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Loss of Selenoprotein Iodothyronine Deiodinase 3 Expression Correlates with Progression of Complete Hydatidiform Mole to Gestational Trophoblastic Neoplasia

  • Gynecologic Oncology: Original Article
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Abstract

To investigate if differences in imprinting at tropho-microRNA (miRNA) genomic clusters can distinguish between pre-gestational trophoblastic neoplasia cases (pre-GTN) and benign complete hydatidiform mole (CHM) cases at the time of initial uterine evacuation. miRNA sequencing was performed on frozen tissue from 39 CHM cases including 9 GTN cases. DIO3, DLK1, RTL1, and MEG 3 mRNA levels were assessed by qRT-PCR. Protein abundance was assessed by Western blot for DIO3, DLK1, and RTL1. qRT-PCR and Western blot were performed for selenoproteins and markers of oxidative stress. Immunohistochemistry (IHC) was performed for DIO3 on an independent validation set of clinical samples (n = 42) and compared to normal placenta controls across gestational ages. Relative expression of the 14q32 miRNA cluster was lower in pre-GTN cases. There were no differences in protein abundance of DLK1 or RTL1. Notably, there was lower protein expression of DIO3 in pre-GTN cases (5-fold, p < 0.03). There were no differences in mRNA levels of DIO3, DLK1, RTL1 or MEG 3. mRNA levels were higher in all CHM cases compared to normal placenta. IHC showed syncytiotrophoblast-specific DIO3 immunostaining in benign CHM cases and normal placenta, while pre-GTN cases of CHM lacked DIO3 expression. We describe two new biomarkers of pre-GTN CHM cases: decreased 14q32 miRNA expression and loss of DIO3 expression by IHC. Differences in imprinting between benign CHM and pre-GTN cases may provide insight into the fundamental development of CHM.

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Acknowledgements

The authors are thankful for the support of the Donald P. Goldstein, MD Trophoblastic Tumor Registry Endowment, the Dyett Family Trophoblastic Disease Research and Registry Endowment, and the International Research Networks (IRN) under Sao Paulo State University- UNESP’s CAPES-PrInt PROJECT.

Funding

This study was completed with the support of a Brigham and Women’s Hospital Expanding the Boundaries grant. Funding for tissue transport and sample maintenance for the International Trophoblastic Disease Biobank was provided by both the Donald P. Goldstein, MD Trophoblastic Tumor Registry Endowment and the Dyett Family Trophoblastic Disease Research and Registry Endowment. Funding for processing and storage of fresh tissue samples from CHM was provided by the São Paulo Research Foundation-FAPESP (finance code 2020/08830-6) and the Brazil’s Coordination for the Improvement of Higher Educacional Personnel (CAPES) helped to maintain the International Research Network (IRN) under Sao Paulo State University- UNESP’s CAPES-PrInt PROJECT (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior- CAPES; finance code 001 [I.M.]).

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  1. Lawrence H. Lin

    Present address: Department of Pathology, New York University Langone Health, New York, NY, USA

Authors and Affiliations

  1. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA, 02115, USA

    Jessica D. St. Laurent & Kevin M. Elias

  2. New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, 75 Francis St, Boston, MA, 02115, USA

    Jessica D. St. Laurent, Arnold Castaneda, Kathleen T. Hasselblatt, Donald P. Goldstein, Neil S. Horowitz, Ross S. Berkowitz & Kevin M. Elias

  3. University of Sao Paulo Trophoblastic Disease Center, University of Sao Paulo Medical School, Sao Paulo, Brazil

    Lawrence H. Lin

  4. Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    David M. Owen

  5. Botucatu Trophoblastic Disease Center, Clinical Hospital of Botucatu Medical School, Sao Paulo State University, Sao Paulo State University-UNESP, Botucatu, Sao Paulo, Brazil

    Izildinha Maestá

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St. Laurent, J.D., Lin, L.H., Owen, D.M. et al. Loss of Selenoprotein Iodothyronine Deiodinase 3 Expression Correlates with Progression of Complete Hydatidiform Mole to Gestational Trophoblastic Neoplasia. Reprod. Sci. 28, 3200–3211 (2021). https://doi.org/10.1007/s43032-021-00634-y

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