Contributions of Accelerated Skin Aging in Recessive Dystrophic Epidermolysis Bullosa to Squamous Cell Carcinoma Development

Principal Investigator: Natasha Y. Frank

Authors: Siyuan Wu, Catherine A. A. Lee, Yuen Ting Chow, Eric Kofman, Megan Riddle, Cindy Eide, Markus H. Frank, Jakub Tolar, Kristen P. Hook, Saud H. AlDubayan, Natasha Y. Frank
Lay Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating skin genetic disorder. RDEB patients suffer from severe skin erosion, blistering and shearing, are at high risk of developing squamous cell carcinoma (SCC) tumors and have extremely high death rates. Recent studies highlighted several similarities between normal skin aging and skin changes observed in RDEB, such as ultrastructural changes, defects in wound healing and increased inflammation. Here, we hypothesize that accelerated skin aging contributes to SCC tumor development in RDEB patients.

To test our hypothesis, we performed whole genome sequencing (WGS) and RNAseq of blood, normal skin and tumor samples obtained from a RDEB patient. WGS confirmed 2 germline mutations on the COL7A1 gene, which were interpreted to cause the disease. When comparing tumor to normal skin, we identified mutational signatures associated with age-related cancer mutagenesis, APOBEC enzymes and DNA base excision repair mechanism. RNAseq revealed 4089 genes changed expression in tumor compared to skin. Among them, 31 up-regulated and 71 down-regulated genes overlapped with a previously identified list of genes important in both aging and RDEB and are specifically associated with epidermal formation, inflammation and metabolism. Thus, our study suggests skin aging-associated mutations and transcriptional changes contribute to RDEB-SCC development.

Scientific Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a debilitating genetic disorder characterized by severe skin erosion, blistering, and shearing. It is caused by mutations in the COL7A1 gene, which encodes a major component of an anchoring fibril connecting the epidermis with the dermis. In addition to severe skin inflammation and scarring, RDEB patients are at high risk of developing squamous cell carcinoma (SCC), aggressive cancer with extremely high mortality. Despite significant advances in dissecting RDEB pathogenesis, the mechanisms of tumorigenic disease progression are still not fully understood. Recent studies highlighted several similarities between normal skin aging and skin changes in RDEB, such as ultrastructural abnormalities, defects in wound healing, and increased inflammation. Here, we hypothesize that accelerated skin aging contributes to SCC development in RDEB.

To test this hypothesis, we performed whole-genome sequencing (WGS) of blood, skin, and SCC tumor samples from a patient with RDEB. In addition, we compared skin and tumor transcriptomes by RNAseq. Consistent with the patient diagnosis, WGS detected two compound heterozygous germline COL7A1 pathogenic variants, c.1732C>A and c.3551-3T>G, in all three tissues. Additionally, WGS revealed significant enrichment of clock-like age-related mutational signatures, APOBEC signatures, and defective base excision repair signatures in tumor compared to skin. Moreover, RNAseq analyses revealed that the SCC-specific genomic variants in 630 genes resulted in significant changes in their RNA expression. Gene Ontology analysis of these differentially expressed transcripts revealed significant enrichment of categories associated with extracellular matrix organization, cell adhesion, and morphogenesis. Intriguingly, 14 of the differentially-expressed genes were shared with previously described RDEB- and normal skin aging-specific transcriptome signatures (Breitenbach et al., 2015). Thus, our pilot study points to a possibility that skin aging-associated transcriptional changes might contribute to accelerated SCC development in RDEB patients.

Clinical Implications
RDEB is a rare genetic disorder and currently there is no cure. Our study explores the relationship between aging and RDEB and calls for a possibility of anti-aging treatment, perhaps even stem cell therapy, for RDEB patients in the future.

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