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

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dc.contributor.authorCho, Raymond
dc.contributor.authorAlexandrov, Ludmil
dc.contributor.authorden Breems, Nicoline
dc.contributor.authorAtanasova, Velina
dc.contributor.authorFarshchian, Mehdi
dc.contributor.authorPurdom, Elizabeth
dc.contributor.authorNguyen, Tran
dc.contributor.authorCoarfa, Cristian
dc.contributor.authorRajapakshe, Kimal
dc.contributor.authorPrisco, Marco
dc.contributor.authorSahu, Joya
dc.contributor.authorTassone, Patrick
dc.contributor.authorGreenawalt, Evan
dc.contributor.authorCollisson, Eric
dc.contributor.authorWu, Wei
dc.contributor.authorYao, Hui
dc.contributor.authorSu, Xiaoping
dc.contributor.authorGuttmann-Gruber, Christina
dc.contributor.authorPiñón, Josefina
dc.contributor.authorHashmi, Raabia
dc.contributor.authorFuentes, Ignacia
dc.date.accessioned2019-07-09T13:19:47Z
dc.date.available2019-07-09T13:19:47Z
dc.date.issued2018
dc.description.abstractRecessive 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.
dc.identifier.citationSci Transl Med. 2018 Aug 22; 10 (455)
dc.identifier.urihttp://hdl.handle.net/11447/2509
dc.identifier.uri10.1126/scitranslmed.aas9668
dc.language.isoen
dc.publisherAmerican Association for the Advancement of Science
dc.subjectRDEB
dc.subjectSkin disease
dc.subjectCancer
dc.subjectAPOBEC
dc.subjectCarcinoma
dc.titleAPOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa
dc.typeArticle

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