Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma

Jeffrey P. North, Justin Golovato, Charles J. Vaske, J. Zachary Sanborn, Andrew Nguyen, Wei Wu, Benjamin Goode, Meredith Stevers, Kevin McMullen, Bethany Elena Perez-White, Eric A. Collisson, Michele Bloomer, David A. Solomon, Stephen C. Benz, Raymond J. Cho*

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole-exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominates in 10/32 samples, while nine show microsatellite instability (MSI) profiles. UV-damage SeC exhibited poorly differentiated, infiltrative histopathology compared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Moreover, UV-damage SeC transcriptomes and anatomic distribution closely resemble those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations per Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquires far fewer mutations without a dominant signature, but show frequent truncations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers.

Original languageEnglish (US)
Article number1894
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

mutations
Microsatellite Repeats
cancer
Carcinoma
Mutation
Ports and harbors
cells
Sun
Microsatellite Instability
Squamous Cell Carcinoma
damage
microsatellites
Exome
signatures
Neoplasms
Skin
Solar System
Keratinocytes
Transcriptome
ontogeny

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

North, J. P., Golovato, J., Vaske, C. J., Sanborn, J. Z., Nguyen, A., Wu, W., ... Cho, R. J. (2018). Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma. Nature communications, 9(1), [1894]. https://doi.org/10.1038/s41467-018-04008-y
North, Jeffrey P. ; Golovato, Justin ; Vaske, Charles J. ; Sanborn, J. Zachary ; Nguyen, Andrew ; Wu, Wei ; Goode, Benjamin ; Stevers, Meredith ; McMullen, Kevin ; Perez-White, Bethany Elena ; Collisson, Eric A. ; Bloomer, Michele ; Solomon, David A. ; Benz, Stephen C. ; Cho, Raymond J. / Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma. In: Nature communications. 2018 ; Vol. 9, No. 1.
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abstract = "Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole-exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominates in 10/32 samples, while nine show microsatellite instability (MSI) profiles. UV-damage SeC exhibited poorly differentiated, infiltrative histopathology compared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Moreover, UV-damage SeC transcriptomes and anatomic distribution closely resemble those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations per Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquires far fewer mutations without a dominant signature, but show frequent truncations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers.",
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North, JP, Golovato, J, Vaske, CJ, Sanborn, JZ, Nguyen, A, Wu, W, Goode, B, Stevers, M, McMullen, K, Perez-White, BE, Collisson, EA, Bloomer, M, Solomon, DA, Benz, SC & Cho, RJ 2018, 'Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma', Nature communications, vol. 9, no. 1, 1894. https://doi.org/10.1038/s41467-018-04008-y

Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma. / North, Jeffrey P.; Golovato, Justin; Vaske, Charles J.; Sanborn, J. Zachary; Nguyen, Andrew; Wu, Wei; Goode, Benjamin; Stevers, Meredith; McMullen, Kevin; Perez-White, Bethany Elena; Collisson, Eric A.; Bloomer, Michele; Solomon, David A.; Benz, Stephen C.; Cho, Raymond J.

In: Nature communications, Vol. 9, No. 1, 1894, 01.12.2018.

Research output: Contribution to journalArticle

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T1 - Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma

AU - North, Jeffrey P.

AU - Golovato, Justin

AU - Vaske, Charles J.

AU - Sanborn, J. Zachary

AU - Nguyen, Andrew

AU - Wu, Wei

AU - Goode, Benjamin

AU - Stevers, Meredith

AU - McMullen, Kevin

AU - Perez-White, Bethany Elena

AU - Collisson, Eric A.

AU - Bloomer, Michele

AU - Solomon, David A.

AU - Benz, Stephen C.

AU - Cho, Raymond J.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole-exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominates in 10/32 samples, while nine show microsatellite instability (MSI) profiles. UV-damage SeC exhibited poorly differentiated, infiltrative histopathology compared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Moreover, UV-damage SeC transcriptomes and anatomic distribution closely resemble those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations per Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquires far fewer mutations without a dominant signature, but show frequent truncations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers.

AB - Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole-exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominates in 10/32 samples, while nine show microsatellite instability (MSI) profiles. UV-damage SeC exhibited poorly differentiated, infiltrative histopathology compared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Moreover, UV-damage SeC transcriptomes and anatomic distribution closely resemble those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations per Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquires far fewer mutations without a dominant signature, but show frequent truncations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers.

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