Objectives : Basal cell carcinoma of the skin (BCC) is the most common malignant neoplasm in humans. BCC is primarily driven by aberrant activation of the Sonic Hedgehog (Hh) pathway. However, its extensive phenotypical variation remains to be explained.

Methods : 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.

Results : 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 additional driver mutations in other genes implicated in BCC tumorigenesis. Recurrent 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 DNA sequencing, 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 in RNAseq experiments.

Conclusion : 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.