A recurrent somatic missense mutation in GNAS gene identified in familial thyroid follicular cell carcinomas in German longhaired pointer dogs

Yun Yu; Freek Manders; Guy C M Grinwis; Martien A M Groenen; Richard P M A Crooijmans

doi:10.1186/s12864-022-08885-y

A recurrent somatic missense mutation in GNAS gene identified in familial thyroid follicular cell carcinomas in German longhaired pointer dogs

Yun Yu, Freek Manders, Guy C M Grinwis, Martien A M Groenen, Richard P M A Crooijmans

VPDC Pathology

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: We previously reported a familial thyroid follicular cell carcinoma (FCC) in a large number of Dutch German longhaired pointers and identified two deleterious germline mutations in the TPO gene associated with disease predisposition. However, the somatic mutation profile of the FCC in dogs has not been investigated at a genome-wide scale.

RESULTS: Herein, we comprehensively investigated the somatic mutations that potentially contribute to the inherited tumor formation and progression using high depth whole-genome sequencing. A GNAS p.A204D missense mutation was identified in 4 out of 7 FCC tumors by whole-genome sequencing and in 20 out of 32 dogs' tumors by targeted sequencing. In contrast to this, in the human TC, mutations in GNAS gene have lower prevalence. Meanwhile, the homologous somatic mutation in humans has not been reported. These findings suggest a difference in the somatic mutation landscape between TC in these dogs and human TC. Moreover, tumors with the GNAS p.A204D mutation had a significantly lower somatic mutation burden in these dogs. Somatic structural variant and copy number alterations were also investigated, but no potential driver event was identified.

CONCLUSION: This study provides novel insight in the molecular mechanism of thyroid carcinoma development in dogs. German longhaired pointers carrying GNAS mutations in the tumor may be used as a disease model for the development and testing of novel therapies to kill the tumor with somatic mutations in the GNAS gene.

Original language	English
Article number	669
Pages (from-to)	1-13
Journal	BMC Genomics
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s12864-022-08885-y
Publication status	Published - Dec 2022

Bibliographical note

Funding Information:
We thank the “Nederlands Kankerfonds voor Dieren” for providing financial support for this study. We also thank the breeder association for providing pedigree information. We thank Johan de Vos and Mariska de Ruijsscher and for their contribution in sampling. We thank Ruben van Boxtel for his advises on mutational signatures analyses. We thank Markus J. van Roosmalen for his suggestions on somatic variants analyses. We thank Kimberley Laport for technical assistance for the RNA and DNA isolations and validation of the GNAS mutation. Library preparation/sequencing are performed by Novogene (UK) Company Limited. Yun’s PhD study was supported by China Scholarship Council (CSC). †

Funding Information:
We thank the “Nederlands Kankerfonds voor Dieren” for providing financial support for this study. We also thank the breeder association for providing pedigree information. We thank Johan de Vos†and Mariska de Ruijsscher and for their contribution in sampling. We thank Ruben van Boxtel for his advises on mutational signatures analyses. We thank Markus J. van Roosmalen for his suggestions on somatic variants analyses. We thank Kimberley Laport for technical assistance for the RNA and DNA isolations and validation of the GNAS mutation. Library preparation/sequencing are performed by Novogene (UK) Company Limited. Yun’s PhD study was supported by China Scholarship Council (CSC).

Publisher Copyright:
© 2022, The Author(s).

Keywords

Dog
Driver mutation
Familial cancer
GNAS
Mutational signature
Thyroid carcinoma
Whole genome sequencing

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

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title = "A recurrent somatic missense mutation in GNAS gene identified in familial thyroid follicular cell carcinomas in German longhaired pointer dogs",

abstract = "BACKGROUND: We previously reported a familial thyroid follicular cell carcinoma (FCC) in a large number of Dutch German longhaired pointers and identified two deleterious germline mutations in the TPO gene associated with disease predisposition. However, the somatic mutation profile of the FCC in dogs has not been investigated at a genome-wide scale.RESULTS: Herein, we comprehensively investigated the somatic mutations that potentially contribute to the inherited tumor formation and progression using high depth whole-genome sequencing. A GNAS p.A204D missense mutation was identified in 4 out of 7 FCC tumors by whole-genome sequencing and in 20 out of 32 dogs' tumors by targeted sequencing. In contrast to this, in the human TC, mutations in GNAS gene have lower prevalence. Meanwhile, the homologous somatic mutation in humans has not been reported. These findings suggest a difference in the somatic mutation landscape between TC in these dogs and human TC. Moreover, tumors with the GNAS p.A204D mutation had a significantly lower somatic mutation burden in these dogs. Somatic structural variant and copy number alterations were also investigated, but no potential driver event was identified.CONCLUSION: This study provides novel insight in the molecular mechanism of thyroid carcinoma development in dogs. German longhaired pointers carrying GNAS mutations in the tumor may be used as a disease model for the development and testing of novel therapies to kill the tumor with somatic mutations in the GNAS gene.",

keywords = "Dog, Driver mutation, Familial cancer, GNAS, Mutational signature, Thyroid carcinoma, Whole genome sequencing",

author = "Yun Yu and Freek Manders and Grinwis, \{Guy C M\} and Groenen, \{Martien A M\} and Crooijmans, \{Richard P M A\}",

note = "Funding Information: We thank the “Nederlands Kankerfonds voor Dieren” for providing financial support for this study. We also thank the breeder association for providing pedigree information. We thank Johan de Vos and Mariska de Ruijsscher and for their contribution in sampling. We thank Ruben van Boxtel for his advises on mutational signatures analyses. We thank Markus J. van Roosmalen for his suggestions on somatic variants analyses. We thank Kimberley Laport for technical assistance for the RNA and DNA isolations and validation of the GNAS mutation. Library preparation/sequencing are performed by Novogene (UK) Company Limited. Yun{\textquoteright}s PhD study was supported by China Scholarship Council (CSC). † Funding Information: We thank the “Nederlands Kankerfonds voor Dieren” for providing financial support for this study. We also thank the breeder association for providing pedigree information. We thank Johan de Vos†and Mariska de Ruijsscher and for their contribution in sampling. We thank Ruben van Boxtel for his advises on mutational signatures analyses. We thank Markus J. van Roosmalen for his suggestions on somatic variants analyses. We thank Kimberley Laport for technical assistance for the RNA and DNA isolations and validation of the GNAS mutation. Library preparation/sequencing are performed by Novogene (UK) Company Limited. Yun{\textquoteright}s PhD study was supported by China Scholarship Council (CSC). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s12864-022-08885-y",

language = "English",

volume = "23",

pages = "1--13",

journal = "BMC Genomics",

issn = "1471-2164",

publisher = "BioMed Central",

number = "1",

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TY - JOUR

T1 - A recurrent somatic missense mutation in GNAS gene identified in familial thyroid follicular cell carcinomas in German longhaired pointer dogs

AU - Yu, Yun

AU - Manders, Freek

AU - Grinwis, Guy C M

AU - Groenen, Martien A M

AU - Crooijmans, Richard P M A

N1 - Funding Information: We thank the “Nederlands Kankerfonds voor Dieren” for providing financial support for this study. We also thank the breeder association for providing pedigree information. We thank Johan de Vos and Mariska de Ruijsscher and for their contribution in sampling. We thank Ruben van Boxtel for his advises on mutational signatures analyses. We thank Markus J. van Roosmalen for his suggestions on somatic variants analyses. We thank Kimberley Laport for technical assistance for the RNA and DNA isolations and validation of the GNAS mutation. Library preparation/sequencing are performed by Novogene (UK) Company Limited. Yun’s PhD study was supported by China Scholarship Council (CSC). † Funding Information: We thank the “Nederlands Kankerfonds voor Dieren” for providing financial support for this study. We also thank the breeder association for providing pedigree information. We thank Johan de Vos†and Mariska de Ruijsscher and for their contribution in sampling. We thank Ruben van Boxtel for his advises on mutational signatures analyses. We thank Markus J. van Roosmalen for his suggestions on somatic variants analyses. We thank Kimberley Laport for technical assistance for the RNA and DNA isolations and validation of the GNAS mutation. Library preparation/sequencing are performed by Novogene (UK) Company Limited. Yun’s PhD study was supported by China Scholarship Council (CSC). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - BACKGROUND: We previously reported a familial thyroid follicular cell carcinoma (FCC) in a large number of Dutch German longhaired pointers and identified two deleterious germline mutations in the TPO gene associated with disease predisposition. However, the somatic mutation profile of the FCC in dogs has not been investigated at a genome-wide scale.RESULTS: Herein, we comprehensively investigated the somatic mutations that potentially contribute to the inherited tumor formation and progression using high depth whole-genome sequencing. A GNAS p.A204D missense mutation was identified in 4 out of 7 FCC tumors by whole-genome sequencing and in 20 out of 32 dogs' tumors by targeted sequencing. In contrast to this, in the human TC, mutations in GNAS gene have lower prevalence. Meanwhile, the homologous somatic mutation in humans has not been reported. These findings suggest a difference in the somatic mutation landscape between TC in these dogs and human TC. Moreover, tumors with the GNAS p.A204D mutation had a significantly lower somatic mutation burden in these dogs. Somatic structural variant and copy number alterations were also investigated, but no potential driver event was identified.CONCLUSION: This study provides novel insight in the molecular mechanism of thyroid carcinoma development in dogs. German longhaired pointers carrying GNAS mutations in the tumor may be used as a disease model for the development and testing of novel therapies to kill the tumor with somatic mutations in the GNAS gene.

AB - BACKGROUND: We previously reported a familial thyroid follicular cell carcinoma (FCC) in a large number of Dutch German longhaired pointers and identified two deleterious germline mutations in the TPO gene associated with disease predisposition. However, the somatic mutation profile of the FCC in dogs has not been investigated at a genome-wide scale.RESULTS: Herein, we comprehensively investigated the somatic mutations that potentially contribute to the inherited tumor formation and progression using high depth whole-genome sequencing. A GNAS p.A204D missense mutation was identified in 4 out of 7 FCC tumors by whole-genome sequencing and in 20 out of 32 dogs' tumors by targeted sequencing. In contrast to this, in the human TC, mutations in GNAS gene have lower prevalence. Meanwhile, the homologous somatic mutation in humans has not been reported. These findings suggest a difference in the somatic mutation landscape between TC in these dogs and human TC. Moreover, tumors with the GNAS p.A204D mutation had a significantly lower somatic mutation burden in these dogs. Somatic structural variant and copy number alterations were also investigated, but no potential driver event was identified.CONCLUSION: This study provides novel insight in the molecular mechanism of thyroid carcinoma development in dogs. German longhaired pointers carrying GNAS mutations in the tumor may be used as a disease model for the development and testing of novel therapies to kill the tumor with somatic mutations in the GNAS gene.

KW - Dog

KW - Driver mutation

KW - Familial cancer

KW - GNAS

KW - Mutational signature

KW - Thyroid carcinoma

KW - Whole genome sequencing

UR - https://www.scopus.com/pages/publications/85138460372

U2 - 10.1186/s12864-022-08885-y

DO - 10.1186/s12864-022-08885-y

M3 - Article

C2 - 36151521

SN - 1471-2164

VL - 23

SP - 1

EP - 13

JO - BMC Genomics

JF - BMC Genomics

IS - 1

M1 - 669

ER -

A recurrent somatic missense mutation in GNAS gene identified in familial thyroid follicular cell carcinomas in German longhaired pointer dogs

Abstract

Bibliographical note

Keywords

UN SDGs

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