Hypermethylation of SOX2 gene in hydatidiform mole and choriocarcinoma

This study investigated the expression and methylation profiles of SOX2, a stem cell-related transcription factor, in placentas and gestational trophoblastic disease. The methylation status of SOX2 promoter region in 55 hydatidiform moles, 4 choriocarcinoma, 23 first trimester, and 15 term placentas was evaluated by methylation-specific polymerase chain reaction. The methylated allele was found in 4.4% (1/23) of first trimester placentas, 26.7% (4/15) term placentas, and 56.4% (31/55) of hydatidiform moles and all choriocarcinoma samples and cell lines. A significant reduction in SOX2 messenger RNA expression was found in the hydatidiform moles (P = .027) when compared with that in the placentas. SOX2 messenger RNA expression was significantly correlated with SOX2 hypermethylation (P < .001). SOX2 expression was restored in choriocarcinoma cell lines following treatment to 5-Aza-2(')-deoxycytidine and/or Trichostatin A, demethylation and histone deacetylase inhibitors, respectively, and the response was synergistic. Epigenetic mechanisms may play important role on the transcriptional regulation of SOX2 and contribute to pathogenesis of gestational trophoblastic disease.link_to_subscribed_fulltex

ΔNp73 expression is a potentially useful prognostic marker to predict development of persistent gestational trophoblastic neoplasia requiring chemotherapy in patients suffering from complete hydatidiform moles

Background ΔNp73 is an anti-apoptotic, NH2-terminal truncated isoform encoded by p73 gene. ΔNp73 overexpression has been found in some cancers but its expression in gestational trophoblastic diseases (GTD) has never been reported. Aims of study (1) to investigate ΔNp73 expression in normal placentas and GTD (2) to compare ΔNp73 expression in choriocarcinoma cell lines treated by demethylating agent with untreated controls (3) to correlate ΔNp73 expression with development of persistent gestational trophoblastic neoplasia (GTN) and occurrence of metastases. Method Immunohistochemical study was performed for ΔNp73 expression on 73 paraffin sections including first trimester placenta (11), term placenta (6), partial moles (12), complete moles (33), choriocarcinoma (5) and hydropic abortion (6). Western blotting analysis was performed on first trimester placenta (3), term placenta (3), hydatidiform moles (7), 1 normal extravillous trophoblast cell line and 2 choriocarcinoma cell lines (JEG-3 and JAR). Two choriocarcinoma cell lines (JEG-3 and JAR) were treated with demethylating agent 5-aza-2’deoxycytidine. Total RNA was extracted from these treated cell lines, as well as from untreated controls. Reverse transcription followed by real-time polymerase chain reaction was then performed to assess ΔNp73 expression. Results ΔNp73 was expressed in villous cytotrophoblasts, intervillous trophoblast islands, syncitiotrophoblasts, deciduas and extravillous trophoblasts. ΔNp73 expression decreased with advancing gestation, with lower expression in term placentas compared with first trimester placentas (p<0.001). Significant difference was found in ΔNp73 expression with normal placentas showing the strongest expression, followed by hydatidiform moles and choriocarcinoma (p<0.001). Western blotting analysis showed strong expression in normal placentas but markedly reduced expression in choriocarcinoma cell lines. ΔNp73 expression was significantly higher in 5-aza-2’deoxycytidine-treated choriocarcinoma cell lines than in untreated controls. Complete moles which subsequently developed persistent GTN requiring chemotherapy showed significantly higher ΔNp73 expression than those which regressed spontaneously (p=0.034). There was no significant difference in ΔNp73 expression between cases of persistent GTN with metastases and cases without. Conclusion ΔNp73 may play a role in the development of hydatidiform moles and choriocarcinoma. It is a potentially useful prognostic marker to predict development of persistent GTN requiring chemotherapy in patients with complete moles. The unexpected down-regulation of ΔNp73, which is supposed to be anti-apoptotic, in choriocarcinoma may be contributed by aberrant methylation of the p73 gene promoter region

Oct4 is Epigenetically Regulated by Methylation in Normal Placenta and Gestational Trophoblastic Disease

Oct4 is a transcription factor that plays a crucial role in maintaining pluripotency of embryonic stem cells. Down-regulation of Oct4 is associated with the differentiation of trophectoderm cell lineage, from which the normal placenta derives. We investigated the methylation and expression status of Oct4 in normal placenta and gestational trophoblastic disease (GTD) as attempts to investigate the role of Oct4 in the pathogenesis of GTD. By methylation-specific PCR, we observed both methylated and unmethylated Oct4 alleles in all 25 first trimester and 10 term placentas while 33% (18/54) of hydatidiform moles, and two choriocarcinoma cell line (JEG3 and JAR), only displayed methylated Oct4 allele. By quantitative TaqMan real-time PCR, Oct4 mRNA was significantly reduced in hydatidiform moles (P = 0.04), JEG3 and JAR (P = 0.024) when compared with normal placentas. Oct4 methylation was significantly correlated with Oct4 mRNA expression in placenta and GTD (P = 0.012). Hypermethylation in minimal promoter and exon 1 region of Oct4 were confirmed in JEG3 and JAR by bisulfite genomic sequencing. The Oct4 mRNA expression in JEG3 and JAR increased after treatment with 5-aza-2′-deoxycytidine and/or trichostatin A. Our findings suggest that Oct4 is down-regulated by hypermethylation in normal placenta and GTD and such process is important in pathogenesis of GTD. © 2008 Elsevier Ltd. All rights reserved.link_to_subscribed_fulltex

Hypermethylation of RAS effector related genes and DNA methyltransferase 1 expression in endometrial carcinogenesis

Epigenetic aberration is known to be important in human carcinogenesis. Promoter methylation status of RAS effector related genes, RASSF1A, RASSF2A, hDAB2IP (m2a and m2b regions) and BLU, was evaluated in 76 endometrial carcinomas and their non-neoplastic endometrial tissue by methylation specific PCR. Hypermethylation of at least one of the 5 genes was detected in 73.7% of carcinomas. There were significant correlations between methylation of hDAB2IP and RASSF1A, RASSF2A (p = 0.042, p = 0.012, respectively). Significantly, more frequent RASSF1A hypermethylation was found in Type I endometrioid carcinomas than Type II carcinomas (p = 0.049). Among endometrioid cancers, significant association between RASSF1A hypermethylation and advanced stage, as well as between methylation of hDAB2IP at m2a region with deep myometrial invasion (p < 0.05) was observed. mRNA expression of RASSF1, RASSF2A and BLU in endometrial cancer cell lines significantly increased after treatment with the demethylating agent 5-Aza-2′-deoxycytidine supporting the repressive effect of hypermethylation on their transcription. Immunohistochemical study of DNMT1 on eight normal endometrium, 16 hyperplastic endometrium without atypia, 40 atypical complex hyperplasia and 79 endometrial carcinomas showed progressive increase in DNMT1 immunoreactivity from normal endometrium to endometrial hyperplasia and endometrioid carcinomas (p = 0.001). Among carcinomas, distinctly higher DNMT1 expression was observed in Type I endometrioid carcinomas (p < 0.001). DNMT1 immunoreactivity correlated with RASSF1A and RASSF2A methylation (p < 0.05). The data suggested that hypermethylation of RAS related genes, particularly RASSF1A, was involved in endometrial carcinogenesis with possible divergent patterns in different histological types. DNMT1 protein overexpression might contribute to such aberrant DNA hypermethylation of specific tumor suppressor genes in endometrial cancers. © 2008 Wiley-Liss, Inc.link_to_subscribed_fulltex

Predictors of next-generation sequencing panel selection using a shared decision-making approach

Genetic testing: Understanding cancer patient preferences Thanks to next-generation sequencing (NGS) it is possible to test multiple genes for cancer susceptibility quickly and cheaply. At the National Cancer Centre Singapore, shared decision-making is used to actively encourage the involvement of patients in the selection of either a ‘breast cancer panel’ (BCP) or a broader ‘multi-cancer panel’ (MCP) test. Joanne Ngeow at the Centre’s Cancer Genetics Service and colleagues examined the choices made by 265 patients with breast and/or ovarian cancer following detailed pre-test counselling by the genetics team. The majority of patients selected the MCP, potentially highlighting a willingness to accept the additional uncertainty that comes with broader NGS panels. Interestingly, a personal history of ovarian cancer and Chinese ethnicity, but not a family history of cancer, were significantly associated with panel selection

The ELFIN Mission.

The Electron Loss and Fields Investigation with a Spatio-Temporal Ambiguity-Resolving option (ELFIN-STAR, or heretoforth simply: ELFIN) mission comprises two identical 3-Unit (3U) CubeSats on a polar (∼93∘ inclination), nearly circular, low-Earth (∼450&nbsp;km altitude) orbit. Launched on September 15, 2018, ELFIN is expected to have a &gt;2.5 year lifetime. Its primary science objective is to resolve the mechanism of storm-time relativistic electron precipitation, for which electromagnetic ion cyclotron (EMIC) waves are a prime candidate. From its ionospheric vantage point, ELFIN uses its unique pitch-angle-resolving capability to determine whether measured relativistic electron pitch-angle and energy spectra within the loss cone bear the characteristic signatures of scattering by EMIC waves or whether such scattering may be due to other processes. Pairing identical ELFIN satellites with slowly-variable along-track separation allows disambiguation of spatial and temporal evolution of the precipitation over minutes-to-tens-of-minutes timescales, faster than the orbit period of a single low-altitude satellite (Torbit ∼ 90&nbsp;min). Each satellite carries an energetic particle detector for electrons (EPDE) that measures 50&nbsp;keV to 5&nbsp;MeV electrons with Δ E/E &lt; 40% and a fluxgate magnetometer (FGM) on a ∼72&nbsp;cm boom that measures magnetic field waves (e.g., EMIC waves) in the range from DC to 5&nbsp;Hz Nyquist (nominally) with &lt;0.3&nbsp;nT/sqrt(Hz) noise at 1&nbsp;Hz. The spinning satellites (Tspin ∼ 3&nbsp;s) are equipped with magnetorquers (air coils) that permit spin-up or -down and reorientation maneuvers. Using those, the spin axis is placed normal to the orbit plane (nominally), allowing full pitch-angle resolution twice per spin. An energetic particle detector for ions (EPDI) measures 250&nbsp;keV - 5&nbsp;MeV ions, addressing secondary science. Funded initially by CalSpace and the University Nanosat Program, ELFIN was selected for flight with joint support from NSF and NASA between 2014 and 2018 and launched by the ELaNa XVIII program on a Delta II rocket (with IceSatII as the primary). Mission operations are currently funded by NASA. Working under experienced UCLA mentors, with advice from The Aerospace Corporation and NASA personnel, more than 250 undergraduates have matured the ELFIN implementation strategy; developed the instruments, satellite, and ground systems and operate the two satellites. ELFIN's already high potential for cutting-edge science return is compounded by concurrent equatorial Heliophysics missions (THEMIS, Arase, Van Allen Probes, MMS) and ground stations. ELFIN's integrated data analysis approach, rapid dissemination strategies via the SPace Environment Data Analysis System (SPEDAS), and data coordination with the Heliophysics/Geospace System Observatory (H/GSO) optimize science yield, enabling the widest community benefits. Several storm-time events have already been captured and are presented herein to demonstrate ELFIN's data analysis methods and potential. These form the basis of on-going studies to resolve the primary mission science objective. Broad energy precipitation events, precipitation bands, and microbursts, clearly seen both at dawn and dusk, extend from tens of keV to &gt;1&nbsp;MeV. This broad energy range of precipitation indicates that multiple waves are providing scattering concurrently. Many observed events show significant backscattered fluxes, which in the past were hard to resolve by equatorial spacecraft or non-pitch-angle-resolving ionospheric missions. These observations suggest that the ionosphere plays a significant role in modifying magnetospheric electron fluxes and wave-particle interactions. Routine data captures starting in February 2020 and lasting for at least another year, approximately the remainder of the mission lifetime, are expected to provide a very rich dataset to address questions even beyond the primary mission science objective