Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma
Open accessAbstract
We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1(P29S)) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1(P29S) showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.
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Most mutations in human melanomas show the UV signature of C→T substitutions at adjacent pyrimidines.
“Yet melanin's ROS generating properties do not explain its role in melanoma development because most mutations in human melanomas display the UV signature of C →T substitutions at sites of adjacent pyrimidines (8, 9).”
From Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure (2015) · cites this paper as [9]
The Results (Landscape of nonsynonymous somatic mutations; page unavailable) report an excess of UV-linked C>T mutations at dipyrimidines in sun-exposed melanomas. The Discussion says the UV signature was not detected in acral, mucosal, or ocular melanomas. Thus the source supports the signature in sun-exposed melanomas, but not the claim as stated for human melanomas generally. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPUVA therapy is linked to increased melanoma risk.
“Furthermore, an increased risk of melanoma has also been linked to psoralen and UVA (PUVA) therapy 15.”
From Mechanisms and prevention of <scp>UV</scp>‐induced melanoma (2018) · cites this paper as [15]
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mTORC1 activation blocks BrafV600E-induced growth arrest but is insufficient for melanoma formation
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Germline MC1R status influences somatic mutation burden in melanoma
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KLF4 is regulated by RAS/RAF/MEK/ERK signaling through E2F1 and promotes melanoma cell growth
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- Authors
- Krauthammer, M., Kong, Y., Ha, B. H., Evans, P., Bacchiocchi, A., McCusker, J. P., Cheng, E., Davis, M. J., Goh, G., Choi, M., Ariyan, S., Narayan, D., Dutton-Regester, K., Capatana, A., Holman, E. C., Bosenberg, M., Sznol, M., Kluger, H. M., Brash, D. E., Stern, D. F., Materin, M. A., Lo, R. S., Mane, S., Ma, S., Kidd, K. K., Hayward, N. K., Lifton, R. P., Schlessinger, J., Boggon, T. J., & Halaban, R.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Yale Cancer Center (US)
- University of California, Los Angeles (US)
- QIMR Berghofer Medical Research Institute (AU)
- Corresponding author
- Halaban, Ruth
- ORCID
- Krauthammer, Michael
- Kong, Yong
- Ha, Byung Hak
- Evans, Perry
- Bacchiocchi, Antonella
- McCusker, Jamie P
- Davis, Matthew J
- Goh, Gerald
- Choi, Murim
- Narayan, Deepak
- Holman, Edna C
- Bosenberg, Marcus
- Sznol, Mario
- Kluger, Harriet M
- Brash, Douglas E
- Stern, David F
- Materin, Miguel A
- Lo, Roger S
- Mane, Shrikant
- Ma, Shuangge
- Hayward, Nicholas K
- Lifton, Richard P
- Schlessinger, Joseph
- Boggon, Titus J
- Halaban, Ruth
- Venue
- Nature Genetics
- Published
- 2012-07-29
- Volume
- 44
- Issue
- 9
- Pages
- 1006-1014
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3432702
- OpenAlex
- W2035000040
- Cited by
- 1,191
- References
- 83
- Citations by year
- 2026: 33 · 2025: 34 · 2024: 40 · 2023: 62 · 2022: 60 · 2021: 66 · 2020: 109 · 2019: 98 · 2018: 89 · 2017: 113 · 2016: 118 · 2015: 119 · 2014: 113 · 2013: 113 · 2012: 21
- FWCI
- 47.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA121974)
- U.S. National Library of Medicine (T15LM007056)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- melanoma, somatic mutations, Rac1, UV-induced mutations, mutational landscape, PPP6C, BRAF, NRAS, melanocyte proliferation, melanocyte migration, acral melanoma, uveal melanoma, mucosal melanoma
- MeSH terms
- Uveal Melanoma, Aged, Aged, 80 and over, DNA Mutational Analysis, Female, Gene Frequency, Humans, Male, Melanoma, Middle Aged, Models, Molecular, Mutation, Skin Neoplasms, Uveal Neoplasms, Case-Control Studies, Proto-Oncogene Proteins p21(ras), Sequence Analysis, DNA, Genetic Predisposition to Disease, rac1 GTP-Binding Protein, Proto-Oncogene Proteins B-raf, Exome
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