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Genomic analysis reveals novel secondary drivers and progression pathways in skin basal cell carcinoma

Basal cell carcinoma of the skin (BCC) is the most common malignant neoplasm in humans. BCC is primarily driven by the aberrant activation of the Sonic Hedgehog (Hh) pathway. However, its extensive phenotypical variation remains to be explained. The genetic profiling of 293 BCCs revealed the highest mutation rate observed in cancer (65 Mutations/Mb), with strong prevalence of UV-light signature mutations. 85% of BCCs harbored mutations in Hh pathway genes: mutually exclusive PTCH1 (73%) and SMO (20%) (P=6.6x10-8), SUFU (8%), and in TP53 (61%). 85% of BCCs also harbored secondary driver mutations in other genes implicated in BCC tumorigenesis. Recurrent secondary driver mutations were observed in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), RAC1 (1%) and N/K/H-RAS (2%). Loss of function (LoF) and deleterious missense mutations were observed in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). In line with the mutational profiles detected by RNAseq, we observed activation of the Hh pathway as well as upregulation of target genes of the Hippo-YAP pathway and activation of MYCN target genes. The functional analysis of the novel tumorigenic driver mutations in MYCN, PTPN14 and LATS1 demonstrates their relevance in BCC tumorigenesis and provides an expanded molecular understanding of BCC.

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Dataset ID Description Technology Samples
EGAD00001001857 Illumina HiSeq 2000 381
Publications Citations
In silico analyses of the tumor microenvironment highlight tumoral inflammation, a Th2 cytokine shift and a mesenchymal stem cell-like phenotype in advanced in basal cell carcinomas.
J Cell Commun Signal 14: 2020 245-254
The transcriptional landscape analysis of basal cell carcinomas reveals novel signalling pathways and actionable targets.
Life Sci Alliance 4: 2021 e202000651
c-FOS drives reversible basal to squamous cell carcinoma transition.
Cell Rep 37: 2021 109774
Comparison of the Basal Cell Carcinoma (BCC) Tumour Microenvironment to Other Solid Malignancies.
Cancers (Basel) 15: 2023 305