Epidermolysis bullosa (EB) comprises rare genodermatoses associated with widespread blistering due to fragility of the skin. Squamous cell carcinomas (SCC) are major complications of EB. We analysed molecular and mutational signatures of 48 SCC obtained from patients with EB, 10 with recessive dystrophic epidermolysis bullosa (RDEB), seven with Kindler syndrome (KS) and one patient with junctional epidermolysis bullosa (JEB). 
Although we observed significant tumour heterogeneity, some common characteristics emerged. All EB SCC samples showed high EGFR and COX-2 expression, and expression of at least one immune checkpoint, CTLA-4, PD-1 or PD-L1. No correlation of the IDO expression and peritumoral inflammatory infiltrate was observed in EB SCC. Based on these findings, considering the high expression of immune biomarkers in EB SCC, combination therapies of immune checkpoint inhibitors, EGFR inhibitors and the COX-2 anti-inflammatory drug could be potential treatments for EB SCC patients.
The signature of somatic mutations in EB SCC was heterogeneous with widely varying numbers of alterations. All mutational signatures of EB SCC were similar to those of head and neck SCC and UV SCC. KS SCC showed higher tumour mutational burden as compared to RDEB SCC and JEB SCC. The mutational profiles of RDEB SCC and JEB SCC were similar, while KS SCC was distinct. We found recurrently altered genes (TP53, CDKN2A, NOTCH1/2, KNSTRN) but also a wide spectrum of oncogenic mutations affecting cell cycle, DNA damage response, tyrosine kinases, PI3K-AKT-mTOR and RAF-MEK-ERK pathways in all EB SCC.
Taken together, we have immunohistochemically and genetically characterized SCC in a cohort of patients with rare genodermatoses and identified diverse arrays of immune signatures and oncogenic alterations that can guide future studies and potential treatments of this disease.

Molecular and mutational signatures of squamous cell carcinomas in epidermolysis bullosa