What is the clinical significance of TERT, SPEN, PARP4, MGA, FANCG, CSMD3, MRE11, PTCH1, and ZFHX3 gene mutations in a melanoma tumor?

Clinical Significance of Melanoma Tumor Mutations

The TERT promoter mutation (C228T) in this melanoma is the most clinically significant finding, as it is a Tier 1/2 actionable mutation associated with aggressive disease, poor prognosis, and increased risk of metastasis, while the remaining mutations are variants of uncertain significance (VUS) that currently lack established clinical utility for treatment decisions. 1

Key Actionable Mutation: TERT Promoter

TERT promoter C228T mutation (13% variant allele frequency):

• This mutation creates a new binding site for transcription factors that increases telomerase expression by up to twofold, allowing melanoma cells to maintain telomere length and achieve cellular immortality 2
• TERT promoter mutations occur in 74% of metastatic melanoma cell lines, 85% of metastatic tumor tissues, and 33% of primary melanomas, making this one of the most common non-coding mutations in melanoma 2
• This mutation associates with increased patient age, greater Breslow thickness, tumor ulceration, and sun-exposed anatomical sites—all parameters connected with poor clinical outcomes 3
• The mutation tends to co-occur with BRAF and CDKN2A alterations, suggesting cooperative oncogenic mechanisms 3
• Patients with TERT promoter mutations have reduced survival and increased risk of disease progression, establishing this as a negative prognostic marker 4, 5

Variants of Uncertain Significance (VUS)

The remaining mutations (SPEN, PARP4, MGA, FANCG, CSMD3, MRE11, PTCH1, ZFHX3) are all classified as VUS:

• VUS designation means these genetic changes have insufficient evidence to determine whether they are pathogenic, benign, or clinically neutral 6
• These mutations are not currently actionable for treatment decisions and should not influence therapeutic choices 1
• While some genes (PTEN, NF1, CDK4, CDKN2A) are recognized as important in melanoma pathogenesis, the specific variants listed here lack validation as pathogenic mutations 6

Clinical Management Implications

Molecular testing priorities according to ESMO guidelines:

• BRAF testing is mandatory for all stage III and IV melanoma patients, as this directly determines eligibility for targeted therapy with BRAF/MEK inhibitors 1
• If BRAF is wild-type at V600, testing for NRAS and c-KIT mutations is recommended to identify patients for clinical trials 1
• The TERT promoter mutation identified here does not currently have FDA-approved targeted therapies, but it provides important prognostic information and may qualify the patient for clinical trials investigating telomerase inhibitors 4

Prognostic Interpretation

This mutation profile suggests:

• The presence of TERT promoter mutation indicates biologically aggressive disease with higher metastatic potential 3, 5
• The low variant allele frequency (13%) suggests this mutation may be present in a subclone of tumor cells, though it remains clinically significant 3
• More intensive surveillance and consideration of adjuvant therapy may be warranted given the adverse prognostic implications 4, 5

Critical Pitfalls to Avoid

• Do not make treatment decisions based on VUS mutations, as their clinical significance remains unproven 6
• Do not assume the absence of BRAF V600 mutations means no targetable alterations exist—testing for class II and III BRAF mutations, NRAS, and c-KIT should be performed 1
• Do not overlook the prognostic value of TERT promoter mutations when counseling patients about disease trajectory and surveillance intensity 3, 5
• Ensure mutation analysis was performed in an accredited laboratory with appropriate quality controls, as required by ESMO guidelines 1