Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer

M. L. Read; J. C. Fong; B. Modasia; A. Fletcher; W. Imruetaicharoenchoke; R. J. Thompson; H. Nieto; J. J. Reynolds; A. Bacon; U. Mallick; A. Hackshaw; J. C. Watkinson; K. Boelaert; A. S. Turnell; V. E. Smith; C. J. McCabe

doi:10.1038/onc.2017.154

Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer

M. L. Read
, J. C. Fong
, B. Modasia
, A. Fletcher
, W. Imruetaicharoenchoke
, R. J. Thompson
, H. Nieto
, J. J. Reynolds
, A. Bacon
, U. Mallick
, A. Hackshaw
, J. C. Watkinson
, K. Boelaert
, A. S. Turnell
, V. E. Smith
, C. J. McCabe^*

^*Corresponding author for this work

Freeman Hospital
University College London
University Hospitals Birmingham NHS Foundation Trust
University College Birmingham

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

24 Citations (Scopus)

Abstract

The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P = 2.4 × 10^-4) compared with either PBF- (P = 1.5 × 10^-3) or PTTG-expressing thyrocytes (P = NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes with a mean genetic instability (GI) index of 35.872.6%, as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA data sets (n = 322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the receptor tyrosine kinase-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well described to drive neoplastic growth. We also showed that overall survival (P = 1.91 × 10^-5) and disease-free survival (P = 4.9 × 10^-5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome.

Original language	English
Pages (from-to)	5296-5308
Number of pages	13
Journal	Oncogene
Volume	36
Issue number	37
DOIs	https://doi.org/10.1038/onc.2017.154
Publication status	Published - 14 Sept 2017

Bibliographical note

Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Funding

This work was supported by the Medical Research Council (MR/J001414/1), Wellcome Trust, Cancer Research UK, Get Ahead Charitable Trust and AMEND. Results are in part based upon data generated by the TCGA Research Network: http://cancergenome. nih.gov/.

Funders	Funder number
Get Ahead Charitable Trust
Wellcome Trust
Medical Research Council	MR/J001414/1, G0601811, MR/P000509/1
Cancer Research UK

UN SDGs

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

SDG 3 Good Health and Well-being

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10.1038/onc.2017.154

Cite this

Read, M. L., Fong, J. C., Modasia, B., Fletcher, A., Imruetaicharoenchoke, W., Thompson, R. J., Nieto, H., Reynolds, J. J., Bacon, A., Mallick, U., Hackshaw, A., Watkinson, J. C., Boelaert, K., Turnell, A. S., Smith, V. E., & McCabe, C. J. (2017). Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer. Oncogene, 36(37), 5296-5308. https://doi.org/10.1038/onc.2017.154

@article{bd205526ef5b4277bfc217124afe12d5,

title = "Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer",

abstract = "The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P = 2.4 × 10-4) compared with either PBF- (P = 1.5 × 10-3) or PTTG-expressing thyrocytes (P = NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes with a mean genetic instability (GI) index of 35.872.6\%, as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA data sets (n = 322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the receptor tyrosine kinase-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well described to drive neoplastic growth. We also showed that overall survival (P = 1.91 × 10-5) and disease-free survival (P = 4.9 × 10-5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome.",

author = "Read, \{M. L.\} and Fong, \{J. C.\} and B. Modasia and A. Fletcher and W. Imruetaicharoenchoke and Thompson, \{R. J.\} and H. Nieto and Reynolds, \{J. J.\} and A. Bacon and U. Mallick and A. Hackshaw and Watkinson, \{J. C.\} and K. Boelaert and Turnell, \{A. S.\} and Smith, \{V. E.\} and McCabe, \{C. J.\}",

year = "2017",

month = sep,

day = "14",

doi = "10.1038/onc.2017.154",

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Read, ML, Fong, JC, Modasia, B, Fletcher, A, Imruetaicharoenchoke, W, Thompson, RJ, Nieto, H, Reynolds, JJ, Bacon, A, Mallick, U, Hackshaw, A, Watkinson, JC, Boelaert, K, Turnell, AS, Smith, VE & McCabe, CJ 2017, 'Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer', Oncogene, vol. 36, no. 37, pp. 5296-5308. https://doi.org/10.1038/onc.2017.154

TY - JOUR

T1 - Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer

AU - Read, M. L.

AU - Fong, J. C.

AU - Modasia, B.

AU - Fletcher, A.

AU - Imruetaicharoenchoke, W.

AU - Thompson, R. J.

AU - Nieto, H.

AU - Reynolds, J. J.

AU - Bacon, A.

AU - Mallick, U.

AU - Hackshaw, A.

AU - Watkinson, J. C.

AU - Boelaert, K.

AU - Turnell, A. S.

AU - Smith, V. E.

AU - McCabe, C. J.

PY - 2017/9/14

Y1 - 2017/9/14

N2 - The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P = 2.4 × 10-4) compared with either PBF- (P = 1.5 × 10-3) or PTTG-expressing thyrocytes (P = NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes with a mean genetic instability (GI) index of 35.872.6%, as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA data sets (n = 322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the receptor tyrosine kinase-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well described to drive neoplastic growth. We also showed that overall survival (P = 1.91 × 10-5) and disease-free survival (P = 4.9 × 10-5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome.

AB - The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P = 2.4 × 10-4) compared with either PBF- (P = 1.5 × 10-3) or PTTG-expressing thyrocytes (P = NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes with a mean genetic instability (GI) index of 35.872.6%, as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA data sets (n = 322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the receptor tyrosine kinase-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well described to drive neoplastic growth. We also showed that overall survival (P = 1.91 × 10-5) and disease-free survival (P = 4.9 × 10-5) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome.

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SN - 0950-9232

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ER -

Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer

Abstract

Bibliographical note

Funding

UN SDGs

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