Verrucous carcinoma in epidermolysis bullosa simplex is possibly associated with a novel mutation in the keratin 5 gene

Abstract

Epidermolysis bullosa simplex (EBS) is mainly caused by mutations in the KRT5 and KRT14 genes. Squamous cell carcinoma (SCC) represents the second most frequent skin neoplasia with complex aetiology. The molecular events disrupting the orchestrated interplay between the cytoskeleton, cell adhesion molecules and signalling proteins are ill understood in SCC. We describe the molecular background and the unusual course of the disease in a patient with EBS Dowling-Meara, severe keratoderma and a massive verrucous carcinoma. Skin and tumour samples from the patient were analysed using light microscopy, immunohistochemistry and immunofluorescence mapping. Mutation analysis of the KRT5 and KRT14 genes identified the novel KRT5 mutation p.E477D. Invasive tumour areas were characterized by downregulation of keratins 5 and 14, reduced and irregular desmocollin-2 expression and increased expression of keratins 6, 16 and 17. Levels of Ki-67 were increased and levels of E-cadherin strongly reduced in the tumour tissue. In this case a novel KRT5 mutation led to increased fragility of keratinocytes. Desmosome and adherens junctions were destabilized, which may trigger keratinocyte-mediated inflammation, possibly via p120-catenin-dependent signalling, suggesting a link between a keratin mutation and SCC, which adds weight to the hypothesis that disturbance of the cytoskeleton represents a major cause in the appearance of the malignant phenotype. Some individuals with EBS may be at risk of developing secondary SCC.

Epidermolysis bullosa simplex–generalized severe type due to keratin 5 p.Glu477Lys mutation: Genotype‐phenotype correlation and in silico modeling analysis

“…In addition to the p.Glu477Lys mutation in K5 reported here and by others, two other missense mutations at the 477 position in exon 7 have been reported . Schumann et al describe a heterozygote for p.Glu477Asp.…”

“…In addition to the p.Glu477Lys mutation in K5 reported here and by others, two other missense mutations at the 477 position in exon 7 have been reported . Schumann et al describe a heterozygote for p.Glu477Asp. This mutation replaces an acidic, negatively charged amino acid (glutamic acid) by another acidic, negatively charged amino acid (asparagine), which may result in less drastic changes in dimer and tetramer formation and a less severe phenotype.…”

“…In addition to the p.Glu477Lys mutation in K5 reported here and by others, two other missense mutations at the 477 position in exon 7 have been reported. 10,37 Schumann et al 37 The K5 p.Glu477Gly mutation identified in this patient predicts a glutamic acid to glycine substitution. Because glycine is a small and amphoteric amino acid residue, this substitution may be less deleterious than glutamic acid to lysine, despite being at the same location.…”

Distinct Impact of Two Keratin Mutations Causing Epidermolysis Bullosa Simplex on Keratinocyte Adhesion and Stiffness

“…The K5p.Glu477Asp mutation in the helix termination motif of K5 causes severe generalized EBS accompanied by massive verrucous carcinoma (Schumann et al, 2012). The mechanisms by which these and additional mutations cause EBS and contribute to the very rare occurrence of basal cell or squamous cell carcinoma (Stacey et al, 2009;Baek et al, 2011;Schumann et al, 2012;Fine et al, 2009) remain incompletely understood.…”

Phenotypic spectrum of epidermolysis bullosa associated with α6β4 integrin mutations

“…Immunofluorescence staining of skin was performed using a panel of antibodies to components of the epidermal basement membrane zone as described previously. 18 The antibodies for a6b4 integrin were the monoclonal b4 integrin antibody 3E1 (Gibco, Karlsruhe, Germany) and monoclonal a6 integrin antibody NKI-GoH3 (Chemicon/Millipore, Temecula, CA, U.S.A.). The staining was observed with an Axiophot â fluorescence microscope (Carl Zeiss, G€ ottingen, Germany).…”