Cargando…

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

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 cu...

Descripción completa

Detalles Bibliográficos
Autores principales: 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, Alexander, Trent, Jeffrey M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126841/
https://www.ncbi.nlm.nih.gov/pubmed/30188888
http://dx.doi.org/10.1371/journal.pgen.1007589
_version_ 1783353379199647744
author 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, Alexander
Trent, Jeffrey M.
author_facet 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, Alexander
Trent, Jeffrey M.
author_sort Hendricks, William P. D.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6126841
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-61268412018-09-15 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, Alexander Trent, Jeffrey M. PLoS Genet Research Article 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. Public Library of Science 2018-09-06 /pmc/articles/PMC6126841/ /pubmed/30188888 http://dx.doi.org/10.1371/journal.pgen.1007589 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
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, Alexander
Trent, Jeffrey M.
Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis
title Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis
title_full Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis
title_fullStr Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis
title_full_unstemmed Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis
title_short Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis
title_sort somatic inactivating ptprj mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126841/
https://www.ncbi.nlm.nih.gov/pubmed/30188888
http://dx.doi.org/10.1371/journal.pgen.1007589
work_keys_str_mv AT hendrickswilliampd somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT zismannvictoria somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT sivaprakasamkarthigayini somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT legendrechristophe somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT poormankelsey somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT tembewaibhav somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT perdigonesnieves somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT kieferjeffrey somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT liangwinnie somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT delucavalerie somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT starkmitchell somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT ruhealison somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT fromanroe somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT duesberynicholass somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT washingtonmegan somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT aldrichjessica somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT neffmarkw somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT huentelmanmatthewj somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT haywardnicholas somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT brownkevin somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT thammdouglas somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT postgerald somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT khannachand somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT davisbarbara somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT breenmatthew somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT sekulicalexander somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis
AT trentjeffreym somaticinactivatingptprjmutationsanddysregulatedpathwaysidentifiedincaninemalignantmelanomabyintegratedcomparativegenomicanalysis