Mutational landscape of aggressive cutaneous squamous cell carcinoma
Open accessPublished version of a preprint
Abstract
PURPOSE: Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC. EXPERIMENTAL DESIGN: Whole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias. RESULTS: Despite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion. CONCLUSIONS: The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC.
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Whole-exome sequencing found a mutational landscape consistent with prior cSCC studies.
“Whole-exome sequencing found a mutational landscape consistent with prior cSCC studies (Lee et al., 2014, Li et al., 2015, Pickering et al., 2014, South et al., 2014) (Figures S1D–S1F).”
From Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma (2020) · cites this paper as Pickering et al., 2014
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- Authors
- Pickering, C. R., Zhou, J. H., Lee, J. J., Drummond, J. A., Peng, S. A., Saade, R. E., Tsai, K. Y., Curry, J. L., Tetzlaff, M. T., Lai, S. Y., Yu, J., Muzny, D. M., Doddapaneni, H., Shinbrot, E., Covington, K. R., Zhang, J., Seth, S., Caulin, C., Clayman, G. L., El-Naggar, A. K., Gibbs, R. A., Weber, R. S., Myers, J. N., Wheeler, D. A., & Frederick, M. J.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Baylor College of Medicine (US)
- 1Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 2Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Corresponding author
- Wheeler, David A.
- Frederick, Mitchell J.
- ORCID
- Pickering, Curtis R.
- Zhou, Jane H.
- Drummond, Jennifer A.
- Peng, S. Andrew
- Saade, Rami E.
- Tsai, Kenneth Y.
- Curry, Jonathan L.
- Tetzlaff, Michael T.
- Lai, Stephen Y.
- Yu, Jun
- Muzny, Donna M.
- Doddapaneni, Harshavardhan
- Shinbrot, Eve
- Covington, Kyle R.
- Zhang, Jianhua
- Seth, Sahil
- Clayman, Gary L.
- Gibbs, Richard A.
- Weber, Randal S.
- Myers, Jeffrey N.
- Wheeler, David A.
- Frederick, Mitchell J.
- Venue
- Clinical Cancer Research
- Published
- 2014-12-14
- Volume
- 20
- Issue
- 24
- Pages
- 6582-6592
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4367811
- OpenAlex
- W2157466346
- Cited by
- 612
- References
- 33
- Citations by year
- 2026: 30 · 2025: 34 · 2024: 49 · 2023: 51 · 2022: 71 · 2021: 81 · 2020: 80 · 2019: 66 · 2018: 54 · 2017: 34 · 2016: 39 · 2015: 19 · 2014: 1 · 2013: 1
- FWCI
- 23.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Clinical Cancer Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA097007, P30CA0CA16672, T32CA163185, P30CA016672)
- National Institute of Dental and Craniofacial Research (RC2DE020958)
- Topics
- Health Sciences › Medicine › Epidemiology › Nonmelanoma Skin Cancer Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Dermatology › Cancer and Skin Lesions
- Keywords
- cutaneous squamous cell carcinoma, mutational landscape, driver genes, tumor suppressor, KMT2C, Notch1, Notch2, PARD3, RASA1, TP53, CDKN2A, HRAS, caspase-8, FAT1, Ajuba, bone invasion, UV mutagenesis, therapeutic target, prognosis
- MeSH terms
- Carcinoma, Squamous Cell, Humans, Mutation, Prognosis, Skin Neoplasms, Cluster Analysis, Disease Progression, Computational Biology, Genomics, DNA Copy Number Variations, High-Throughput Nucleotide Sequencing, Exome
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