Dissecting the genetic factors of IBCC to aid in understanding its aggressive nature and identify new personalised treatment modalities

Fresh frozen tissue was taken from 20 BCC patients. Whole exome sequencing of 10 nodular (nBCC) and 10 morphoeic BCC were carried out followed by a transcriptome analysis using RNA sequencing (n=6). Differential expression (DE) from normal eyelid stroma was deemed significant if P1 or <-1. Quantitative RT-PCR and protein immunohistochemistry was performed for validation.

Tumour mutational burden is 1533, 2073 and UV signature is 88%, 85% for IBCC, nBCC respectively. Novel IBCC drivers include SMARCA4 and EPHA3. DE was 288 and 276 genes for IBCC and nodBCC compared to stoma respectively. Comparing subtypes, 128 genes were differentially expressed, with the majority up regulated in IBCC including EPHB4. Shared genes include VCAN. Hedgehog (Hh) pathway protein expression was greater in IBCC including the surrounding non-tumour tissue. Novel activated pathways include axonal guidance and extracellular matrix receptor interaction (ECM) pathway.

Despite a reduced mutational burden in IBCC, the presence of significant driver mutations may explain its aggressive nature. Furthermore, the hyper expression of the Hh pathway including the surrounding non-tumour tissue may aid its local migration. Axonal guidance and ECM could also play a role in this behaviour. Regardless of trends, the extent of tumour heterogeneity demands personalised genetic mapping of the tumour to direct developing novel treatment modalities such as inhibitors of EPHA3, VCAN, Gli1/2 and EPHB4.