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

Lookup NU author(s): Dr Ujjal Mallick

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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 35.8±2.6%, 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.

Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: Oncogene

Year: 2017

Volume: 36

Issue: 37

Pages: 5296-5308

Print publication date: 14/09/2017

Online publication date: 15/05/2017

Acceptance date: 17/04/2017

ISSN (print): 0950-9232

ISSN (electronic): 1476-5594

Publisher: Nature

URL: https://doi.org/10.1038/onc.2017.154

DOI: 10.1038/onc.2017.154

PubMed id: 28504713

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