TY - JOUR
T1 - APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa
AU - Cho, Raymond J.
AU - Alexandrov, Ludmil B.
AU - Den Breems, Nicoline Y.
AU - Atanasova, Velina S.
AU - Farshchian, Mehdi
AU - Purdom, Elizabeth
AU - Nguyen, Tran N.
AU - Coarfa, Cristian
AU - Rajapakshe, Kimal
AU - Prisco, Marco
AU - Sahu, Joya
AU - Tassone, Patrick
AU - Greenawalt, Evan J.
AU - Collisson, Eric A.
AU - Wu, Wei
AU - Yao, Hui
AU - Su, Xiaoping
AU - Guttmann-Gruber, Christina
AU - Hofbauer, Josefina Piñón
AU - Hashmi, Raabia
AU - Fuentes, Ignacia
AU - Benz, Stephen C.
AU - Golovato, Justin
AU - Ehli, Erik A.
AU - Davis, Christel M.
AU - Davies, Gareth E.
AU - Covington, Kyle R.
AU - Murrell, Dedee F.
AU - Salas-Alanis, Julio C.
AU - Palisson, Francis
AU - Bruckner, Anna L.
AU - Robinson, William
AU - Has, Cristina
AU - Bruckner-Tuderman, Leena
AU - Titeux, Matthias
AU - Jonkman, Marcel F.
AU - Rashidghamat, Elham
AU - Lwin, Su M.
AU - Mellerio, Jemima E.
AU - McGrath, John A.
AU - Bauer, Johann W.
AU - Hovnanian, Alain
AU - Tsai, Kenneth Y.
AU - South, Andrew P.
N1 - Publisher Copyright:
Copyright © 2018 The Authors, some rights reserved.
PY - 2018/8/22
Y1 - 2018/8/22
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.aas9668
DO - 10.1126/scitranslmed.aas9668
M3 - Article
C2 - 30135250
AN - SCOPUS:85052242398
SN - 1946-6234
VL - 10
JO - Science translational medicine
JF - Science translational medicine
IS - 455
M1 - eaas9668
ER -