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

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.