The Genetic Evolution of Melanoma from Precursor Lesions
- 1From the Departments of Dermatology and Pathology (A.H.S., I.Y., E.T., A.G., J.N., L.P., B.R., B.C.B.) and the Helen Diller Family Comprehensive Cancer Center (A.H.S., I.Y., E.T., A.G., B.C.B.), University of California, San Francisco (UCSF), San Francisco; the Departments of Dermatology and Pathology, Cleveland Clinic, Cleveland (I.K.); the Department of Pathology, Orlando Health, Orlando, FL (A.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); and the Department of Dermatology, Dorset County Hospital, Dorchester (C.D.), and the Department of Dermatology, St. John's Institute of Dermatology, London (W.R., A.R.) - both in the United Kingdom.
- 0From the Departments of Dermatology and Pathology (A.H.S., I.Y., E.T., A.G., J.N., L.P., B.R., B.C.B.) and the Helen Diller Family Comprehensive Cancer Center (A.H.S., I.Y., E.T., A.G., B.C.B.), University of California, San Francisco (UCSF), San Francisco; the Departments of Dermatology and Pathology, Cleveland Clinic, Cleveland (I.K.); the Department of Pathology, Orlando Health, Orlando, FL (A.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); and the Department of Dermatology, Dorset County Hospital, Dorchester (C.D.), and the Department of Dermatology, St. John's Institute of Dermatology, London (W.R., A.R.) - both in the United Kingdom.
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View abstract on PubMed
Summary
This summary is machine-generated.Melanoma progression involves a specific order of genetic mutations, starting with BRAF or NRAS and TERT promoter mutations, and is strongly linked to ultraviolet radiation exposure.
Area Of Science
- Oncology
- Dermatology
- Genetics
Background
- The order of pathogenic mutations in melanoma development is largely unknown.
- Understanding melanoma's genetic progression is crucial for targeted therapies.
Purpose Of The Study
- To define the sequence of genetic alterations during melanoma progression.
- To identify key mutations and their timing in melanoma development.
- To investigate the role of ultraviolet radiation in melanoma evolution.
Main Methods
- Sequencing of 293 cancer-relevant genes in 37 primary melanomas and precursor lesions.
- Histopathological analysis of benign, intermediate, and malignant melanocytic lesions.
- Assessment of mutation burden, TERT promoter mutations, CDKN2A inactivation, and copy-number alterations.
Main Results
- Melanoma initiation involves mitogen-activated protein kinase pathway mutations (BRAF V600E in benign, NRAS in intermediate lesions).
- TERT promoter mutations are frequent in early-stage intermediate lesions and melanoma in situ.
- CDKN2A inactivation occurs in invasive melanomas, while PTEN and TP53 mutations are found in advanced stages.
- Ultraviolet radiation signature is present throughout melanoma progression, and copy-number alterations increase with invasiveness.
Conclusions
- A defined order of genetic alterations drives melanoma progression, with distinct subtypes showing different evolutionary paths.
- An intermediate category of melanocytic neoplasia is identified, characterized by multiple genetic hits and specific histopathology.
- Ultraviolet radiation is a significant factor in both the initiation and progression of melanoma.
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