GLI2 and FLNB Define Periocular Morphoeic Basal Cell Carcinoma

Area of Science:

• Dermatology
• Oncology
• Molecular Biology

Background:

• Morphoeic basal cell carcinoma (mBCC) shows higher recurrence rates than nodular BCC (nodBCC).
• The genetic and molecular factors driving mBCC invasiveness remain largely uncharacterized.
• Understanding these factors is crucial for developing targeted therapies.

Purpose of the Study:

• To compare the genetic and molecular profiles of mBCC and nodBCC.
• To identify potential driver genes and molecular pathways involved in mBCC behavior.
• To elucidate the role of FLNB and Hedgehog signaling in mBCC pathogenesis.

Main Methods:

• Whole-exome sequencing (WES) and RNA sequencing of 20 BCC tumors (10 mBCC, 10 nodBCC).
• Bioinformatic analyses including driver gene detection (OncodriveFM, MutSigCV) and gene-set enrichment analysis.
• Experimental validation using RT-PCR, keratinocyte models, and immunostaining for Hedgehog pathway analysis.

Main Results:

• FLNB identified as a potential driver gene with a mutational cluster in Filamin domain 24.
• mBCC showed a significant reduction in FLNB expression compared to normal eyelids.
• FLNB knockdown in keratinocytes induced an mBCC-like phenotype.
• Aberrant, Gli2-dominant Hedgehog signaling was observed in mBCC on multiple molecular levels.

Conclusions:

• FLNB acts as a potential tumor suppressor; its loss contributes to the morphoeic phenotype.
• Aberrant Hedgehog pathway activation, driven by Gli2, is a key feature of mBCC.
• These findings highlight FLNB and Hedgehog signaling as potential therapeutic targets for mBCC.