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

Raymond J. Cho, Ludmil B. Alexandrov, Nicoline Y. Den Breems, Velina S. Atanasova, Mehdi Farshchian, Elizabeth Purdom, Tran N. Nguyen, Cristian Coarfa, Kimal Rajapakshe, Marco Prisco, Joya Sahu, Patrick Tassone, Evan J. Greenawalt, Eric A. Collisson, Wei Wu, Hui Yao, Xiaoping Su, Christina Guttmann-Gruber, Josefina Piñón Hofbauer, Raabia Hashmi & 24 others Ignacia Fuentes, Stephen C. Benz, Justin Golovato, Erik A. Ehli, Christel M. Davis, Gareth E. Davies, Kyle R. Covington, Dedee F. Murrell, Julio C. Salas-Alanis, Francis Palisson, Anna L. Bruckner, William Robinson, Cristina Has, Leena Bruckner-Tuderman, Matthias Titeux, Marcel F. Jonkman, Elham Rashidghamat, Su M. Lwin, Jemima E. Mellerio, John A. McGrath, Johann W. Bauer, Alain Hovnanian, Kenneth Y. Tsai, Andrew P. South

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Copyright © 2018 The Authors, some rights reserved. 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.
Original languageEnglish
JournalScience Translational Medicine
DOIs
Publication statusPublished - 22 Aug 2018
Externally publishedYes

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Epidermolysis Bullosa Dystrophica
Squamous Cell Carcinoma
Mutation
Neoplasms
Skin
Exome
RNA Sequence Analysis
Ultraviolet Rays
Transcriptome

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Cho, R. J., Alexandrov, L. B., Den Breems, N. Y., Atanasova, V. S., Farshchian, M., Purdom, E., ... South, A. P. (2018). APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.aas9668
Cho, Raymond J. ; Alexandrov, Ludmil B. ; Den Breems, Nicoline Y. ; Atanasova, Velina S. ; Farshchian, Mehdi ; Purdom, Elizabeth ; Nguyen, Tran N. ; Coarfa, Cristian ; Rajapakshe, Kimal ; Prisco, Marco ; Sahu, Joya ; Tassone, Patrick ; Greenawalt, Evan J. ; Collisson, Eric A. ; Wu, Wei ; Yao, Hui ; Su, Xiaoping ; Guttmann-Gruber, Christina ; Hofbauer, Josefina Piñón ; Hashmi, Raabia ; Fuentes, Ignacia ; Benz, Stephen C. ; Golovato, Justin ; Ehli, Erik A. ; Davis, Christel M. ; Davies, Gareth E. ; Covington, Kyle R. ; Murrell, Dedee F. ; Salas-Alanis, Julio C. ; Palisson, Francis ; Bruckner, Anna L. ; Robinson, William ; Has, Cristina ; Bruckner-Tuderman, Leena ; Titeux, Matthias ; Jonkman, Marcel F. ; Rashidghamat, Elham ; Lwin, Su M. ; Mellerio, Jemima E. ; McGrath, John A. ; Bauer, Johann W. ; Hovnanian, Alain ; Tsai, Kenneth Y. ; South, Andrew P. / APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa. In: Science Translational Medicine. 2018.
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title = "APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa",
abstract = "Copyright {\circledC} 2018 The Authors, some rights reserved. 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.",
author = "Cho, {Raymond J.} and Alexandrov, {Ludmil B.} and {Den Breems}, {Nicoline Y.} and Atanasova, {Velina S.} and Mehdi Farshchian and Elizabeth Purdom and Nguyen, {Tran N.} and Cristian Coarfa and Kimal Rajapakshe and Marco Prisco and Joya Sahu and Patrick Tassone and Greenawalt, {Evan J.} and Collisson, {Eric A.} and Wei Wu and Hui Yao and Xiaoping Su and Christina Guttmann-Gruber and Hofbauer, {Josefina Pi{\~n}{\'o}n} and Raabia Hashmi and Ignacia Fuentes and Benz, {Stephen C.} and Justin Golovato and Ehli, {Erik A.} and Davis, {Christel M.} and Davies, {Gareth E.} and Covington, {Kyle R.} and Murrell, {Dedee F.} and Salas-Alanis, {Julio C.} and Francis Palisson and Bruckner, {Anna L.} and William Robinson and Cristina Has and Leena Bruckner-Tuderman and Matthias Titeux and Jonkman, {Marcel F.} and Elham Rashidghamat and Lwin, {Su M.} and Mellerio, {Jemima E.} and McGrath, {John A.} and Bauer, {Johann W.} and Alain Hovnanian and Tsai, {Kenneth Y.} and South, {Andrew P.}",
year = "2018",
month = "8",
day = "22",
doi = "10.1126/scitranslmed.aas9668",
language = "English",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",

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Cho, RJ, Alexandrov, LB, Den Breems, NY, Atanasova, VS, Farshchian, M, Purdom, E, Nguyen, TN, Coarfa, C, Rajapakshe, K, Prisco, M, Sahu, J, Tassone, P, Greenawalt, EJ, Collisson, EA, Wu, W, Yao, H, Su, X, Guttmann-Gruber, C, Hofbauer, JP, Hashmi, R, Fuentes, I, Benz, SC, Golovato, J, Ehli, EA, Davis, CM, Davies, GE, Covington, KR, Murrell, DF, Salas-Alanis, JC, Palisson, F, Bruckner, AL, Robinson, W, Has, C, Bruckner-Tuderman, L, Titeux, M, Jonkman, MF, Rashidghamat, E, Lwin, SM, Mellerio, JE, McGrath, JA, Bauer, JW, Hovnanian, A, Tsai, KY & South, AP 2018, 'APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa', Science Translational Medicine. https://doi.org/10.1126/scitranslmed.aas9668

APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa. / Cho, Raymond J.; Alexandrov, Ludmil B.; Den Breems, Nicoline Y.; Atanasova, Velina S.; Farshchian, Mehdi; Purdom, Elizabeth; Nguyen, Tran N.; Coarfa, Cristian; Rajapakshe, Kimal; Prisco, Marco; Sahu, Joya; Tassone, Patrick; Greenawalt, Evan J.; Collisson, Eric A.; Wu, Wei; Yao, Hui; Su, Xiaoping; Guttmann-Gruber, Christina; Hofbauer, Josefina Piñón; Hashmi, Raabia; Fuentes, Ignacia; Benz, Stephen C.; Golovato, Justin; Ehli, Erik A.; Davis, Christel M.; Davies, Gareth E.; Covington, Kyle R.; Murrell, Dedee F.; Salas-Alanis, Julio C.; Palisson, Francis; Bruckner, Anna L.; Robinson, William; Has, Cristina; Bruckner-Tuderman, Leena; Titeux, Matthias; Jonkman, Marcel F.; Rashidghamat, Elham; Lwin, Su M.; Mellerio, Jemima E.; McGrath, John A.; Bauer, Johann W.; Hovnanian, Alain; Tsai, Kenneth Y.; South, Andrew P.

In: Science Translational Medicine, 22.08.2018.

Research output: Contribution to journalArticle

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.

PY - 2018/8/22

Y1 - 2018/8/22

N2 - Copyright © 2018 The Authors, some rights reserved. 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 - Copyright © 2018 The Authors, some rights reserved. 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.

U2 - 10.1126/scitranslmed.aas9668

DO - 10.1126/scitranslmed.aas9668

M3 - Article

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

ER -