M Verheecke1, A Cortès Calabuig2, J Finalet Ferreiro2, V Brys2, R Van Bree3, G Verbist2, T Everaert4, L Leemans4, M M Gziri5, I Boere6, M J Halaska7, J Vanhoudt2, F Amant8, K Van Calsteren9. 1. Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Department of Obstetrics and Gynecology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. 2. Genomics Core, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. 3. Department of Reproduction and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. 4. Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. 5. Department of Obstetrics and Gynecology, Cliniques Universitaires St. Luc, Hippokrateslaan 10, 1200 Brussels, Belgium. 6. Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. 7. Department of Obstetrics and Gynaecology, 3rd Medical Faculty, Charles University, Prague 5, Faculty Hospital Kralovske Vinohrady, Srobarova 1150/50, 100 34, Prague 10, Czech Republic. 8. Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Department of Gynaecologic Oncology, Center for Gynaecologic Oncology, Amsterdam, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. Electronic address: f.amant@nki.nl. 9. Department of Obstetrics and Gynecology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium; Department of Reproduction and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
Abstract
INTRODUCTION: Fetal growth restriction (FGR) carries an increased risk of perinatal mortality and morbidity. A major cause of FGR is placental insufficiency. After in utero chemotherapy-exposure, an increased incidence of FGR has been reported. In a prospective cohort study we aimed to explore which pathways may contribute to chemotherapy-associated FGR. METHODS: Placental biopsies were collected from 25 cancer patients treated with chemotherapy during pregnancy, and from 66 control patients. Differentially expressed pathways between chemotherapy-exposed patients and controls were examined by whole transcriptome shotgun sequencing (WTSS) and Ingenuity Pathway Analysis (IPA). Immunohistochemical studies for 8-OHdG and eNOS (oxidative DNA damage), proliferation (PCNA) and apoptosis (Cleaved Caspase 3) were performed. The expression level of eNOS, PCNA and IGFBP6 was verified by real-time quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). RESULTS: Most differential expressed genes between chemotherapy-exposed patients and controls were related to growth, developmental processes, and radical scavenging networks. The duration of chemotherapy exposure had an additional impact on the expression of genes related to the superoxide radicals degeneration network. Immunohistochemical analyses showed a significantly increased expression of 8-OHdG (P = 0.003) and a decreased expression of eNOS (P=0.015) in the syncytiotrophoblast of the placenta of cancer patients. A decreased expression of PCNA was detected by immunohistochemistry as RT-qPCR (NS). CONCLUSION: Chemotherapy exposure during pregnancy results in an increase of oxidative DNA damage and might impact the placental cellular growth and development, resulting in an increased incidence of FGR in this specific population. Further large prospective cohort studies and longitudinal statistical analyses are needed.
INTRODUCTION: Fetal growth restriction (FGR) carries an increased risk of perinatal mortality and morbidity. A major cause of FGR is placental insufficiency. After in utero chemotherapy-exposure, an increased incidence of FGR has been reported. In a prospective cohort study we aimed to explore which pathways may contribute to chemotherapy-associated FGR. METHODS: Placental biopsies were collected from 25 cancerpatients treated with chemotherapy during pregnancy, and from 66 control patients. Differentially expressed pathways between chemotherapy-exposed patients and controls were examined by whole transcriptome shotgun sequencing (WTSS) and Ingenuity Pathway Analysis (IPA). Immunohistochemical studies for 8-OHdG and eNOS (oxidative DNA damage), proliferation (PCNA) and apoptosis (Cleaved Caspase 3) were performed. The expression level of eNOS, PCNA and IGFBP6 was verified by real-time quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). RESULTS: Most differential expressed genes between chemotherapy-exposed patients and controls were related to growth, developmental processes, and radical scavenging networks. The duration of chemotherapy exposure had an additional impact on the expression of genes related to the superoxide radicals degeneration network. Immunohistochemical analyses showed a significantly increased expression of 8-OHdG (P = 0.003) and a decreased expression of eNOS (P=0.015) in the syncytiotrophoblast of the placenta of cancerpatients. A decreased expression of PCNA was detected by immunohistochemistry as RT-qPCR (NS). CONCLUSION: Chemotherapy exposure during pregnancy results in an increase of oxidative DNA damage and might impact the placental cellular growth and development, resulting in an increased incidence of FGR in this specific population. Further large prospective cohort studies and longitudinal statistical analyses are needed.
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