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John Bladen, Michèle Beaconsfield, Edel O’Toole, Michael Philpott; Deciphering the molecular basis of periocular infiltrative basal cell carcinoma. Invest. Ophthalmol. Vis. Sci. 2016;57(12):No Pagination Specified.
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© ARVO (1962-2015); The Authors (2016-present)
Basal cell carcinoma (BCC) is the commonest cancer worldwide and constitutes the vast majority of eyelid tumours. Infiltrative BCC (iBCC) is a particularly aggressive subtype, which invades local tissue and adjacent structures in an uncompromising manner. Little is known about the genetics of iBCC and the differences that render it more aggressive compared to the more benign nodular (nBCC) subtype
Fresh frozen tissue was collected from 20 BCC patients; 10 iBCC and 10 nBCC subtypes. Laser capture microdissection and nucleic acid extraction was performed. Whole exome sequencing of 20 BCC tumour and blood-matched controls were undertaken along with RNA sequencing of 3 iBCC and 3 nBCC tumour and stroma-matched controls. Differential expression (DE) from normal eyelid was deemed significant if P<0.01, Log2FC >1 or <-1. Quantitative RT-PCR and protein immunohistochemistry was performed for validation.
For iBCC and nBCC, the average tumour mutational burden was 1533 and 2073, and UV signature was 88% and 85%, respectively. PTCH1 mutations were present in 80% of IBCC and 60% of nBCC. Novel iBCC driver included EPHA3 in 3 out of 10 patients. DE revealed 288 and 276 genes for iBCC and nBCC compared to normal, respectively. When both subtypes were compared, 128 genes were differentially expressed, with the majority upregulated in iBCC including LAMB3 and EPHB4. Shared genes included VCAN and GPC3. Immunohistochemistry confirmed Hedgehog (Hh) pathway expression, but to a much greater extent in iBCC including the surrounding non-tumour stromal tissue. Two key novel activated pathways were detected; axonal guidance and extracellular matrix (ECM) receptor interaction pathways.
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 compared to nBCC including surrounding non-tumour stromal tissue may aid its local migration. Discovery of novel axonal guidance and ECM receptor interaction pathways 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.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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