Loss of ten-eleven translocation 1 (TET1) expression as a diagnostic and prognostic biomarker of endometrial carcinoma

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.

Fig 1

H&E staining in samples of normal endometrium (A), premalignant endometrial lesions, including EH without atypia (B) and AH (C), as well as malignant samples of EC, including G1 of EmAC (D), G2 of EmAC (E), G3 of EmAC (F), SC (G), MC (H), and CC (I); TET1 expression in samples of normal endometrium (A1), EH without atypia (B1), AH (C1), G1 of EmAC (D1), G2 of EmAC (E1), G3 of EmAC (F1), SC (G1), MC (H1), and CC (I1); 5-hmC expression in samples of normal endometrium (A2), EH without atypia (B2), AH (C2), G1 of EmAC (D2), G2 of EmAC (E2), G3 of EmAC (F2), SC (G2), MC (H2), and CC (I2); 5-mC expression in samples of normal endometrium (A3), EH without atypia (B3), AH (C3), G1 of EmAC (D3), G2 of EmAC (E3), G3 of EmAC (F3), SC (G3), MC (H3), and CC (I3).

Fig 2. TET1 mRNA expression in normal endometrium and ECs.

Fig 3. Comparison of TET1 IHC score and TET1 mRNA level.

The two parameters were compared and analyzed by simple linear regression. The TET1 mRNA copies were calculated and shown with every 10,000 copies of GAPDH. The dotted line means the 95% confidence interval of simple linear regression analysis.

Fig 4. Kaplan–Meier analysis stratified according to TET1 expression score.

Analysis to assess the prognostic value of the TET1 immunoreactivity in relation to OS.

Fig 5. Kaplan–Meier analysis stratified according to TET1 expression score.

Analysis to assess the prognostic value of the TET1 immunoreactivity in relation to PFS.