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Updated: Jul 31, 2025
A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
Melanoma in a patient with DNMT3A overgrowth syndrome
David Y Chen1, Leslie A Sutton2, Sai Mukund Ramakrishnan3
1Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri 63110, USA; davidchen@wustl.edu.
Abstract:
Alterations in epigenetic regulators are increasingly recognized as early events in tumorigenesis; thus, patients with acquired or inherited variants in epigenetic regulators may be at increased risk for developing multiple types of cancer. DNMT3A overgrowth syndrome (DOS), caused by germline pathogenic variants in the DNA methyltransferase gene DNMT3A, has been associated with a predisposition toward development of hematopoietic and neuronal malignancies. DNMT3A deficiency has been described to promote keratinocyte proliferation in mice. Although altered DNA methylation patterns are well-recognized in melanoma, the role of DNA methyltransferases in melanoma pathogenesis is not clear. We report the case of an adult DOS patient with a germline DNMT3A loss-of-function mutation, who developed an early-onset melanoma with regional lymph node metastatic disease. Exome sequencing of the primary tumor identified an additional acquired, missense DNMT3A mutation in the dominant tumor clone, suggesting that the loss of DNMT3A function was relevant for the development of this tumor.
Insights
Patients with DNMT3A overgrowth syndrome (DOS), caused by DNA methyltransferase gene variants, may have increased cancer risk. A DOS patient developed early-onset melanoma, suggesting a link between DNMT3A dysfunction and melanoma development.
Area of Science:
- Epigenetics and Cancer Genomics
- Dermatology and Oncology
Background:
- Epigenetic regulator alterations are early tumorigenesis events, increasing cancer risk in individuals with germline variants.
- DNMT3A overgrowth syndrome (DOS), due to germline DNA methyltransferase 3A (DNMT3A) variants, is linked to hematopoietic and neuronal malignancies.
- DNMT3A deficiency promotes keratinocyte proliferation in mice, but its role in melanoma pathogenesis remains unclear.
Observation:
- An adult DOS patient with a germline DNMT3A loss-of-function mutation developed early-onset melanoma with metastasis.
- Exome sequencing revealed an acquired DNMT3A missense mutation in the primary tumor's dominant clone.
Findings:
- The study suggests that dual DNMT3A dysfunction (germline and acquired) is implicated in melanoma development.
- Loss of DNMT3A function appears relevant to the pathogenesis of melanoma in this DOS patient.
Implications:
- This case highlights a potential role for DNA methyltransferases in melanoma, particularly in individuals with underlying epigenetic regulatory disorders.
- Further research into DNMT3A's function in melanoma could reveal novel therapeutic targets for epigenetic-driven cancers.
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