives and what the implications would be.
How does sun exposure interact with my genetic risk for melanoma?
Sun exposure, particularly harmful UV radiation, is a major environmental factor that interacts with your genetic makeup. For individuals with certain genetic predispositions, the same amount of sun exposure might lead to a higher risk of cellular damage and melanoma development compared to someone without those genetic factors.
What does it mean if my melanoma is related to genes like *MC1R*?
Variants in *MC1R* are often linked to fair skin, red hair, and a reduced ability to tan, making individuals more susceptible to sun damage and increasing their melanoma risk [PMID:24107693]. It indicates that your natural skin type and response to UV light contribute to your overall melanoma risk profile.
References
- Firnhaber J. Skin Cancer. Primary care. 2025. PMID: 40835287
- Harte M, Knepil G. Skin cancer detection. British dental journal. 2019. PMID: 31605039
- Watson M, Holman DM, Maguire-Eisen M. Ultraviolet Radiation Exposure and Its Impact on Skin Cancer Risk. Seminars in oncology nursing. 2016. PMID: 27539279
- Rohrer TE, Ratner D. Skin cancer. Seminars in cutaneous medicine and surgery. 2011. PMID: 21540014
- O'Leary K. HIV and skin cancer risk. Nature medicine. 2022. PMID: 34992301
- Garrubba C, Donkers K. Skin cancer. JAAPA : official journal of the American Academy of Physician Assistants. 2020. PMID: 31990836
- Yusuf N. Immunomodulation of Skin Cancer. International journal of molecular sciences. 2023. PMID: 37445639
- Wilkinson D. Skin cancer 1. Australian journal of general practice. 2024. PMID: 39099112