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. PTCH1, FLNB, 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 FLNB Filamin domain 24 and a 4-fold reduction in expression compared to normal eyelids in mBCC only. FLNB 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. FLNB is a potential tumour suppressor, with its loss producing a morphoeic phenotype in vitro.