Abstract
Basal cell carcinoma (BCC) is the most common skin cancer and human malignancy. Although most BCCs are easily managed, some are aggressive locally, require Mohs micrographic surgery, or can even metastasize. In the latter, resistance to Sonic Hedgehog inhibitors may occur. Despite their frequent occurrence in clinical practice, their transcriptional landscape remains poorly understood. By analyzing BCC RNA sequencing data according to clinically important features (all BCCs versus normal skin, high-risk versus low-risk BCCs based solely on histopathological subtypes with aggressive features, advanced versus non-advanced BCCs, and vismodegib-resistant versus vismodegib-sensitive tumors), we have identified novel differentially regulated genes and new targetable pathways implicated in BCC tumorigenesis. Pathways as diverse as IL-17, TLR, Akt/PI3K, cadherins, integrins, PDGF, and Wnt/β-catenin are promising therapeutic avenues for local and systemic agents in managing this common malignancy, including through drug re-purposing of existing medications. We experimentally validated several of these targets as biomarkers in our patient-derived cohort of primary BCC tumors.
Highlights
Basal cell carcinoma (BCC) is the most common skin malignancy and the most frequent of all human cancers [1]
After re-analyzing RNA sequencing (RNA-Seq) data of 75 BCC samples and 34 normal skin samples from the three publicly available datasets (Table S1 for breakdown), we have identified a total of 2,588 genes that were up-regulated and another 2,651 genes that were down-regulated in BCC compared with normal skin (Table S2)
We further confirm the importance of increased sonic hedgehog (Shh) pathway activity for BCC tumorigenesis
Summary
Basal cell carcinoma (BCC) is the most common skin malignancy and the most frequent of all human cancers [1]. The lifetime risk for BCC is estimated to be 30% in individuals with fair (Fitzpatrick I-III) skin [2]. In the autosomal dominant Nevoid BCC syndrome, known as the Gorlin–Goltz syndrome, loss-of-function mutations in PTCH1 (Patched), and less often in PTCH2, SUFU, and SMO (Smoothened) result in GLI-mediated unopposed transcription of Shh target genes [4]. In sporadic BCCs, the central role of PTCH1 mutations in carcinogenesis has been confirmed by exome sequencing [5]. In addition to the Shh pathway, TP53 is suggested to play a role in sporadic BCC [6, 7], likely through direct inhibition of GLI transcription factors [8]
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