Mutational Landscape of Aggressive Cutaneous Squamous Cell Carcinoma

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.

Regulation of RNF144A E3 Ubiquitin Ligase Activity by Self-association through Its Transmembrane Domain

“…It is possible that additional mechanisms might contribute to the regulation of RNF144A. During the preparation of this manuscript, two more somatic mutations, A255fs*30 and L260M, were identified on the TM domain (37,38). It would be very interesting to investigate the potential effects of these somatic mutations.…”

Molecular mechanisms of perineural spread of cutaneous carcinoma: a potential role for receptor tyrosine kinases and other biomarkers

“…(132) One of the major recognised cellular drivers of SCC is loss of function of the tumour suppressor gene TP53. Data supports a strong correlation between solar ultraviolet radiation (UVR) and mutational burden in the p53 gene with up to 90% of squamous cell carcinomas exhibiting p53 mutations.…”

“…(132) The authors concluded that the mutational signature of advanced cSCC is similar to mucosal HNSCC and dominated by tumour suppressor genes, with 8 of the top mutated genes shared between these tumour types. Similarly, an earlier study by Dooley et al (2003) found genetic profiles between oral SCC cell lines and facial cutaneous SCC cell lines to be highly similar across 23…”

WNT Signaling in Cutaneous Squamous Cell Carcinoma: A Future Treatment Strategy?

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