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

Research output: Contribution to journalArticle

Authors

External organisations

  • Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
  • University College London

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=2.4x10-4) compared to either PBF-(P=1.5x10-3) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes (mean 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 datasets (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 RTK-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=1.91x10-5) and disease-free survival (P=4.9x10-5) 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.

Details

Original languageEnglish
Article number72326
JournalOncogene
Early online date15 May 2017
Publication statusE-pub ahead of print - 15 May 2017

Keywords

  • DNA repair, DNA damage, p53, thyroid, PTTG1IP