SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma

Sharadha Sakthikumar, Ingegerd Elvers, Jaegil Kim, Maja L. Arendt, Rachael Thomas, Jason Turner-Maier, Ross Swofford, Jeremy Johnson, Steven E. Schumacher, Jessica Alfoldi, Erik Axelsson, C. Guillermo Couto, William C. Kisseberth, Mats E. Pettersson, Gad Getz, Jennifer R.S. Meadows, Jaime F. Modiano, Matthew Breen, Marcin Kierczak, Karin Forsberg-Nilsson & 2 others Voichita D. Marinescu, Kerstin Lindblad-Toh

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species.

Original languageEnglish (US)
Pages (from-to)3421-3431
Number of pages11
JournalCancer Research
Volume78
Issue number13
DOIs
StatePublished - Jul 1 2018

Fingerprint

Exome
Osteosarcoma
Canidae
Dogs
Histone Code
Genes
Bone Neoplasms
Mutation
Mutation Rate
Tumor Suppressor Genes
Oncogenes
Neoplasms

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Sakthikumar, S., Elvers, I., Kim, J., Arendt, M. L., Thomas, R., Turner-Maier, J., ... Lindblad-Toh, K. (2018). SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma. Cancer Research, 78(13), 3421-3431. https://doi.org/10.1158/0008-5472.CAN-17-3558

SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma. / Sakthikumar, Sharadha; Elvers, Ingegerd; Kim, Jaegil; Arendt, Maja L.; Thomas, Rachael; Turner-Maier, Jason; Swofford, Ross; Johnson, Jeremy; Schumacher, Steven E.; Alfoldi, Jessica; Axelsson, Erik; Couto, C. Guillermo; Kisseberth, William C.; Pettersson, Mats E.; Getz, Gad; Meadows, Jennifer R.S.; Modiano, Jaime F.; Breen, Matthew; Kierczak, Marcin; Forsberg-Nilsson, Karin; Marinescu, Voichita D.; Lindblad-Toh, Kerstin.

In: Cancer Research, Vol. 78, No. 13, 01.07.2018, p. 3421-3431.

Research output: Contribution to journalArticle

Sakthikumar, S, Elvers, I, Kim, J, Arendt, ML, Thomas, R, Turner-Maier, J, Swofford, R, Johnson, J, Schumacher, SE, Alfoldi, J, Axelsson, E, Couto, CG, Kisseberth, WC, Pettersson, ME, Getz, G, Meadows, JRS, Modiano, JF, Breen, M, Kierczak, M, Forsberg-Nilsson, K, Marinescu, VD & Lindblad-Toh, K 2018, 'SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma', Cancer Research, vol. 78, no. 13, pp. 3421-3431. https://doi.org/10.1158/0008-5472.CAN-17-3558
Sakthikumar S, Elvers I, Kim J, Arendt ML, Thomas R, Turner-Maier J et al. SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma. Cancer Research. 2018 Jul 1;78(13):3421-3431. https://doi.org/10.1158/0008-5472.CAN-17-3558
Sakthikumar, Sharadha ; Elvers, Ingegerd ; Kim, Jaegil ; Arendt, Maja L. ; Thomas, Rachael ; Turner-Maier, Jason ; Swofford, Ross ; Johnson, Jeremy ; Schumacher, Steven E. ; Alfoldi, Jessica ; Axelsson, Erik ; Couto, C. Guillermo ; Kisseberth, William C. ; Pettersson, Mats E. ; Getz, Gad ; Meadows, Jennifer R.S. ; Modiano, Jaime F. ; Breen, Matthew ; Kierczak, Marcin ; Forsberg-Nilsson, Karin ; Marinescu, Voichita D. ; Lindblad-Toh, Kerstin. / SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma. In: Cancer Research. 2018 ; Vol. 78, No. 13. pp. 3421-3431.
@article{9bfec9a815a94f4c8fbb80e14af2cb29,
title = "SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma",
abstract = "Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83{\%} of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species.",
author = "Sharadha Sakthikumar and Ingegerd Elvers and Jaegil Kim and Arendt, {Maja L.} and Rachael Thomas and Jason Turner-Maier and Ross Swofford and Jeremy Johnson and Schumacher, {Steven E.} and Jessica Alfoldi and Erik Axelsson and Couto, {C. Guillermo} and Kisseberth, {William C.} and Pettersson, {Mats E.} and Gad Getz and Meadows, {Jennifer R.S.} and Modiano, {Jaime F.} and Matthew Breen and Marcin Kierczak and Karin Forsberg-Nilsson and Marinescu, {Voichita D.} and Kerstin Lindblad-Toh",
year = "2018",
month = "7",
day = "1",
doi = "10.1158/0008-5472.CAN-17-3558",
language = "English (US)",
volume = "78",
pages = "3421--3431",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "13",

}

TY - JOUR

T1 - SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma

AU - Sakthikumar, Sharadha

AU - Elvers, Ingegerd

AU - Kim, Jaegil

AU - Arendt, Maja L.

AU - Thomas, Rachael

AU - Turner-Maier, Jason

AU - Swofford, Ross

AU - Johnson, Jeremy

AU - Schumacher, Steven E.

AU - Alfoldi, Jessica

AU - Axelsson, Erik

AU - Couto, C. Guillermo

AU - Kisseberth, William C.

AU - Pettersson, Mats E.

AU - Getz, Gad

AU - Meadows, Jennifer R.S.

AU - Modiano, Jaime F.

AU - Breen, Matthew

AU - Kierczak, Marcin

AU - Forsberg-Nilsson, Karin

AU - Marinescu, Voichita D.

AU - Lindblad-Toh, Kerstin

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species.

AB - Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species.

UR - http://www.scopus.com/inward/record.url?scp=85049233966&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049233966&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-17-3558

DO - 10.1158/0008-5472.CAN-17-3558

M3 - Article

VL - 78

SP - 3421

EP - 3431

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 13

ER -