GLI2 and FLNB Define Periocular Morphoeic Basal Cell Carcinoma

Morphoeic basal cell carcinoma (mBCC) has a higher risk of local recurrence than the more indolent nodular (nodBCC) subtype. Little is known about the genetic and molecular makeup of mBCC that determines its invasive behaviour: a comparison of mBCC with nodBCC was carried out. Whole-exome sequencing (WES) of 20 BCC tumours (10 eyelid morphoeic and 10 nodular) underwent driver gene detection using OncodriveFM and MutSigCV, followed by a randomisation analysis procedure. Samples underwent RNA sequencing, gene-set enrichment analysis and candidates verified by RT-PCR. <i>PTCH1</i>, <i>FLNB,</i> and double-knockdown human keratinocyte models were used to validate phenotype and gene expression. Hedgehog pathway analysis of 20 additional BCCs underwent immunostaining verification. Our analysis revealed FLNB as a potential driver with a mutational cluster in <i>FLNB</i> Filamin domain 24 and a 4-fold reduction in expression compared to normal eyelids in mBCC only. <i>FLNB</i> knockdown demonstrated an mBCC phenotype. Aberrant Gli2 dominant hedgehog (Hh) signalling was seen in mBCC on three molecular levels: mutational significance, transcriptome profile, and protein expression. Gli2-dominant Hh overexpression was seen in the tumour plus stroma of eyelid morphoeic but not nodular BCC. <i>FLNB</i> is a potential tumour suppressor, with its loss producing a morphoeic phenotype in vitro.