Recessive Dystrophic Epidermolysis Bullosa–Associated Squamous-Cell Carcinoma: An Enigmatic Entity with Complex Pathogenesis COMMENTARYSee related article on pg 2438 © 2007 The Society for Investigative Dermatology www.jidonline.org 2295 Recessive Dystrophic Epidermolysis Bullosa–Associated Squamous-Cell Carcinoma: An Enigmatic Entity with Complex Pathogenesis Ulrich Rodeck1 and Jouni Uitto1 Expression of either collagen VII or the noncollagenous (NC1) fragment derived from it has been suggested to be indispensable for the development of squamous- cell carcinomas (SCCs) in patients affected by recessive dystrophic epidermoly- sis bullosa (RDEB). This view is challenged here by the observation that SCCs do develop in RDEB patients lacking expression of collagen VII altogether. The aggres- sive behavior of RDEB-associated SCCs remains unexplained. Journal of Investigative Dermatology (2007) 127, 2295–2296. doi:10.1038/sj.jid.5700939 The term epidermolysis bullosa (EB) represents a heterogeneous group of mechanobullous disorders characterized by skin fragility and blister formation. In addition to the skin, a number of other specialized epithelia, including the oral mucous membranes as well as those of the respiratory, vesicourinary, and gas- trointestinal tract, can be affected (Fine et al., 1999). In milder forms of EB, blis- ters may be confined to limited areas of the skin, primarily the hands and feet. In contrast, in the most severe forms of EB, minimal trauma can result in widespread blistering and cutaneous erosions that heal slowly, if at all. The clinical course of the recessive dystrophic form of EB (RDEB, the Hallopeau–Siemens type; OMIM#226600) is unrelenting, and the affected patients develop severe mutilat- ing scarring and are at high risk of devel- oping squamous-cell carcinomas (SCCs) of the skin. Unlike sporadic SCCs in the general population, the RDEB-associ- ated SCCs readily metastasize and have emerged as a prevalent life-threatening complication in these patients (Fine et al., 1999). The cutaneous fragility in RDEB is caused by mutations in the COL7A1 gene, which encodes type VII collagen, a structural component of anchoring fibrils at the cutaneous basement membrane zone (Varki et al., 2007). Wild-type colla- gen VII contributes to the structural integ- rity of the basement membrane zone by tethering the lamina densa of the dermo- epidermal basement membrane to the underlying papillary dermis (Shimizu et al., 1997). A wide spectrum of COL7A1 mutations that affect either collagen VII protein production or fibrillar assem- bly have been linked to DEB. In RDEB patients, premature STOP codons are frequently observed, predicting expres- sion of truncated collagen VII, including the noncollagenous 1 (NC1) domain, but lacking C-terminal sequences nec- essary for collagen VII assembly. The molecular genetic hallmark of the most severe RDEB is STOP codon mutations in both alleles, spanning the entire length of the collagen VII polypeptide (Varki et al., 2007). Ortiz-Urda and colleagues (2005) recently demonstrated that expression of the NC1 fragment was required for malignant transformation of a series of keratinocytes isolated from RDEB patients. In addition, they observed that expression of either full-length collagen VII or the NC1 fragment was necessary for tumorigenic conversion of normal keratinocytes from non-RDEB individu- als. Pourreyron et al. (2007, this issue) revisited the requirement of collagen VII expression for SCC development in another series of SCC cell lines isolated from RDEB patients. They demonstrate that 2 of 11 patients investigated devel- oped SCC in the absence of collagen VII or NC1 expression and conclude that, in RDEB patients, expression of collagen VII fragments is not a necessary requirement for SCC development. In support of this notion, we have identified in the DebRA Molecular Diagnostics Laboratory muta- tion database seven RDEB patients who were compound heterozygotes with two COL7A1 STOP codon mutations in trans upstream from the NC1/C7 junc- tion (Varki et al., 2007). These patients are predicted not to express NC1, yet two of three, who were over 30 years of age, have developed aggressive SCCs (J. Uitto, unpublished observations). Can these seemingly contradictory results be reconciled? The answer may lie in the use of distinct experimental systems that were employed to assess malignant transformation. Ortiz-Urda et al. (2005) based their study on the use of an experimental model system to assess the tumorigenic potential of normal kera- tinocytes. To achieve tumorigenicity in immunodeficient mice, they retrovirally transduced normal keratinocytes with oncogenic Ras (Ha-Ras-V12) and the NF-κB inhibitor IκBα. Thus, expression of collagen VII appears to be an absolute requirement for tumor formation driven by Ha-Ras, leaving open the question of whether this observation can be general- ized to RDEB patients. Pourreyron et al. (2007) resolve this question by demon- strating that expression of collagen VII or fragments thereof is not strictly required 1Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Correspondence: Dr Ulrich Rodeck, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, 233 S. 10th Street, Philadelphia, Pennsylvania 19107, USA. E-mail: Ulrich.Rodeck@mail.tju.edu | Expression of collagen VII fragments is not a necessary requirement for SCC development. http://www.jidonline.org http://www.nature.com/doifinder/10.1038/sj.jid.5700939 mailto:Ulrich.Rodeck@mail.tju.edu COMMENTARY 2296 Journal of Investigative Dermatology (2007), Volume 127 for SCC development in patients. Clearly, their findings must be confirmed in a larger cohort of RDEB patients afflicted with SCCs. However, their work high- lights the importance of molecular epi- demiology in patients to ascertain the relevancy of findings in experimental models of skin tumor development. Of course, it is possible that the requirement of NC1 expression for SCC development is restricted to a subset of RDEB patients in which Ha-Ras muta- tions occur. In sporadic SCCs Ras muta- tions are infrequent and typically occur late in tumor progression (Campbell et al., 1993; Clark et al., 1993). Unfortunately, the activation state of Ha- Ras in RDEB-associated SCCs is current- ly unknown. If a high frequency of Ras mutations should be prevalent in RDEB- associated SCCs, it would be of interest to determine whether the tumors formed in the absence of collagen VII expression exhibit deregulated signaling pathways normally dependent on the presence of either collagen VII or the NC1 domain (Rodeck et al., 2007). Regardless of the results of future efforts to resolve these issues, expression of the NC1 domain of collagen VII alone is not likely to pro- vide a reliable diagnostic tool to iden- tify patients at risk of SCC development. Instead, collagen VII joins a long list of extracellular matrix components that have been implicated in SCC develop- ment at the microenvironment of the tumor–host interface, including collagen IV, collagen I, fibronectin, and laminin 332 (formerly laminin 5) (Abelev and Lazarevich, 2006; Marinkovich, 2007). Much like these, collagen VII may act as a “modifier” of the transformed state by enhancing the malignant potential of initiated keratinocytes. Yet none of these extracellular matrix components is likely to be an absolute requirement for tumor progression. RDEB, more so than less aggressive forms of EB, is characterized by chronic wound healing and excessive scar for- mation that last decades before SCCs are manifest. An interesting parallel to SCCs arising in continuously remodeling scar tissue is Marjolin’s ulcers—SCCs that typically arise in burn scars many years after the initial scarring event (Phillips et al., 1998). Interestingly, these SCCs are also very aggressive and invasive, much like RDEB-associated SCCs. These paral- lels raise the question of whether, regard- less of collagen VII/NC1 expression sta- tus, chronic wound healing represents the driving force for the development of highly malignant SCCs in both the gen- eral population and RDEB patients. CONFLICT OF INTEREST The authors state no conflict of interest. REFERENCES Abelev GI Lazarevich NL (2006) Control of differentiation in progression of epithelial tumors. Adv Cancer Res 95:61–113 Campbell C, Quinn AG, Rees JL (1993) Codon 12 Harvey-ras mutations are rare events in non- melanoma human skin cancer. Br J Dermatol 128:111–4 Clark LJ, Edington K, Swan IR, McLay KA, Newlands WJ, Wills LC et al. (1993) The absence of Harvey ras mutations during development and progression of squamous-cell carcinomas of the head and neck. Br J Cancer 68:617–20 Fine J-D, Bauer EA, McGuire J, Moshell A (1999) Epidermolysis Bullosa. Johns Hopkins University Press, Baltimore, MD, 1–444 Marinkovich MP (2007) Tumour microenvironment: laminin 332 in squamous-cell carcinoma. Nat Rev Cancer 7:370–80 Ortiz-Urda S, Garcia J, Green CL, Chen L, Lin Q, Veitch DP et al. (2005) Type VII collagen is required for Ras-driven human epidermal tumorigenesis. Science 307:1773–6 Phillips TJ, Salman SM, Bhawan J, Rogers GS (1998) Burn scar carcinoma: diagnosis and management. Dermatol Surg 24:561–5 Pourreyron C, Cox G, Mao X, Volz A, Baksh N, Wong T et al. (2007) Patients with recessive dystrophic epidermolysis bullosa develop squamous-cell carcinoma regardless of type VII collagen expression. J Invest Dermatol 127:2438–44 Rodeck U, Fertala A, Uitto J (2007) Anchorless keratinocyte survival: an emerging pathogenic mechanism for squamous cell carcinomas in recessive dystrophic epidermolysis bullosa. Exp Dermatol 16:465–7 Shimizu H, Ishiko A, Masunaga T, Kurihara Y, Sato M, Bruckner-Tuderman L et al. (1997) Most anchoring fibrils in human skin originate and terminate in the lamina densa. Lab Invest 76:753–63 Varki R, Sadowski S, Uitto J, Pfendner E (2007) Epidermolysis bullosa. II. Type VII collagen mutations in phenotype–genotype correlations in the dystrophic subtypes. J Med Genet 44:181–92 See related article on pg 2323 Genital and Nongenital Nonmelanoma Skin Cancer: More Epidemiological Studies Are Needed Andreas Stang1 Although black men in the United States have a lower mortality of nongenital nonmelanoma skin cancer (NMSC) than white men, they have a higher mortal- ity of genital NMSC than white men. Mortality of NMSC has declined over time. Ethnicity-specific incidence and survival analyses of NMSC can be used to deter- mine to what degree earlier detection and/or more efficient therapies have con- tributed to these observations. Journal of Investigative Dermatology (2007) 127, 2296–2299. doi:10.1038/sj.jid.5700895 The burden of nonmelanoma skin cancer (NMSC) can be described by a variety of measures, including mortality. Although death among people with NMSC is the exception rather than the rule, detailed analyses of routinely collected mortal- ity data provide important insights into the burden of disease. For example, although the age-standardized mortality rates of NMSC decreased in the territory 1Clinical Epidemiology Unit, Institute of Medical Epidemiology, Biometry, and Informatics, Medical Faculty, Martin-Luther-University of Halle-Wittenberg, Halle, Germany Correspondence: Dr Andreas Stang, Clinical Epidemiology Unit, Institute of Medical Epidemiology, Biometry, and Informatics, Medical Faculty, Martin-Luther-University of Halle-Wittenberg, Magdeburger Strasse 27, Halle 06097, Germany. E-mail: andreas.stang@medizin.uni-halle.de