What is the significance of the genetic component in melanoma and other skin cancers?

From the Guidelines

The genetic component in melanoma and other skin cancers is highly significant, substantially influencing both risk and treatment approaches, with approximately 10% of melanoma cases having a hereditary basis. The significance of the genetic component in melanoma and other skin cancers can be understood by looking at the risk factors and treatment approaches. According to 1, risk factors for melanoma include skin type, personal history of prior melanoma, multiple clinically atypical moles or dysplastic nevi, a positive family history of melanoma, and, rarely, inherited genetic mutations.

Key Points

• Approximately 10% of melanoma cases have a hereditary basis, with mutations in genes like CDKN2A, CDK4, and BAP1 increasing lifetime risk by up to 70% 1.
• Familial melanoma often presents with multiple primary tumors, earlier onset (before age 40), and distinctive patterns such as multiple atypical nevi.
• For patients with family history of melanoma, genetic testing may be warranted, particularly if there are multiple affected relatives or early-onset cases.
• Beyond hereditary factors, acquired genetic mutations in genes like BRAF (present in about 50% of melanomas) and NRAS have revolutionized treatment approaches, enabling targeted therapies such as BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (trametinib, cobimetinib) that significantly improve survival in advanced disease.

Treatment Approaches

Understanding a patient's genetic profile also helps determine immunotherapy effectiveness, as tumor mutational burden often correlates with response to checkpoint inhibitors like pembrolizumab and nivolumab. For non-melanoma skin cancers, genetic syndromes like xeroderma pigmentosum and basal cell nevus syndrome dramatically increase cancer susceptibility and require specialized management approaches including enhanced surveillance and early intervention. As noted in 1, genetic counseling could be considered for individuals with a strong family history of invasive melanoma or pancreatic cancer.

Prevention

Behavioral counseling interventions aimed at reducing UV radiation exposure, such as using broad-spectrum sunscreen, wearing hats or other shade-protective clothing, avoiding the outdoors from 10 a.m. to 3 p.m., and avoiding indoor tanning, can moderately increase the use of sun-protective behaviors, especially in children, adolescents, and young adults 10 to 24 years of age, as found in 1. Therefore, considering the genetic component is crucial in the management and prevention of melanoma and other skin cancers.

From the Research

Genetic Component of Melanoma and Other Skin Cancers

The genetic component of melanoma and other skin cancers is significant, with an estimated 5%-10% of all cutaneous melanoma cases occurring in families 2, 3, 4.

• High-Penetrance Susceptibility Genes: The major high-penetrance susceptibility gene involved in melanoma predisposition is CDKN2A, with germline mutations identified in 20%-40% of melanoma families 2.
• Other Susceptibility Genes: Mutations in other genes, such as CDK4, BAP1, TERT, POT1, ACD, TERF2IP, and MITF, are rare and contribute to a further 10% of familial clustering of melanoma 2, 3.
• Genetic Testing: Genetic testing for melanoma is currently recommended only for CDKN2A and CDK4, with the role of multigene panel testing remaining under debate 2.
• Genetic Counseling: Individuals from melanoma families must receive genetic counseling to be informed about the inclusion criteria for genetic testing, the probability of an inconclusive result, and the genetic risk for melanoma and other cancers 2, 4.

Clinical and Dermoscopic Features

• Dermoscopic Patterns: Patients with CDKN2A germline mutations may develop specific clinical and dermoscopic features, such as high atypical nevus counts and specific dermoscopic patterns 3, 5.
• Multiple Primary Melanomas: Patients who develop multiple primary melanomas may have a higher risk of carrying a CDKN2A germline mutation, and dermoscopy can be useful in identifying these patients 5.

Prevention and Detection Behaviors

• Genetic Testing and Counseling: Genetic testing and counseling may increase skin self-examinations and sun protection habits in individuals with a family history of melanoma 6.
• Skin Cancer Prevention: Patients at risk of melanoma should be encouraged to adhere to a correct ultraviolet exposure, skin self-examination, and regular dermatological screening 2, 4.