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; 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

doi:10.1126/scitranslmed.aas9668

Research ArticleCancer

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

View ORCID ProfileRaymond J. Cho ¹,
View ORCID ProfileLudmil B. Alexandrov²,
Nicoline Y. den Breems³,
Velina S. Atanasova⁴,
Mehdi Farshchian⁴,
View ORCID ProfileElizabeth Purdom⁵,
Tran N. Nguyen⁶,
View ORCID ProfileCristian Coarfa⁷,
View ORCID ProfileKimal Rajapakshe⁷,
Marco Prisco⁴,
Joya Sahu⁴,
View ORCID ProfilePatrick Tassone⁸,
Evan J. Greenawalt⁴,
Eric A. Collisson⁹,¹⁰,
Wei Wu⁹,¹⁰,¹¹,
Hui Yao¹²,
Xiaoping Su¹²,
View ORCID ProfileChristina Guttmann-Gruber¹³,
View ORCID ProfileJosefina Piñón Hofbauer¹³,
Raabia Hashmi⁴,
Ignacia Fuentes¹⁴,¹⁵,
View ORCID ProfileStephen C. Benz¹⁶,
View ORCID ProfileJustin Golovato¹⁷,
View ORCID ProfileErik A. Ehli¹⁸,
View ORCID ProfileChristel M. Davis¹⁸,
Gareth E. Davies¹⁸,
Kyle R. Covington¹⁹,
View ORCID ProfileDedee F. Murrell²⁰,
View ORCID ProfileJulio C. Salas-Alanis²¹,
Francis Palisson¹⁴,²²,
Anna L. Bruckner²³,
William Robinson²⁴,
View ORCID ProfileCristina Has²⁵,
Leena Bruckner-Tuderman²⁵,
View ORCID ProfileMatthias Titeux²⁶,²⁷,
View ORCID ProfileMarcel F. Jonkman²⁸,
Elham Rashidghamat²⁹,
View ORCID ProfileSu M. Lwin²⁹,
Jemima E. Mellerio²⁹,
John A. McGrath²⁹,
Johann W. Bauer¹³,
View ORCID ProfileAlain Hovnanian²⁶,²⁷,
View ORCID ProfileKenneth Y. Tsai⁶ and
View ORCID ProfileAndrew P. South ⁴,*

¹Department of Dermatology, University of California, San Francisco, CA 94115, USA.
²Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
³Department of Mathematics, University of Auckland, Auckland 1010, New Zealand.
⁴Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
⁵Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA.
⁶Departments of Anatomic Pathology and Tumor Biology, Moffitt Cancer Center, Tampa, FL 33612, USA.
⁷Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁸Department of Otolaryngology–Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
⁹Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA.
¹⁰Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
¹¹Translational Medical Center, Central Hospital, Zhengzhou University, Zhengzhou, China.
¹²Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.
¹³EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology, University Hospital Salzburg, Paracelsus Medical University, A-5020 Salzburg, Austria.
¹⁴Fundación DEBRA Chile, Santiago 7760099, Chile.
¹⁵Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago 7710162, Chile.
¹⁶NantOmics LLC, Santa Cruz, CA 95060, USA.
¹⁷NantOmics LLC, Culver City, CA 90233, USA.
¹⁸Avera Institute for Human Genetics, Sioux Falls, SD 57108, USA.
¹⁹Castle Biosciences Inc., Friendswood, TX 77546, USA.
²⁰St. George Hospital, University of New South Wales, Sydney, New South Wales 2217, Australia.
²¹Escuela de Medicina y Ciencias de la Salud TecSalud del Tecnologico de Monterrey, Morones Prieto 3000, Los doctores, Monterrey, Nuevo León 64710, Mexico.
²²Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7710162, Chile.
²³Departments of Dermatology and Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
²⁴Cutaneous Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
²⁵Department of Dermatology, Medical Center–University of Freiburg, 79104 Freiburg, Germany.
²⁶INSERM UMR 1163, Paris, France.
²⁷Imagine Institute, 75015 Paris, France.
²⁸Center for Blistering Diseases, Department of Dermatology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands.
²⁹St. John’s Institute of Dermatology, King’s College London (Guy’s Campus), London SE1 9RT, UK.

↵*Corresponding author. Email: andrew.south{at}jefferson.edu

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Science Translational Medicine 22 Aug 2018:
Vol. 10, Issue 455, eaas9668
DOI: 10.1126/scitranslmed.aas9668

Raymond J. Cho

1Department of Dermatology, University of California, San Francisco, CA 94115, USA.

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Ludmil B. Alexandrov

2Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.

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Nicoline Y. den Breems

3Department of Mathematics, University of Auckland, Auckland 1010, New Zealand.

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Velina S. Atanasova

4Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

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Mehdi Farshchian

4Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

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Elizabeth Purdom

5Department of Statistics, University of California, Berkeley, Berkeley, CA 94720, USA.

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Tran N. Nguyen

6Departments of Anatomic Pathology and Tumor Biology, Moffitt Cancer Center, Tampa, FL 33612, USA.

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Cristian Coarfa

7Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

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Kimal Rajapakshe

7Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

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Marco Prisco

4Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

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Joya Sahu

4Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

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Patrick Tassone

8Department of Otolaryngology–Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.

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Evan J. Greenawalt

4Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

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Eric A. Collisson

9Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA.

10Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.

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Wei Wu

9Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA.

10Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.

11Translational Medical Center, Central Hospital, Zhengzhou University, Zhengzhou, China.

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Hui Yao

12Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.

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Xiaoping Su

12Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.

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Christina Guttmann-Gruber

13EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology, University Hospital Salzburg, Paracelsus Medical University, A-5020 Salzburg, Austria.

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Josefina Piñón Hofbauer

13EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology, University Hospital Salzburg, Paracelsus Medical University, A-5020 Salzburg, Austria.

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Raabia Hashmi

4Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

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Ignacia Fuentes

14Fundación DEBRA Chile, Santiago 7760099, Chile.

15Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago 7710162, Chile.

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Stephen C. Benz

16NantOmics LLC, Santa Cruz, CA 95060, USA.

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Justin Golovato

17NantOmics LLC, Culver City, CA 90233, USA.

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Erik A. Ehli

18Avera Institute for Human Genetics, Sioux Falls, SD 57108, USA.

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Christel M. Davis

18Avera Institute for Human Genetics, Sioux Falls, SD 57108, USA.

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Gareth E. Davies

18Avera Institute for Human Genetics, Sioux Falls, SD 57108, USA.

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Kyle R. Covington

19Castle Biosciences Inc., Friendswood, TX 77546, USA.

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Dedee F. Murrell

20St. George Hospital, University of New South Wales, Sydney, New South Wales 2217, Australia.

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Julio C. Salas-Alanis

21Escuela de Medicina y Ciencias de la Salud TecSalud del Tecnologico de Monterrey, Morones Prieto 3000, Los doctores, Monterrey, Nuevo León 64710, Mexico.

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Francis Palisson

14Fundación DEBRA Chile, Santiago 7760099, Chile.

22Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7710162, Chile.

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Anna L. Bruckner

23Departments of Dermatology and Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.

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William Robinson

24Cutaneous Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

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Cristina Has

25Department of Dermatology, Medical Center–University of Freiburg, 79104 Freiburg, Germany.

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Leena Bruckner-Tuderman

25Department of Dermatology, Medical Center–University of Freiburg, 79104 Freiburg, Germany.

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Matthias Titeux

26INSERM UMR 1163, Paris, France.

27Imagine Institute, 75015 Paris, France.

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Marcel F. Jonkman

28Center for Blistering Diseases, Department of Dermatology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands.

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Elham Rashidghamat

29St. John’s Institute of Dermatology, King’s College London (Guy’s Campus), London SE1 9RT, UK.

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Su M. Lwin

29St. John’s Institute of Dermatology, King’s College London (Guy’s Campus), London SE1 9RT, UK.

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Jemima E. Mellerio

29St. John’s Institute of Dermatology, King’s College London (Guy’s Campus), London SE1 9RT, UK.

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John A. McGrath

29St. John’s Institute of Dermatology, King’s College London (Guy’s Campus), London SE1 9RT, UK.

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Johann W. Bauer

13EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology, University Hospital Salzburg, Paracelsus Medical University, A-5020 Salzburg, Austria.

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Alain Hovnanian

26INSERM UMR 1163, Paris, France.

27Imagine Institute, 75015 Paris, France.

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Kenneth Y. Tsai

6Departments of Anatomic Pathology and Tumor Biology, Moffitt Cancer Center, Tampa, FL 33612, USA.

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Andrew P. South

4Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.

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For correspondence: andrew.south@jefferson.edu

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Mutational signature sleuthing

Individuals with the inherited skin disease recessive dystrophic epidermolysis bullosa (RDEB) are predisposed to developing aggressive squamous cell carcinomas (SCCs), although why this patient group is prone to these cancers at such early ages is unknown. Cho et al. sequenced multiple RDEB SCC tumors and found that the mutation profile in these carcinomas was most consistent with APOBEC-associated mutagenesis, unlike other types of SCC that may be driven by ultraviolet light or tobacco smoke exposure. This finding could open up new lines of thinking on how to successfully prevent or target SCCs in RDEB patients.

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

Mutational signature sleuthing

Science Translational Medicine

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