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

13 Citations (Scopus)

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

Fingerprint

melanoma
Canidae
mutation
Melanoma
genomics
Mutation
dogs
tumor
Extremities
comparative genomic hybridization
RNA Sequence Analysis
Skin
tumor suppressor genes
Comparative Genomic Hybridization
Mitogen-Activated Protein Kinase Kinases
Solar System
Mutation Rate
point mutation
Ultraviolet Rays
Cell Cycle Checkpoints

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., ... 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

Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis. / Hendricks, William P.D.; Zismann, Victoria; Sivaprakasam, Karthigayini; Legendre, Christophe; Poorman, Kelsey; Tembe, Waibhav; Perdigones, Nieves; Kiefer, Jeffrey; Liang, Winnie; DeLuca, Valerie; Stark, Mitchell; Ruhe, Alison; Froman, Roe; Duesbery, Nicholas S.; Washington, Megan; Aldrich, Jessica; Neff, Mark W.; Huentelman, Matthew J.; Hayward, Nicholas; Brown, Kevin; Thamm, Douglas; Post, Gerald; Khanna, Chand; Davis, Barbara; Breen, Matthew; Sekulic, Aleksandar D; Trent, Jeffrey M.

In: PLoS Genetics, Vol. 14, No. 9, e1007589, 01.09.2018.

Research output: Contribution to journalArticle

Hendricks, WPD, 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, NS, Washington, M, Aldrich, J, Neff, MW, Huentelman, MJ, Hayward, N, Brown, K, Thamm, D, Post, G, Khanna, C, Davis, B, Breen, M, Sekulic, AD & Trent, JM 2018, 'Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis', PLoS Genetics, vol. 14, no. 9, e1007589. https://doi.org/10.1371/journal.pgen.1007589
Hendricks, William P.D. ; Zismann, Victoria ; Sivaprakasam, Karthigayini ; Legendre, Christophe ; Poorman, Kelsey ; Tembe, Waibhav ; Perdigones, Nieves ; Kiefer, Jeffrey ; Liang, Winnie ; DeLuca, Valerie ; Stark, Mitchell ; Ruhe, Alison ; Froman, Roe ; Duesbery, Nicholas S. ; Washington, Megan ; Aldrich, Jessica ; Neff, Mark W. ; Huentelman, Matthew J. ; Hayward, Nicholas ; Brown, Kevin ; Thamm, Douglas ; Post, Gerald ; Khanna, Chand ; Davis, Barbara ; Breen, Matthew ; Sekulic, Aleksandar D ; Trent, Jeffrey M. / Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis. In: PLoS Genetics. 2018 ; Vol. 14, No. 9.
@article{bf474cfede474773a6502a4d31f7d068,
title = "Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis",
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.",
author = "Hendricks, {William P.D.} and Victoria Zismann and Karthigayini Sivaprakasam and Christophe Legendre and Kelsey Poorman and Waibhav Tembe and Nieves Perdigones and Jeffrey Kiefer and Winnie Liang and Valerie DeLuca and Mitchell Stark and Alison Ruhe and Roe Froman and Duesbery, {Nicholas S.} and Megan Washington and Jessica Aldrich and Neff, {Mark W.} and Huentelman, {Matthew J.} and Nicholas Hayward and Kevin Brown and Douglas Thamm and Gerald Post and Chand Khanna and Barbara Davis and Matthew Breen and Sekulic, {Aleksandar D} and Trent, {Jeffrey M.}",
year = "2018",
month = "9",
day = "1",
doi = "10.1371/journal.pgen.1007589",
language = "English (US)",
volume = "14",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis

AU - Hendricks, William P.D.

AU - Zismann, Victoria

AU - Sivaprakasam, Karthigayini

AU - Legendre, Christophe

AU - Poorman, Kelsey

AU - Tembe, Waibhav

AU - Perdigones, Nieves

AU - Kiefer, Jeffrey

AU - Liang, Winnie

AU - DeLuca, Valerie

AU - Stark, Mitchell

AU - Ruhe, Alison

AU - Froman, Roe

AU - Duesbery, Nicholas S.

AU - Washington, Megan

AU - Aldrich, Jessica

AU - Neff, Mark W.

AU - Huentelman, Matthew J.

AU - Hayward, Nicholas

AU - Brown, Kevin

AU - Thamm, Douglas

AU - Post, Gerald

AU - Khanna, Chand

AU - Davis, Barbara

AU - Breen, Matthew

AU - Sekulic, Aleksandar D

AU - Trent, Jeffrey M.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85054569490&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054569490&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1007589

DO - 10.1371/journal.pgen.1007589

M3 - Article

C2 - 30188888

AN - SCOPUS:85054569490

VL - 14

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 9

M1 - e1007589

ER -