Supplemental Tables S1-S4 and S6-S13. Supplemental Table S1: Summary of Patient Characteristics. Supplemental Table S2: Patient Characteristics and Key Mutations. Supplemental Table S3: Tumor purity and ploidy calculations. Supplemental Table S4: Sequencing Coverages. Supplemental Table S6: Allele fraction analysis. Supplemental Table S7: MutSig analysis. Supplemental Table S8: IntOGen mutational significance analysis. Supplemental Table S9: Chi-square mutational significance analysis. Supplemental Table S10: Multinomial mutational significance analysis. Supplemental Table S11: Kappa analysis for gene-gene associations. Supplemental Table S12: ABSOLUTE copy number analysis segmentation data. Supplemental Table S13: Clinical and mutation associations.
ARTICLE 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. Clin Cancer Res; 20(24); 6582–92. ©2014 AACR.
