EGAD00001004016
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 predominated 10/32 samples, while 9 were instead defined by
microsatellite instability (MSI) mutations. UV-damage SeC exhibited
poorly differentiated, infiltrative histopathologycompared to MSI
signature SeC (p = 0.003), features previously associated with
dissemination. Strikingly, UV-damage SeC transcriptomes and anatomic
distributionclosely resembling 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/Mb, predicting immunotherapeutic
response. In contrast, ocular SeC acquire far fewer mutations without
a dominant signature, but show frequent truncating mutations in the
ZNF750 epidermal differentiation regulator. Our data exemplify how
different mutational processes convergently drive histopathologically
related but clinically distinct cancers.
Illumina HiSeq 2500
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