Identification of Tumor Suppressors and Oncogenes from Genomic and Epigenetic Features in Ovarian Cancer

The identification of genetic and epigenetic alterations from primary tumor cells has become a common method to identify genes critical to the development and progression of cancer. We seek to identify those genetic and epigenetic aberrations that have the most impact on gene function within the tumor. First, we perform a bioinformatic analysis of copy number variation (CNV) and DNA methylation covering the genetic landscape of ovarian cancer tumor cells. We separately examined CNV and DNA methylation for 42 primary serous ovarian cancer samples using MOMA-ROMA assays and 379 tumor samples analyzed by The Cancer Genome Atlas. We have identified 346 genes with significant deletions or amplifications among the tumor samples. Utilizing associated gene expression data we predict 156 genes with altered copy number and correlated changes in expression. Among these genes CCNE1, POP4, UQCRB, PHF20L1 and C19orf2 were identified within both data sets. We were specifically interested in copy number variation as our base genomic property in the prediction of tumor suppressors and oncogenes in the altered ovarian tumor. We therefore identify changes in DNA methylation and expression for all amplified and deleted genes. We statistically define tumor suppressor and oncogenic features for these modalities and perform a correlation analysis with expression. We predicted 611 potential oncogenes and tumor suppressors candidates by integrating these data types. Genes with a strong correlation for methylation dependent expression changes exhibited at varying copy number aberrations include CDCA8, ATAD2, CDKN2A, RAB25, AURKA, BOP1 and EIF2C3. We provide copy number variation and DNA methylation analysis for over 11,500 individual genes covering the genetic landscape of ovarian cancer tumors. We show the extent of genomic and epigenetic alterations for known tumor suppressors and oncogenes and also use these defined features to identify potential ovarian cancer gene candidates

Pulmonary Hypertension in Pregnancy: A Report of 49 Cases at Four Tertiary North American Sites.

To access publisher's full text version of this article click on the hyperlink belowTo identify whether pregnancy outcomes vary by etiology and severity of pulmonary hypertension and whether contemporary therapies influence outcomes.A retrospective review of medical records at four academic institutions was conducted to identify pregnant women with pulmonary hypertension (2001-2015). International Classification of Diseases, 9th Revision codes for pulmonary hypertension and pregnancy were used to identify potential participants. Medical records were abstracted for demographics, management, and outcomes. Women were classified according to the 2013 World Health Organization (WHO) pulmonary hypertension classification groups 1-5. Mild pulmonary hypertension was defined as a mean pulmonary artery pressure 25-49 mm Hg and severe pulmonary hypertension as mean pulmonary artery pressure 50 mm Hg or greater or systolic pulmonary artery pressure 70 mm Hg or greater. Descriptive statistics were used to compare outcomes.Forty-nine women were identified. Mortality rate was 16% (n=8/49); all deaths occurred postpartum, and seven of eight deaths occurred in women with WHO group 1 pulmonary hypertension (mortality rate 23%, n=7/30). Of the women who had documented live births with known mode of delivery (n=41), mortality was 4 of 22 among women with severe pulmonary hypertension and 1 of 19 among women with mild pulmonary hypertension. Mortality among women who delivered by cesarean was 4 of 22 and was 1 of 19 among women who delivered vaginally. Neuraxial anesthesia was performed in 20 of 22 cesarean and 17 of 19 vaginal deliveries with no anesthesia-related adverse events. Women with severe pulmonary hypertension needed more advanced therapies such as inotropes, pulmonary vasodilators, and extracorporeal membrane oxygenation than did women with mild pulmonary hypertension, 19 of 26 compared with 7 of 22. Preterm delivery was more common in women with severe compared with mild pulmonary hypertension, 19 of 23 compared with 8 of 17. There was one 25-week intrauterine fetal demise, but no neonatal deaths.In this large series of pulmonary hypertension in pregnancy, mortality remained high despite advanced therapies. Maternal mortality was specific to WHO group 1 pulmonary hypertension and possibly associated with severe pulmonary hypertension. In selected patients with a favorable prognosis for vaginal birth, a trial of labor can be considered

Cerebrospinal fluid levels of leptin, proopiomelanocortin, and agouti-related protein in human pregnancy:evidence for leptin resistance

CONTEXT: Leptin suppresses appetite by modulating the expression of hypothalamic neuropeptides including proopiomelanocortin (POMC) and agouti-related peptide (AgRP). Yet during pregnancy, caloric consumption increases despite elevated plasma leptin levels. DESIGN AND PARTICIPANTS: To investigate this paradox, we measured leptin and soluble leptin receptor in plasma and leptin, POMC, and AgRP in cerebrospinal fluid (CSF) from 21 fasting pregnant women before delivery by cesarean section at a university hospital and from 14 fasting nonpregnant women. RESULTS: Prepregnancy body mass index was 24.6 ± 1.1 (se) vs. 31.3 ± 1.3 at term vs. 26.5 ± 1.6 kg/m(2) in controls. Plasma leptin (32.9 ± 4.6 vs. 16.7 ± 3.0 ng/ml) and soluble leptin receptor (30.9 ± 2.3 vs. 22.1 ± 1.4 ng/ml) levels were significantly higher in pregnant women. However, mean CSF leptin did not differ between the two groups (283 ± 34 vs. 311 ± 32 pg/ml), consistent with a relative decrease in leptin transport into CSF during pregnancy. Accordingly, the CSF/plasma leptin percentage was 1.0 ± 0.01% in pregnant subjects vs. 2.1 ± 0.2% in controls (P < 0.0001). Mean CSF AgRP was significantly higher in pregnant subjects (32.3 ± 2.7 vs. 23.5 ± 2.5 pg/ml; P = 0.03). Mean CSF POMC was not significantly different in pregnant subjects (200 ± 13.6 vs. 229 ± 17.3 fmol/ml; P = 0.190). However, the mean AgRP/POMC ratio was significantly higher among pregnant women (P = 0.003), consistent with an overall decrease in melanocortin tone favoring increased food intake during pregnancy. CONCLUSIONS: These data demonstrate that despite peripheral hyperleptinemia, positive energy balance is achieved during pregnancy by a relative decrease in central leptin concentrations and resistance to leptin's effects on target neuropeptides that regulate energy balance