APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin and mucous membrane fragility disorder complicated by early-onset, highly malignant cutaneous squamous cell carcinomas (SCCs). The molecular etiology of RDEB SCC, which arises at sites of sustained tissue damage, is unknown. We performed detailed molecular analysis using whole-exome, whole-genome, and RNA sequencing of 27 RDEB SCC tumors, including multiple tumors from the same patient and multiple regions from five individual tumors. We report that driver mutations were shared with spontaneous, ultraviolet (UV) light-induced cutaneous SCC (UV SCC) and head and neck SCC (HNSCC) and did not explain the early presentation or aggressive nature of RDEB SCC. Instead, endogenous mutation processes associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) deaminases dominated RDEB SCC. APOBEC mutation signatures were enhanced throughout RDEB SCC tumor evolution, relative to spontaneous UV SCC and HNSCC mutation profiles. Sixty-seven percent of RDEB SCC driver mutations was found to emerge as a result of APOBEC and other endogenous mutational processes previously associated with age, potentially explaining a >1000-fold increased incidence and the early onset of these SCCs. Human papillomavirus-negative basal and mesenchymal subtypes of HNSCC harbored enhanced APOBEC mutational signatures and transcriptomes similar to those of RDEB SCC, suggesting that APOBEC deaminases drive other subtypes of SCC. Collectively, these data establish specific mutagenic mechanisms associated with chronic tissue damage. Our findings reveal a cause for cancers arising at sites of persistent inflammation and identify potential therapeutic avenues to treat RDEB SCC.

p53-Regulated Long Noncoding RNA PRECSIT Promotes Progression of Cutaneous Squamous Cell Carcinoma via STAT3 Signaling

“…The mutation frequency of cSCC is higher than in melanoma or in other squamous cell carcinomas. 10,12,13 Mutational inactivation of the tumor suppressor TP53 gene is an early event in epidermal carcinogenesis, leading to genomic instability in keratinocytes and further malignant transformation. Interestingly, TP53 mutations are not detected in SK, benign skin tumors with a clear UV mutation signature.…”

Humanization of Tumor Stroma by Tissue Engineering as a Tool to Improve Squamous Cell Carcinoma Xenograft

“…SCC-cells and stromal fibroblasts derived from recessive dystrophic epidermolysis bullosa (RDEB) patients were used during this experimentation, given their high predisposition of RDEB patients to develop very aggressive SCC. Moreover, the similarities of the molecular profile between RDEB dermal cells with that of CAFs, which promotes the invasion of tumor cells, has been widely studied [6,[13][14][15][16][17]. In the first approach, to assess the tumorigenic potential of the SCC-derived cell lines used, immunodeficient mice were injected with tumor keratinocytes (EB4 or EB106), without the addition of exogenous stroma (2 × 10 6 cells/animal.…”

“…Many of the aggressive SCC of the skin develops in areas with chronic ulcers as in hereditary conditions like epidermolysis bullosa [13,14,26]. The reason for this different behavior is still a subject of controversy and collaborative studies have recently shed light onto the matter [9,17,[27][28][29]. Recently, attention has been focused on a possible role of the stroma.…”

MiRNA-10b marks aggressive squamous cell carcinomas, and confers a cancer stem cell-like phenotype

“…S7E). To nominate a disease relevant miR-10b target, we analyzed publicly available survival data from metastatic stage IV head and neck squamous cell carcinoma (HNSCC) (n = 86 patients, The Cancer Genome Atlas / TCGA), as this cancer type was previously described to have high genetic similarities to RDEB-SCC (8). The top 20 candidate miR-10b targets with highest inverse correlation were then used to stratify HNSCC patients (Supplementary Fig.…”