TY - JOUR
T1 - High tumoral expression of PBF and PTTG modulates the DNA damage response and is associated with poor survival in thyroid cancer
AU - Read, Martin
AU - Fong, Jim
AU - Imruetaicharoenchoke, Waraporn
AU - Nieto, Hannah
AU - Modasia, Bhavika
AU - Fletcher, Alice
AU - Thompson, Rebecca
AU - Sharma, Neil
AU - Bacon, Andrea
AU - Watkinson, John
AU - Boelaert, Kristien
AU - Turnell, Andrew
AU - Smith, Vicki
AU - McCabe, Christopher
PY - 2016/11/4
Y1 - 2016/11/4
N2 - 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.
AB - 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.
UR - http://www.endocrine-abstracts.org/ea/0044/ea0044P246.htm
U2 - 10.1530/endoabs.44.P246
DO - 10.1530/endoabs.44.P246
M3 - Abstract
SN - 1470-3947
VL - 44
JO - Endocrine Abstracts
JF - Endocrine Abstracts
M1 - P246
ER -