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

Nature Communications
Jeffrey P NorthRaymond J Cho

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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Citations

Mar 22, 2019·Journal of Cutaneous Pathology·UNKNOWN Task Force/Committee MembersAndras Schaffer
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Datasets Mentioned

BETA
EGAS00001002869

Methods Mentioned

BETA
deamination
RNA-Seq
PCR
Illumina sequencing

Software Mentioned

BWA
R
TableRecalibration
Adobe Illustrator
RSEM
heatmap
gplots
Bowtie2
Sanger
samblaster

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