Molecular Analysis of Short- versus Long-Term Survivors of High-Grade Serous Ovarian Carcinoma.

Despite having similar histologic features, patients with high-grade serous ovarian carcinoma (HGSC) often experience highly variable outcomes. The underlying determinants for long-term survival (LTS, ≥10 years) versus short-term survival (STS, <3 years) are largely unknown. The present study sought to identify molecular predictors of LTS for women with HGSC.

Gene Body Methylation of the Lymphocyte-Specific Gene Results in Its Overexpression and Regulates Cancer mTOR Signaling.

Investigations into the function of nonpromoter DNA methylation have yielded new insights into epigenetic regulation of gene expression. Previous studies have highlighted the importance of distinguishing between DNA methylation in discrete functional regions; however, integrated nonpromoter DNA methylation and gene expression analyses across a wide number of tumor types and corresponding normal tissues have not been performed. Through integrated analysis of gene expression and DNA methylation profiles, we examined 32 tumor types and identified 57 tumor suppressors and oncogenes out of 260 genes exhibiting a correlation of > 0.

Methylation-eQTL analysis in cancer research.

Motivation: DNA methylation is a key epigenetic factor regulating gene expression. While promoter methylation has been well studied, recent publications have revealed that functionally important methylation also occurs in intergenic and distal regions, and varies across genes and tissue types. Given the growing importance of inter-platform integrative genomic analyses, there is an urgent need to develop methods to discover and characterize gene-level relationships between methylation and expression.

Molecular Analysis of Clinically Defined Subsets of High-Grade Serous Ovarian Cancer.

The diversity and heterogeneity within high-grade serous ovarian cancer (HGSC), which is the most lethal gynecologic malignancy, is not well understood. Here, we perform comprehensive multi-platform omics analyses, including integrated analysis, and immune monitoring on primary and metastatic sites from highly clinically annotated HGSC samples based on a laparoscopic triage algorithm from patients who underwent complete gross resection (R0) or received neoadjuvant chemotherapy (NACT) with excellent or poor response. We identify significant distinct molecular abnormalities and cellular changes and immune cell repertoire alterations between the groups, including a higher rate of NF1 copy number loss, and reduced chromothripsis-like patterns, higher levels of strong-binding neoantigens, and a higher number of infiltrated T cells in the R0 versus the NACT groups.

Proteomic Profiling of Signaling Networks Modulated by G-CSF/Plerixafor/Busulfan-Fludarabine Conditioning in Acute Myeloid Leukemia Patients in Remission or with Active Disease prior to Allogeneic Stem Cell Transplantation.

To characterize intracellular signaling in peripheral blood (PB) cells of acute myeloid leukemia (AML) patients undergoing pretransplant conditioning with CXCR4 inhibitor plerixafor, granulocyte colony-stimulating factor (G-CSF), and busulfan plus fludarabine (Bu+Flu) chemotherapy, we profiled 153 proteins in 33 functional groups using reverse phase protein array. CXCR4 inhibition mobilized AML progenitors and clonal AML cells, and this was associated with molecular markers of cell cycle progression. G-CSF/plerixafor and G-CSF/plerixafor/Bu+Flu modulated distinct signaling networks in AML blasts of patients undergoing conditioning with active disease compared to nonleukemic PB cells of patients in remission.

Pan-cancer genomic analysis links 3'UTR DNA methylation with increased gene expression in T cells.

Background: Investigations into the function of non-promoter DNA methylation have yielded new insights into the epigenetic regulation of gene expression. However, integrated genome-wide non-promoter DNA methylation and gene expression analyses across a wide number of tumour types and corresponding normal tissues have not been performed.

Methods: To investigate the impact of non-promoter DNA methylation on cancer pathogenesis, we performed a large-scale analysis of gene expression and DNA methylation profiles, finding enrichment in the 3'UTR DNA methylation positively correlated with gene expression.

Cholangiocarcinoma With Genetic Aberrations: A Unique Clinical Phenotype.

Purpose: genetic aberrations (GAs) occur in an estimated 10% to 16% of intrahepatic cholangiocarcinomas (CCAs). The natural history of CCA with GAs, the prognostic role of coexisting GAs, and the outcome with FGFR-targeted inhibitors are unknown.

Patients And Methods: Patients with CCA with GAs were identified using next-generation sequencing or fluorescence in situ hybridization from four tertiary cancer centers and compared with wild-type counterparts.

Immune cell profiling in cancer: molecular approaches to cell-specific identification.

The immune system has many important regulatory roles in cancer development and progression. Given the emergence of effective immune therapies against many cancers, reliable predictors of response are needed. One method of determining response is by evaluating immune cell populations from treated and untreated tumor samples.

Defining Survivorship Trajectories Across Patients With Solid Tumors: An Evidence-Based Approach.

Importance: Survivorship involves a multidisciplinary approach to surveillance and management of comorbidities and secondary cancers, overseen by oncologists, surgeons, and primary care physicians. Optimal timing and coordination of care, however, is unclear and often based on arbitrary 5-year cutoffs.

Objective: To determine high- and low-risk periods for all tumor types that could define when survivorship care might best be overseen by oncologists and when to transition to primary care physicians.

A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers.

We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs).

Dissecting Pathway Disturbances Using Network Topology and Multi-platform Genomics Data.

Complex diseases such as cancers usually result from accumulated disturbance of pathways instead of the disruptions of one or a few major genes. As opposed to single-platform analyses, it is likely that integrating diverse molecular regulatory elements and their interactions can lead to more insights on pathway-level disturbances of biological systems and their potential consequences in disease development and progression. To explore the benefit of pathway-based analysis, we focus on mutli-platform genomics, epigenomics and transcriptomics (-omics, for short) from 11 cancer types collected by the Cancer Genome Atlas (TCGA) project.

Macrophage depletion through colony stimulating factor 1 receptor pathway blockade overcomes adaptive resistance to anti-VEGF therapy.

Anti-angiogenesis therapy has shown clinical benefit in patients with high-grade serous ovarian cancer (HGSC), but adaptive resistance rapidly emerges. Thus, approaches to overcome such resistance are needed. We developed the setting of adaptive resistance to anti-VEGF therapy, and performed a series of experiments in both immune competent and nude mouse models.

Genetic Polymorphisms of CFH and ARMS2 Do Not Predict Response to Antioxidants and Zinc in Patients with Age-Related Macular Degeneration: Independent Statistical Evaluations of Data from the Age-Related Eye Disease Study.

Purpose: Considerable controversy has erupted in recent years regarding whether genotyping should be part of standard care for patients with age-related macular degeneration (AMD) who are being considered for treatment with antioxidants and zinc. We aimed to determine whether genotype predicts response to supplements in AMD.

Design: Three separate statistical teams reanalyzed data derived from the Age-Related Eye Disease Study (AREDS), receiving data prepared by the AREDS investigators and, separately, data from investigators reporting findings that support the use of genotyping.

Surface PD-L1, E-cadherin, CD24, and VEGFR2 as markers of epithelial cancer stem cells associated with rapid tumorigenesis.

Cancer cells require both migratory and tumorigenic property to establish metastatic tumors outside the primary microenvironment. Identifying the characteristic features of migratory cancer stem cells with tumorigenic property is important to predict patient prognosis and combat metastasis. Here we established one epithelial and two mesenchymal cell lines from ascites of a bladder cancer patient (i.

Maternal 25(OH)D concentrations ≥40 ng/mL associated with 60% lower preterm birth risk among general obstetrical patients at an urban medical center.

Background: Given the high rate of preterm birth (PTB) nationwide and data from RCTs demonstrating risk reduction with vitamin D supplementation, the Medical University of South Carolina (MUSC) implemented a new standard of care for pregnant women to receive vitamin D testing and supplementation.

Objectives: To determine if the reported inverse relationship between maternal 25(OH)D and PTB risk could be replicated at MUSC, an urban medical center treating a large, diverse population.

Methods: Medical record data were obtained for pregnant patients aged 18-45 years between September 2015 and December 2016.

High-throughput profiling of signaling networks identifies mechanism-based combination therapy to eliminate microenvironmental resistance in acute myeloid leukemia.

The bone marrow microenvironment is known to provide a survival advantage to residual acute myeloid leukemia cells, possibly contributing to disease recurrence. The mechanisms by which stroma in the microenvironment regulates leukemia survival remain largely unknown. Using reverse-phase protein array technology, we profiled 53 key protein molecules in 11 signaling pathways in 20 primary acute myeloid leukemia samples and two cell lines, aiming to understand stroma-mediated signaling modulation in response to the targeted agents temsirolimus (MTOR), ABT737 (BCL2/BCL-XL), and Nutlin-3a (MDM2), and to identify the effective combination therapy targeting acute myeloid leukemia in the context of the leukemia microenvironment.

Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer.

The tumor-suppressor gene is mutated in >95% of high-grade serous ovarian cancers. Detecting an autologous antibody response to TP53 that might improve early detection. An immunoassay was developed to measure TP53 autoantibody in sera from 378 cases of invasive epithelial ovarian cancer and 944 age-matched healthy controls from the United States, Australia, and the United Kingdom.

Integrated MicroRNA-mRNA Profiling Identifies Oncostatin M as a Marker of Mesenchymal-Like ER-Negative/HER2-Negative Breast Cancer.

MicroRNAs (miRNAs) simultaneously modulate different oncogenic networks, establishing a dynamic system of gene expression and pathway regulation. In this study, we analyzed global miRNA and messenger RNA (mRNA) expression profiles of 17 cell lines representing different molecular breast cancer subtypes. Spearman's rank correlation test was used to evaluate the correlation between miRNA and mRNA expression.

Functional CAR models for large spatially correlated functional datasets.

We develop a functional conditional autoregressive (CAR) model for spatially correlated data for which functions are collected on areal units of a lattice. Our model performs functional response regression while accounting for spatial correlations with potentially nonseparable and nonstationary covariance structure, in both the space and functional domains. We show theoretically that our construction leads to a CAR model at each functional location, with spatial covariance parameters varying and borrowing strength across the functional domain.

Biphasic components of sarcomatoid clear cell renal cell carcinomas are molecularly similar to each other, but distinct from, non-sarcomatoid renal carcinomas.

Sarcomatoid transformation, wherein an epithelioid carcinomatous tumour component coexists with a sarcomatoid histology, is a predictor of poor prognosis in clear cell renal cell carcinoma. Our understanding of sarcomatoid change has been hindered by the lack of molecular examination. Thus, we sought to characterize molecularly the biphasic epithelioid and sarcomatoid components of sarcomatoid clear cell renal cell carcinoma and compare them to non-sarcomatoid clear cell renal cell carcinoma.

A miR-192-EGR1-HOXB9 regulatory network controls the angiogenic switch in cancer.

A deeper mechanistic understanding of tumour angiogenesis regulation is needed to improve current anti-angiogenic therapies. Here we present evidence from systems-based miRNA analyses of large-scale patient data sets along with in vitro and in vivo experiments that miR-192 is a key regulator of angiogenesis. The potent anti-angiogenic effect of miR-192 stems from its ability to globally downregulate angiogenic pathways in cancer cells through regulation of EGR1 and HOXB9.

Gene Expression Profile of the Clinically Aggressive Micropapillary Variant of Bladder Cancer.

Background: Progression of conventional urothelial carcinoma of the bladder to a tumor with unique microscopic features referred to as micropapillary carcinoma is coupled with aggressive clinical behavior signified by a high propensity for metastasis to regional lymph nodes and distant organs resulting in shorter survival.

Objective: To analyze the expression profile of micropapillary cancer and define its molecular features relevant to clinical behavior.

Design, Setting, And Participants: We retrospectively identified 43 patients with micropapillary bladder cancers and a reference set of 89 patients with conventional urothelial carcinomas and performed whole-genome expression messenger RNA profiling.

Role of Increased n-acetylaspartate Levels in Cancer.

Background: The clinical and biological effects of metabolic alterations in cancer are not fully understood.

Methods: In high-grade serous ovarian cancer (HGSOC) samples (n = 101), over 170 metabolites were profiled and compared with normal ovarian tissues (n = 15). To determine NAT8L gene expression across different cancer types, we analyzed the RNA expression of cancer types using RNASeqV2 data available from the open access The Cancer Genome Atlas (TCGA) website (http://www.

A genome-scale screen reveals context-dependent ovarian cancer sensitivity to miRNA overexpression.

Large-scale molecular annotation of epithelial ovarian cancer (EOC) indicates remarkable heterogeneity in the etiology of that disease. This diversity presents a significant obstacle against intervention target discovery. However, inactivation of miRNA biogenesis is commonly associated with advanced disease.