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

• DOI: 10.1038/s41467-018-04008-y
• Publication Date: 2018-05-08T16:04:38Z
• Authors: Jeffrey P. North; Justin Golovato; Charles J. Vaske; J. Zachary Sanborn; Andrew Nguyen; Wei Wu; Benjamin Goode; Meredith Stevers; Kevin McMullen; Bethany E. Perez ...; Eric A. Collisson; Michele Bloomer; David A. Solomon; Stephen C. Benz; Raymond J. Cho
• Keywords: Keratinocytes; Skin Neoplasms; Ultraviolet Rays; Science; DNA Mutational Analysis; 610; Article; Diagnosis, Differential; 03 medical and health sciences; Rare Diseases; Terminology as Topic; Diagnosis; Exome Sequencing; Genetics; Humans; Climate-Related Exposures and Conditions; Exome; Sebaceous Gland Neoplasms; Cancer; 0303 health sciences; Eye Neoplasms; Carcinoma; Q; 3. Good health; Squamous Cell; Differential; Mutation; Carcinoma, Squamous Cell; Microsatellite Instability; Transcriptome; Microsatellite Repeats

AbstractSebaceous 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.