Abstract
Endometrial carcinoma (EC) is the most common gynecological cancer. However, there is currently no routinely used biomarker for differential diagnosis of malignant and premalignant endometrial lesions. Ten-eleven translocation (TET) proteins, especially TET1, were found to play a significant role in DNA demethylation, via conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). TET1, 5-mC, and 5-hmC expression profiles in endometrial carcinogenesis are currently unclear. We conducted a hospital-based retrospective review of the immunohistochemical expression of TET1, 5-mC, and 5-hmC in 181 endometrial samples. A “high” TET1 and 5-hmC expression score was observed in all cases of normal endometrium (100.0% and 100.0%, respectively) and in most samples of endometrial hyperplasia without atypia (90.9% and 78.8%, respectively) and atypical hyperplasia (90.6% and 93.8%, respectively), but a “high” score was found in only less than half of the EC samples (48.8% and 46.5%, respectively). The TET1 and 5-hmC expression scores were significantly higher in normal endometrium and premalignant endometrial lesions than in ECs (p < 0.001). A “high” 5-mC expression score was observed more frequently for ECs (81.4%) than for normal endometrium (40.0%), endometrial hyperplasia without atypia (51.5%), and atypical hyperplasia (53.1%) (p < 0.001). We also found that TET1 mRNA expression was lower in ECs compared to normal tissues (p = 0.0037). TET1 immunohistochemistry (IHC) scores were highly proportional to the TET1 mRNA levels and we summarize that the TET1 IHC scoring can be used for biomarker determinations. Most importantly, a higher TET1 score in EC cases was associated with a good overall survival (OS) rate, with a hazard ratio (HR) of 0.31 for death (95% confidence interval: 0.11–0.84). Our findings suggest that TET1, 5-mC, and 5-hmC expression is a potential histopathology biomarker for the differential diagnosis of malignant and premalignant endometrial lesions. TET1 is also a potential prognostic marker for EC.
Highlights
In the United States and most developed countries, Endometrial carcinoma (EC) is the most common gynecological malignancy, and its incidence is increasing
We found a significant variation in levels of these three markers between the samples of premalignant endometrial lesions and malignant lesions
High intranuclear immunoreactivity scores were observed for TET1 in all samples of normal endometrium (30/30, 100%) and most samples of premalignant endometrial lesions, including endometrial hyperplasia (EH) without atypia (30/33, 90.9%) and atypical hyperplasia (AH) (29/32, 90.6%); whereas significantly lower TET1 expression was observed in EC cases (42/86, 48.8%), including endometrioid adenocarcinoma (EmAC), serous carcinoma (SC), CC, and mucinous carcinoma (MC) (p < 0.001) (Table 1)
Summary
In the United States and most developed countries, EC is the most common gynecological malignancy, and its incidence is increasing. The estrogen-dependent type I EC includes nuclear grade 1 (G1) and grade 2 (G2) endometrioid adenocarcinoma (EmAC). The less common, clinically aggressive estrogen-independent type II EC includes nuclear grade 3 (G3) EmAC, serous carcinoma (SC), and clear cell carcinoma (CC) [1,2,3]. Most type I EmAC cases are diagnosed at an early stage, cases diagnosed at advanced stages usually present a poor survival rate. It is essential to identify EC at an early stage. There is no reliable biomarker that can be used to successfully distinguish between malignant and premalignant endometrial lesions [4]. Identification of biomarkers to improve the diagnosis is urgently required
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