MicroRNAs as Predictors of Future Uterine Malignancy in Endometrial Hyperplasia without Atypia

Chiao-Yun Lin; Ren-Chin Wu; Lan-Yan Yang; Shih-Ming Jung; Shir-Hwa Ueng; Yun-Hsin Tang; Huei-Jean Huang; Hsiu-Jung Tung; Cheng-Tao Lin; Hsuan-Yu Chen; Angel Chao; Chyong-Huey Lai

doi:10.3390/jpm12020311

MicroRNAs as Predictors of Future Uterine Malignancy in Endometrial Hyperplasia without Atypia

J Pers Med. 2022 Feb 18;12(2):311. doi: 10.3390/jpm12020311.

Authors

Chiao-Yun Lin^{1

2}, Ren-Chin Wu^{2

3}, Lan-Yan Yang^{4

5}, Shih-Ming Jung^{2

3}, Shir-Hwa Ueng^{2

3}, Yun-Hsin Tang^{1

2}, Huei-Jean Huang^{1

2}, Hsiu-Jung Tung^{1

2}, Cheng-Tao Lin^{1

2}, Hsuan-Yu Chen^{1

2}, Angel Chao^{1

2}, Chyong-Huey Lai^{1

2}

Affiliations

¹ Department of Obstetrics and Gynecology, College of Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 333, Taiwan.
² Gynecologic Cancer Research Center, College of Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 333, Taiwan.
³ Department of Pathology, College of Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 333, Taiwan.
⁴ Biostatics Unit, Clinical Trial Center, College of Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 333, Taiwan.
⁵ Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.

Abstract

The histological criteria for classifying endometrial hyperplasia (EH) are based on architectural crowding and nuclear atypia; however, diagnostic agreement among pathologists is poor. We investigated molecular biomarkers of endometrial cancer (EC) risk in women with simple hyperplasia or complex hyperplasia without atypia (SH/CH-nonA). Forty-nine patients with EC preceded by SH/CH-nonA were identified, of which 23 were excluded (15 with complex atypical hyperplasia (CAH), six not consenting, one with a diagnosis <6 months prior, and one lost to follow-up). The EH tissues of these patients were compared with those of patients with SH/CH-nonA that did not progress to EC (control) through microRNA (miRNA) array analysis, and the results were verified in an expanded cohort through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). MiRNA arrays analyses revealed 20 miRNAs that differed significantly (p < 0.05, fold change >4) between the control (n = 12) and case (n = 6) patients. Multiplex RT-qPCR for the 20 miRNAs in the expanded cohort (94 control and 25 case patients) led to the validation of miR-30a-3p (p = 0.0009), miR-141 (p < 0.0001), miR-200a (p < 0.0001), and miR-200b (p < 0.0001) as relevant biomarkers, among which miR-141, miR-200a, and miR-200b regulate the expression of phosphatase and tensin homolog (PTEN). For the prediction of EC, the area under the curve for miR-30a-3p, miR-141, miR-200a, and miR-200b was 0.623, 0.754, 0.783, and 0.704, respectively. The percentage of complete PTEN loss was significantly higher in the case group than in the control group (24% vs. 0%, p < 0.001, Fisher's exact test). A combination of complete PTEN loss and miR-200a provided optimal prediction performance (sensitivity = 0.760; specificity = 1.000; positive predictive value = 1.000; negative predictive value = 0.937; accuracy = 0.947). MiR-30a-3p, miR-141, miR-200a, miR-200b, and complete PTEN loss may be useful tissue biomarkers for predicting EC risk among patients with SH/CH-nonA.

Keywords: endometrial cancer; endometrial hyperplasia; microRNA; phosphatase and tensin homolog (PTEN).