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 language | English (US) |
|---|---|
| Article number | 1894 |
| Journal | Nature communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2018 |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
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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 journal › Article
TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=85047004937&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047004937&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-04008-y
DO - 10.1038/s41467-018-04008-y
M3 - Article
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1894
ER -