Distinct driver genes and the expression of Hedgehog defines morphoeic basal cell carcinoma

Morphoeic basal cell carcinoma (mBCC) has a high risk of local recurrence compared to the more indolent nodular subtype. Little is known about the genetic and molecular makeup of mBCC that determines its invasive behaviour; this study represents the first comprehensive analysis of mBCC within the periocular region. A specific set of driver genes were found in mBCC including FLNB and HECTD4 leading to a loss of function. NodBCC had a different set of driver genes including TP53, FADS1 and PPM1D. BCC located within the face confers a higher risk especially within the H zone, however, this did not confer a higher UV signature or mutational burden. Wnt signalling and natural killer cell cytotoxicity (NK) were two common pathways in nodular and mBCC. NK importance may be greater in mBCC and represents a novel therapeutic target. Aberrant Hedgehog (Hh) pathway signalling was shown to be more critical in mBCC than nodBCC on three molecular levels: mutational burden, transcriptome profile and protein expression. Surrounding mBCC stroma is abnormal, containing mutations in EPHA3, ATR, and GLI3. Hh pathway over-expression is seen in the tumour and stroma of morphoeic tissue, but not nodular, with the stroma potentially contributing to the morphoeic’s aggressive nature and local recurrence risk. These findings have implications for clinical practice by highlighting novel therapeutic targets for mBCC and the potential need to remove surrounding stroma to prevent local recurrence.