Genetic Testing For Melanoma: Who To Test And Key Steps

Genetic testing plays a crucial role in identifying individuals at heightened risk for melanoma, particularly those with familial histories or multiple primary tumours. It examines germline mutations in genes like CDKN2A, BAP1, and others to guide screening, prevention, and management strategies.

What is genetic testing for melanoma?

Genetic testing for melanoma involves analysing DNA from blood, saliva, or tumour tissue to detect inherited (germline) or acquired (somatic) mutations associated with melanoma development. Germline tests assess normal cells for hereditary predispositions, while somatic tests evaluate tumour DNA for prognostic and therapeutic insights. This distinguishes between sporadic cases (~90-95% of melanomas) and hereditary forms, which account for 5-10% but up to 20% in familial clusters.

Key purposes include risk stratification, identifying carriers for intensified surveillance, and informing targeted therapies. For instance, germline panels target genes linked to syndromes like familial atypical multiple mole melanoma (FAMMM) and BAP1 tumour predisposition syndrome.

Who should consider genetic testing?

Testing is recommended for high-risk individuals, not routine for all melanoma patients. Criteria include:

• Personal history of 2 or more invasive melanomas.
• Family history of 3+ melanomas in first- or second-degree relatives.
• Melanoma with onset before age 40, especially with atypical/dysplastic nevi.
• Melanoma combined with pancreatic cancer or ocular melanoma in family.
• Presence of BAPoma syndrome features (uveal melanoma, mesothelioma, renal cancer).

Dermatologists with training can initiate testing in clinics, alongside genetic counsellors. Experts advise against population-wide screening due to low yield in low-risk groups.

Genes associated with hereditary melanoma

Several genes confer susceptibility:

Multi-gene panels increase diagnostic yield to 10-40% in high-risk families.

Types of genetic tests

Germline panels: Comprehensive panels like Melanoma Comprehensive Panel (14 genes: BAP1, BRCA2, CDK4, CDKN2A, MITF, POT1, TP53) or Riskguard (56 genes for multiple cancers).

Somatic/prognostic tests:

• DecisionDx-Melanoma: 31-gene expression profile (GEP) for stage I-III melanoma; predicts recurrence, sentinel lymph node (SLN) positivity (low-risk: 2.8% rate vs. 6.2% for alternatives). Associated with improved survival per NCI-SEER data.
• MyPath Melanoma: 23-gene test for ambiguous melanocytic lesions (benign vs. malignant).
• Merlin: Assesses low-risk pT1-T3 melanomas to avoid SLNB.

Tumour testing for BRAF V600 (40-50% of cases), KIT, NRAS guides targeted therapies like BRAF inhibitors.

How is the test done?

Germline testing uses a simple blood draw or saliva swab ordered by a provider. Tumour tests require formalin-fixed paraffin-embedded (FFPE) tissue from biopsy/resection. Results take 2-6 weeks; pre- and post-test counselling is essential to discuss variants of uncertain significance (VUS), incidental findings, and insurance implications.

Interpreting test results

Results classify as:

• Pathogenic variant: Confirms hereditary risk; carriers need annual full-body exams from age 10-20, sun protection, chemoprevention trials.
• VUS: ~20-30%; reclassification possible over time.
• Negative: Lowers but doesn’t eliminate risk; continue standard screening.

Family cascade testing identifies at-risk relatives.

Management for mutation carriers

Carriers require tailored strategies:

• CDKN2A: Dermatologic screening q3-6 months; pancreatic screening (MRI/EUS) from age 50.
• BAP1: Ocular exams, renal imaging.
• All: Strict UV avoidance, self-exams, consider prophylactic excision of suspicious nevi.

Studies show carriers improve sun protection and screening post-testing.

Benefits and limitations

Benefits: Personalized risk assessment, early detection, family planning, trial eligibility.

Limitations: High VUS rate, incomplete penetrance (e.g., CDKN2A penetrance 14-67%), cost (~$250-$5000), potential discrimination (GINA protects in US).

Prognostic GEPs like DecisionDx outperform AJCC8 staging.

Guidelines for genetic testing

NCCN recommends testing for select families; mainstreaming to dermatology advocated amid rising demand. Panels preferred over single-gene tests.

Frequently Asked Questions (FAQs)

What genes are tested in melanoma panels?

Common genes include CDKN2A, CDK4, BAP1, POT1, MITF, TP53, BRCA2.

Is genetic testing covered by insurance?

Often yes for NCCN criteria; prior authorization needed.

Does a negative test mean no melanoma risk?

No; environmental factors dominate in sporadic cases.

How does DecisionDx-Melanoma help?

It stratifies recurrence/SLN risk, potentially sparing low-risk patients SLNB.

Should children of carriers be tested?

Typically after age 18; earlier if family history extreme.

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medha deb

 

Medha Deb is an editor with a master's degree in Applied Linguistics from the University of Hyderabad. She believes that her qualification has helped her develop a deep understanding of language and its application in various contexts.

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