Identification of unique genomic signatures in patients with fibromyalgia and chronic pain.

Fibromyalgia (FM) is a chronic pain syndrome characterized by widespread pain. The pathophysiology of fibromyalgia is not clearly understood and there are no specific biomarkers available for accurate diagnosis. Here we define genomic signatures using high throughput RNA sequencing on 96 fibromyalgia and 93 control cases.

In-Depth Comparison of Genetic Variants Demonstrates a Close Relationship Between Invasive and Intraductal Components of Prostate Cancer.

Intraductal carcinoma (IDC) of the prostate is often associated with concurrent high-grade invasive prostate cancer (PCa) and poor clinical outcomes. In this context, IDC is thought to represent the retrograde spread of invasive prostatic adenocarcinoma into the acini and ducts. Prior studies have demonstrated a concordance of PTEN loss and genomic instability between the IDC and high-grade invasive components of PCa, but larger genomic association studies to solidify our understanding of the relationship between these 2 lesions are lacking.

Utilization of cytologic cell blocks for targeted sequencing of solid tumors.

Background: Targeted sequencing of cytologic samples has significantly increased in recent years. With increasing numbers of clinical trials for variant specific therapeutics, validating a comprehensive assay for cytologic samples has become clinically important.

Aim: For this study, a retrospective review of cytologic cell blocks from fine needle aspirations and fluid specimens was performed.

Selective time-dependent changes in activity and cell-specific gene expression in human postmortem brain.

As a means to understand human neuropsychiatric disorders from human brain samples, we compared the transcription patterns and histological features of postmortem brain to fresh human neocortex isolated immediately following surgical removal. Compared to a number of neuropsychiatric disease-associated postmortem transcriptomes, the fresh human brain transcriptome had an entirely unique transcriptional pattern. To understand this difference, we measured genome-wide transcription as a function of time after fresh tissue removal to mimic the postmortem interval.

Unique Variant of Cerebrotendinous Xanthomatosis Presenting With Eyelid Involvement Due to Heterozygous CYP7A1 and SLC10A1 Gene Mutations.

We report a case of a novel phenotypic variant of cerebrotendinous xanthomatosis (CTX) with an adult onset, caused by 2 coexisting mutations involving the CYP7A1 and SLC10A1 genes. A 49-year-old male patient presented with eyelid xanthomatosis associated with dermatochalasis, nystagmus, right-sided paresis with hyperreflexia and atypical parkinsonism. Bilateral xanthomatous plaques involving both Achilles tendons were subsequently detected.

Next generation sequencing of cervical high grade dysplasia and invasive squamous cell carcinoma: A case study.

Cervical cancer continues to be a prevalent diagnosis among gynecologic pathology despite widespread screening methods and known pathogenesis by human papilloma virus. We describe a patient who underwent next generation sequencing (NGS) of her high grade squamous dysplasia (HG-SIL) as well as the invasive component of her cervical cancer. This tumor showed an amplification of PIK3CA in the invasive carcinoma in addition to a common E542K mutation both in dysplastic and invasive carcinoma.

Comparison of prostatic adenocarcinoma Gleason 5 and intraductal carcinoma of the prostate with tumor necrosis. A morphometric study.

Intraductal carcinoma of the prostate(IDCP) is defined as a solid or cribriform neoplastic growth confined to ducts and acini, with preservation of the basal cell layer. Since IDCP can often present tumor necrosis (TN), it should be distinguished from Gleason 5 (GP5) invasive adenocarcinoma for staging and clinical purposes. In the present study we reviewed 344 radical prostatectomies performed at our institution and selected all cases with either >5% GP5 or IDCP for assessment of TN on histology slides (n = 59).

The role of next-generation sequencing in the differential diagnosis of composite neoplasms.

Composite neoplasms (CNs) are rare and diagnostically challenging lesions that require differentiating between mixed clonal tumors with divergent phenotypes (MT), collision of 2 independent tumors adjacent to each other (CT), and tumor-to-tumor metastasis (TTM). To that end, pathologists have traditionally used immunohistochemistry and limited molecular studies, such as Sanger sequencing. Herein we evaluate the potential application of NGS in the differential diagnosis of these rare neoplasms.

Tumor necrosis in radical prostatectomies with high-grade prostate cancer is associated with multiple poor prognostic features and a high prevalence of residual disease.

The Gleason grading system and the recently defined Grade Groups are strong, well-established predictors of outcome in prostate cancer. Each Gleason score, however, is the result of a sum of categories (Gleason patterns or GPs) that are intrinsically heterogeneous, as each individual pattern encompasses several tumor morphologies. Although the prognostic value of specific morphologic components of GP4 has recently been demonstrated, the significance of the different patterns of GP5 is largely unknown.

Loss of LKB1 and PTEN tumor suppressor genes in the ovarian surface epithelium induces papillary serous ovarian cancer.

Epithelial ovarian cancer presents mostly with serous, endometrioid or mucinous histology but is treated as a single disease. The development of histotype-specific therapy has been challenging because of the relative lack of studies attributing disrupted pathways to a distinct histotype differentiation. mTOR activation is frequently associated with poor prognosis in serous ovarian cancer, which is the most common and most deadly histotype.

FGF18 as a prognostic and therapeutic biomarker in ovarian cancer.

High-throughput genomic technologies have identified biomarkers and potential therapeutic targets for ovarian cancer. Comprehensive functional validation studies of the biological and clinical implications of these biomarkers are needed to advance them toward clinical use. Amplification of chromosomal region 5q31-5q35.

Array CGH in brain tumors.

Alterations in the copy number of the cancer genome are frequently observed in brain tumors especially gliomas. Some pertinent examples include amplification of the EGFR locus in chromosome 7p and loss of the PTEN locus in 10q in glioblastoma. Meningiomas are often associated with loss of the NF2 locus in 22q.

Genome wide DNA copy number analysis of serous type ovarian carcinomas identifies genetic markers predictive of clinical outcome.

Ovarian cancer is the fifth leading cause of cancer death in women. Ovarian cancers display a high degree of complex genetic alterations involving many oncogenes and tumor suppressor genes. Analysis of the association between genetic alterations and clinical endpoints such as survival will lead to improved patient management via genetic stratification of patients into clinically relevant subgroups.

Inhibition of Hedgehog signaling antagonizes serous ovarian cancer growth in a primary xenograft model.

Background: Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth.

Methodology: We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926.

Maintenance of primary tumor phenotype and genotype in glioblastoma stem cells.

The clinicopathological heterogeneity of glioblastoma (GBM) and the various genetic and phenotypic subtypes in GBM stem cells (GSCs) are well described. However, the relationship between GSCs and the corresponding primary tumor from which they were isolated is poorly understood. We have established GSC-enriched neurosphere cultures from 15 newly diagnosed GBM specimens and examined the relationship between the histopathological and genomic features of GSC-derived orthotopic xenografts and those of the respective patient tumors.

Epigenetic regulation of CD133 and tumorigenicity of CD133 positive and negative endometrial cancer cells.

Background: Recent data provide significant evidence to support the hypothesis that there are sub-populations of cells within solid tumors that have an increased tumor initiating potential relative to the total tumor population. CD133, a cell surface marker expressed on primitive cells of neural, hematopoietic, endothelial and epithelial lineages has been identified as a marker for tumor initiating cells in solid tumors of the brain, colon, pancreas, ovary and endometrium. Our objectives were to assess the relative level of CD133 expressing cells in primary human endometrial tumors, confirm their tumorigenic potential, and determine whether CD133 expression was epigenetically modified.

Assessing Population Level Genetic Instability via Moving Average.

Tumoral tissues tend to generally exhibit aberrations in DNA copy number that are associated with the development and progression of cancer. Genotyping methods such as array-based comparative genomic hybridization (aCGH) provide means to identify copy number variation across the entire genome. To address some of the shortfalls of existing methods of DNA copy number data analysis, including strong model assumptions, lack of accounting for sampling variability of estimators, and the assumption that clones are independent, we propose a simple graphical approach to assess population-level genetic alterations over the entire genome based on moving average.

Genome-wide comparison of paired fresh frozen and formalin-fixed paraffin-embedded gliomas by custom BAC and oligonucleotide array comparative genomic hybridization: facilitating analysis of archival gliomas.

Array comparative genomic hybridization (aCGH) is a powerful tool for detecting DNA copy number alterations (CNA). Because diffuse malignant gliomas are often sampled by small biopsies, formalin-fixed paraffin-embedded (FFPE) blocks are often the only tissue available for genetic analysis; FFPE tissues are also needed to study the intratumoral heterogeneity that characterizes these neoplasms. In this paper, we present a combination of evaluations and technical advances that provide strong support for the ready use of oligonucleotide aCGH on FFPE diffuse gliomas.

A genome-wide screen for microdeletions reveals disruption of polarity complex genes in diverse human cancers.

In a genome-wide screen of 684 cancer cell lines, we identified homozygous intragenic microdeletions involving genes encoding components of the apical-basal cell polarity complexes. Among these, PARD3 is disrupted in cell lines and primary tumors from squamous carcinomas and glioblastomas. Reconstituting PARD3 expression in both cell types restores tight junctions and retards contact-dependent proliferation.

Application of signal processing techniques for estimating regions of copy number variations in human meningioma DNA.

We applied mode-decomposition and matched-filtering, both signal processing techniques used to increase the signal-to-noise ratio (SNR), to array CGH data of human meningioma DNA, in order to extract genomic regions of copy-number changes potentially associated with tumor progression. DNA segments from different chromosomes were decomposed into a small number of dominant components (modes), and low-amplitude modes were eliminated. The SNR of the entire segment was increased and it was possible to identify local changes in the data spatial structure, previously indistinguishable due to noise.

Genomic profiling of atypical meningiomas associates gain of 1q with poor clinical outcome.

Atypical meningiomas exhibit heterogeneous clinical outcomes. It is unclear which atypical meningiomas require aggressive multimodality treatment with surgery and radiation therapy versus surgery alone to prevent recurrence. Detailed molecular-genetic characterization of these neoplasms is necessary to understand their pathogenesis and identify clinically relevant genetic markers.

A role for BRCA1 in uterine leiomyosarcoma.

Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy with a low survival rate. Currently, there is no effective treatment for ULMS. Infrequent occurrences of human ULMS hamper the understanding of the initiation and progression of the disease, thereby limiting the ability to develop efficient therapies.

Genomic profiling distinguishes familial multiple and sporadic multiple meningiomas.

Background: Meningiomas may occur either as familial tumors in two distinct disorders, familial multiple meningioma and neurofibromatosis 2 (NF2), or sporadically, as either single or multiple tumors in individuals with no family history. Meningiomas in NF2 and approximately 60% of sporadic meningiomas involve inactivation of the NF2 locus, encoding the tumor suppressor merlin on chromosome 22q. This study was undertaken to establish whether genomic profiling could distinguish familial multiple meningiomas from sporadic solitary and sporadic multiple meningiomas.

A latent class model with hidden Markov dependence for array CGH data.

Array CGH is a high-throughput technique designed to detect genomic alterations linked to the development and progression of cancer. The technique yields fluorescence ratios that characterize DNA copy number change in tumor versus healthy cells. Classification of tumors based on aCGH profiles is of scientific interest but the analysis of these data is complicated by the large number of highly correlated measures.