Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis

William P.D. Hendricks, Victoria Zismann, Karthigayini Sivaprakasam, Christophe Legendre, Kelsey Poorman, Waibhav Tembe, Nieves Perdigones, Jeffrey Kiefer, Winnie Liang, Valerie DeLuca, Mitchell Stark, Alison Ruhe, Roe Froman, Nicholas S. Duesbery, Megan Washington, Jessica Aldrich, Mark W. Neff, Matthew J. Huentelman, Nicholas Hayward, Kevin BrownDouglas Thamm, Gerald Post, Chand Khanna, Barbara Davis, Matthew Breen, Aleksandar D Sekulic, Jeffrey M. Trent

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Canine malignant melanoma, a significant cause of mortality in domestic dogs, is a powerful comparative model for human melanoma, but little is known about its genetic etiology. We mapped the genomic landscape of canine melanoma through multi-platform analysis of 37 tumors (31 mucosal, 3 acral, 2 cutaneous, and 1 uveal) and 17 matching constitutional samples including long- and short-insert whole genome sequencing, RNA sequencing, array comparative genomic hybridization, single nucleotide polymorphism array, and targeted Sanger sequencing analyses. We identified novel predominantly truncating mutations in the putative tumor suppressor gene PTPRJ in 19% of cases. No BRAF mutations were detected, but activating RAS mutations (24% of cases) occurred in conserved hotspots in all cutaneous and acral and 13% of mucosal subtypes. MDM2 amplifications (24%) and TP53 mutations (19%) were mutually exclusive. Additional low-frequency recurrent alterations were observed amidst low point mutation rates, an absence of ultraviolet light mutational signatures, and an abundance of copy number and structural alterations. Mutations that modulate cell proliferation and cell cycle control were common and highlight therapeutic axes such as MEK and MDM2 inhibition. This mutational landscape resembles that seen in BRAF wild-type and sun-shielded human melanoma subtypes. Overall, these data inform biological comparisons between canine and human melanoma while suggesting actionable targets in both species.

Original languageEnglish (US)
Article numbere1007589
JournalPLoS Genetics
Volume14
Issue number9
DOIs
StatePublished - Sep 1 2018

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ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Hendricks, W. P. D., Zismann, V., Sivaprakasam, K., Legendre, C., Poorman, K., Tembe, W., Perdigones, N., Kiefer, J., Liang, W., DeLuca, V., Stark, M., Ruhe, A., Froman, R., Duesbery, N. S., Washington, M., Aldrich, J., Neff, M. W., Huentelman, M. J., Hayward, N., ... Trent, J. M. (2018). Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis. PLoS Genetics, 14(9), [e1007589]. https://doi.org/10.1371/journal.pgen.1007589