Identification of a novel subgroup of endometrial cancer patients with loss of thyroid hormone receptor beta expression and improved survival

Abstract

Background Endometrial cancer (EC) is the most common gynecologic cancer in women, and the incidence of EC has increased by about 1% per year in the U. S over the last 10 years. Although 5-year survival rates for early-stage EC are around 80%, certain subtypes of EC that lose nuclear hormone receptor (NHR) expression are associated with poor survival rates. For example, estrogen receptor (ER)-negative EC typically harbors a worse prognosis compared to ER-positive EC. The molecular basis for the loss of NHR expression in endometrial tumors and its contribution to poor survival is largely unknown. Furthermore, there are no tools to systematically identify tumors that lose NHR mRNA expression relative to normal tissue. The development of such an approach could identify sets of NHR-based biomarkers for classifying patients into subgroups with poor survival outcomes. Methods Here, a new computational method, termed receptLoss, was developed for identifying NHR expression loss in endometrial cancer relative to adjacent normal tissue. When applied to gene expression data from The Cancer Genome Atlas (TCGA), receptLoss identified 6 NHRs that were highly expressed in normal tissue and exhibited expression loss in a subset of endometrial tumors. Results Three of the six identified NHRs – estrogen, progesterone, and androgen receptors – that are known to lose expression in ECs were correctly identified by receptLoss. Additionally, a novel association was found between thyroid hormone receptor beta (THRB) expression loss, increased expression of miRNA-146a, and increased rates of 5-year survival in the EC TCGA patient cohort. THRB expression loss occurs independently of estrogen and progesterone expression loss, suggesting the discovery of a distinct, clinically-relevant molecular subgroup. Conclusion ReceptLoss is a novel, open-source software tool to systematically identify NHR expression loss in cancer. The application of receptLoss to endometrial cancer gene expression data identified THRB, a previously undescribed biomarker of survival in endometrial cancer. Applying receptLoss to expression data from additional cancer types could lead to the development of biomarkers of disease progression for patients with any other tumor type. ReceptLoss can be applied to expression data from additional cancer types with the goal of identifying biomarkers of differential survival.

Subcellular Distribution of Thyroid Hormone Receptor Beta in Ovarian Cancer

“…When the expression of THRB (encoding TR beta) was tested for association with patients’ overall survival in an independent sample set, the IHC results of our cohort could be confirmed. These data are also supported by an analysis published on the TCGA cohort of endometrial cancer [ 21 ]. Applying the receptLoss algorithm, the authors highlighted that loss of THRB gene expression was linked to favorable prognosis in endometrial cancer [ 21 ].…”

“…These data are also supported by an analysis published on the TCGA cohort of endometrial cancer [ 21 ]. Applying the receptLoss algorithm, the authors highlighted that loss of THRB gene expression was linked to favorable prognosis in endometrial cancer [ 21 ]. In addition, TR beta mutations have been demonstrated to exert tumor-promoting activity in different types of cells [ 22 ].…”

Does Clinical and Biochemical Thyroid Dysfunction Impact on Endometrial Cancer Survival Outcomes? A Prospective Database Study

“…In cancer, changes in circulating levels of thyroid hormones due to thyroid disease and/or altered tumour expression of their receptors may impact tumour growth, invasion, and metastatic potential, and this has been reported in several cancer types, including glioma, myeloma, breast, lung and ovarian cancer [7]. Pique and colleagues applied a novel computational tool, receptLoss, to gene expression data from The CancerGenome Atlas (TCGA) and found an association between thyroid hormone receptor beta (THRB) expression loss and increased five-year survival in women with endometrial cancer [32]. Tumours with THRB expression loss were noted to be enriched with microsatellite instable molecular subtypes of endometrial cancer [32].…”

“…Pique and colleagues applied a novel computational tool, receptLoss, to gene expression data from The CancerGenome Atlas (TCGA) and found an association between thyroid hormone receptor beta (THRB) expression loss and increased five-year survival in women with endometrial cancer [32]. Tumours with THRB expression loss were noted to be enriched with microsatellite instable molecular subtypes of endometrial cancer [32]. The thyroid hormone receptor beta, encoded by the THRB gene, plays a crucial role in normal development, growth, and metabolism.…”

Targeting Thyroid Hormone/Thyroid Hormone Receptor Axis: An Attractive Therapy Strategy in Liver Diseases

“…The TH/TR axis is involved in HCC. Some studies have demonstrated that mutations of TR genes are associated with human carcinoma ( Anyetei-Anum et al, 2018 ; Piqué et al, 2020 ). A clinical study exhibited that hypothyroidism delays hepatocyte growth while hyperthyroidism promotes HCC ( Mishkin et al, 1981 ).…”