High tumoral expression of PBF and PTTG modulates the DNA damage response and is associated with poor survival in thyroid cancer

Martin Read, Jim Fong, Waraporn Imruetaicharoenchoke, Hannah Nieto, Bhavika Modasia, Alice Fletcher, Rebecca Thompson, Neil Sharma, Andrea Bacon, John Watkinson, Kristien Boelaert, Andrew Turnell, Vicki Smith, Christopher McCabe

Research output: Contribution to journalAbstractpeer-review


Despite extensive genomic profiling a better understanding of the contributory factors that promote aggressive thyroid cancer is urgently needed. The proto-oncogenes PBF and PTTG have been implicated in thyroid cancer but there is a lack of information regarding their co-expression and specific roles in tumour progression. Separate studies have previously indicated that PBF and PTTG may disrupt pathways associated with the tumour suppressor p53 that are central to DNA-damage repair (DDR), cell growth and apoptosis. To further investigate this, we examined the association of PBF and PTTG with p53-related genes in the human thyroid TCGA cancer dataset, as well as in a bi-transgenic murine model (Bi-Tg) overexpressing PBF and PTTG specifically in the thyroid gland. Characterisation of primary murine Bi-Tg thyrocytes revealed that co-expression of PBF and PTTG caused extensive repression of DDR genes (31/82 genes; >1.5-fold; P<0.05), including genes with key roles in maintaining genomic integrity such as Brca1. Irradiation exposure to cause DNA damage gave further evidence of significant repression of DDR genes (n=82) between irradiated Bi-Tg and wild-type thyrocytes (P=2.4×10−4) that was greater than either PBF-Tg (P=1.5×10−3) or PTTG-Tg thyrocytes (P=NS). By comparison in the TCGA dataset, there were striking correlations with PBF and PTTG in well-characterised p53-related gene panels (P<0.05; 82–96 genes per panel; n=322 TCGA tumour samples). Importantly, nearly half of the DDR gene alterations in Bi-Tg thyrocytes were also present in TCGA comparing tumours with either low or high PBF/PTTG expression. Furthermore, the overall survival (P=1.91×10−5) and disease-free survival (P=4.9×10−5) was poorer for TCGA individuals with high tumoral PBF/PTTG expression and mutationally activated BRAF than for all other patients. Together our study provides important insights into the role of PBF and PTTG in modulating p53-related genes to promote tumorigenesis. We also identify using PBF and PTTG together as a new clinical indicator for aggressive thyroid cancer.
Original languageEnglish
Article numberP246
JournalEndocrine Abstracts
Publication statusPublished - 4 Nov 2016


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