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Sci Transl Med. 2018 Aug 22;10(455). pii: eaas9668. doi: 10.1126/scitranslmed.aas9668.

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

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Department of Dermatology, University of California, San Francisco, CA 94115, USA.
Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Mathematics, University of Auckland, Auckland 1010, New Zealand.
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA.
Departments of Anatomic Pathology and Tumor Biology, Moffitt Cancer Center, Tampa, FL 33612, USA.
Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Translational Medical Center, Central Hospital, Zhengzhou University, Zhengzhou, China.
Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.
EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology, University Hospital Salzburg, Paracelsus Medical University, A-5020 Salzburg, Austria.
Fundación DEBRA Chile, Santiago 7760099, Chile.
Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago 7710162, Chile.
NantOmics LLC, Santa Cruz, CA 95060, USA.
NantOmics LLC, Culver City, CA 90233, USA.
Avera Institute for Human Genetics, Sioux Falls, SD 57108, USA.
Castle Biosciences Inc., Friendswood, TX 77546, USA.
St. George Hospital, University of New South Wales, Sydney, New South Wales 2217, Australia.
Escuela de Medicina y Ciencias de la Salud TecSalud del Tecnologico de Monterrey, Morones Prieto 3000, Los doctores, Monterrey, Nuevo León 64710, Mexico.
Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7710162, Chile.
Departments of Dermatology and Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Cutaneous Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Dermatology, Medical Center-University of Freiburg, 79104 Freiburg, Germany.
INSERM UMR 1163, Paris, France.
Imagine Institute, 75015 Paris, France.
Center for Blistering Diseases, Department of Dermatology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands.
St. John's Institute of Dermatology, King's College London (Guy's Campus), London SE1 9RT, UK.
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.


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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