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.

Differential Expression of Steroid Hormone Receptors and Ten Eleven Translocation Proteins in Endometrial Cancer Cells

“…The decreased protein expression during 72 hours of estrogen-progesterone treatment, suggests a potential aberrant regulation of TET1 in AN3 cells. Data by other studies report similar findings with decreased TET1 mRNA and protein expression in endometrial cancer tissues compared to normal ( 9 , 36 ). It has been suggested that overexpression of DNMT3a and DNMT3b contribute to hypermethylation of ERα and PR , subsequently silencing these genes in endometrial cancer ( 37 ).…”

Aberrations of DNA methylation in cancer

“…Снижение экспрессии ТЕТ1 характерно для карциномы эндометрия, но не для предраковых заболеваний, таких как гиперплазия эндометрия. Отмечается, что высокий уровень экспрессии TET1 при раке эндометрия коррелирует с хорошими показателями выживаемости, что может быть использовано в качестве прогностического маркера [114]. Опухоли желудка также характеризуются пониженным уровнем экспрессии TET1.…”

Cell‐free DNA 5‐hydroxymethylcytosine as a marker for common cancer detection

“…1,2 Global loss of 5hmC occurs in many cancers and is closely correlated with poor prognosis in multiple malignancies. 1,2,[5][6][7][8][9][10][11] These features indicate that 5hmC is a promising biomarker candidate for cancer detection.…”

“…5hmC levels are correlated with cancer initiation, progression and histological grade and negatively correlated with DNA methylation changes 1,2 . Global loss of 5hmC occurs in many cancers and is closely correlated with poor prognosis in multiple malignancies 1,2,5–11 . These features indicate that 5hmC is a promising biomarker candidate for cancer detection.…”