Patients with Recessive Dystrophic Epidermolysis Bullosa Develop Squamous-Cell Carcinoma Regardless of Type VII Collagen Expression

Abstract

Recent data suggest that individuals with recessive dystrophic epidermolysis bullosa (RDEB) only develop squamous-cell carcinoma (SCC) in the presence of the NC1 domain of type VII collagen. This conclusion was based on experimental work in which cryosections of SCCs from 10 people with RDEB all showed positive type VII collagen immunostaining and observations in a murine model of SCC development in which tumors only occurred using keratinocytes from RDEB subjects that expressed detectable levels of the NC1 domain of the type VII collagen protein. To assess whether the clinical interpretation was valid in another cohort of RDEB patients, we examined expression of type VII collagen in 17 SCC tumors excised from 11 patients. Indirect immunofluorescent staining of SCC cryosections and Western blotting of cultured keratinocyte lysates identified two RDEB individuals who did not express detectable levels of type VII collagen. Mutation analysis revealed that these two patients harbor compound heterozygous nonsense mutations within the region of the COL7A1 gene encoding the NC1 domain. These data suggest that individuals with RDEB can develop SCC regardless of type VII collagen expression and that additional factors have a role in explaining the high incidence of tumors complicating this genodermatosis.

Increased invasive behaviour in cutaneous squamous cell carcinoma with loss of basement-membrane type VII collagen

“…This hypothesis was challenged by work demonstrating that ColVII, specifically its NC1 domain, is required for Ras-driven human skin tumourigenesis and invasion using RDEB keratinocytes co-expressing activated Ha-Ras and the NFκB inhibitor, IκBα, xenotransplanted on immunodeficient mice (OrtizUrda et al, 2005). Ha-Ras mutations have a frequency of less than 10% in sporadic SCCs (Campbell et al, 1993;van der Schroeff et al, 1990) and so far have not been detected in RDEB-associated SCCs (Pourreyron et al, 2007). Hence, it is not known whether NC1 expression is required for tumourigenesis in models of RDEB SCC other than the Ha-Ras/IκBα model.…”

“…Hence, it is not known whether NC1 expression is required for tumourigenesis in models of RDEB SCC other than the Ha-Ras/IκBα model. In fact, RDEB patients who lack ColVII expression can develop SCC (Pourreyron et al, 2007) and patients with dominant dystrophic epidermolysis bullosa with one normal COL7A1 allele rarely develop SCC (Fine et al, 2009), arguing against the idea that the NC1 domain of ColVII is necessary for tumour formation in RDEB.…”

“…In the same model, a specific domain of the laminin 332 β3 chain binds to ColVII, promoting phosphoinositide-3-kinase signalling (Waterman et al, 2007). More recently, using a panel of RDEB SCC tumour samples, it was demonstrated that some RDEB SCC tumours do not have ColVII expression (Pourreyron et al, 2007).…”

Genetic Predisposition to Cutaneous Squamous Cell Carcinoma

“…Research within our lab has found that the aggressive nature of RDEB SCC cannot be accounted for by the overall prevalence of alpha-or beta-HPV infection through demonstrating comparative data for non-RDEB SCC (Purdie et al, 2010). As discussed in the introduction, various independent studies conducted thus far have revealed heterogeneity in the incidence of RAS mutations in human cSCC and we have been unable to detect RAS mutations in six RDEB SCC patients and four non-RDEB SCC patient samples (Pourreyron et al, 2007). Similar to non-RDEB SCC data a proportion of RDEB tumours harbour TP53 mutation and CDKN2A methylation/ aberrant expression (Arbiser et al, 2004;Watt et al, 2011).…”

“…These results suggested that RDEB patients who still express the NC1 domain may be more susceptible to developing cSCC, while conversely, sg-RDEB patients without any detectable type VII collagen expression will be less likely to develop cSCC. However, it has been demonstrated that RDEB patients without any detectable type VII collagen can still develop cSCCs (Pourreyron et al, 2007;Rodeck and Uitto, 2007). The above studies highlight the importance of type VII collagen in tumourigenesis but also suggest that cellular context is important in how type VII collagen exerts its influence.…”