Identification of genetic factors involved in morphoeic basal cell and sebaceous gland carcinoma of human eyelid tumours with a view to identifying potential treatment targets

Abstract

Periocular malignancy represents an increasing burden and currently requires disfiguring surgery in an attempt to cure patients. Basal cell carcinoma (BCC) is the commonest cancer worldwide and morphoeic BCC (mBCC) is an aggressive subtype. Sebaceous gland carcinoma (SGC) is a rare, but life-threatening condition that often requires blinding surgery to prevent mortality, especially in the pagetoid subtype.

MBCC has a high risk of local recurrence compared to the more indolent nodular subtype reflected by a different set of driver genes including FLNB and HECTD4. Surrounding mBCC stroma is abnormal, containing mutations in EPHA3 and GLI3. Four common dysregulated pathways detected using both whole exome and RNA sequencing for mBCC were; ‘hedgehog (Hh) signalling pathway’, ‘BCC’, ‘Natural killer cell mediated cytotoxicity’ and ‘Fc Epsilon RI signalling pathway’. Hh mutational profile for nodular BCC was not reflected in the RNA and protein expression. In contrast, Hh overexpression is seen in the tumour and stroma of morphoeic tissue with the latter potentially being partly responsible for its aggressive nature and risk of recurrence that may warrant removal to prevent recurrence.

SGC has a low overall mutational burden, no UV signature and defective mismatch repair signature. Driver genes included TP53, RB1 and the dynein family is a novel driver possibly involved in chromatid segregation as marked chromosomal instability was demonstrated on copy number analysis. Correlation of whole exome and RNA sequencing data demonstrated upregulated ‘cell cycle’, ‘ubiquitin mediated proteolysis’ and ‘wnt signalling’.

Subtype analysis of pagetoid and nodular SGC revealed the histone gene cluster family as important to both. Oncomir hsa-miR-21 was overexpressed in both and loss of hsa-miR-199a occurs in pagetoid. Increased protein expression of HIST1H2BD was seen in both subtypes as was Hh expression. These novel SGC findings support a chromosomally unstable cancer with the ability to invade extracellular matrix.