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Genomics Pathologys

Prasun Chakraborty, Jeffrey T J Huang, Kevin Hiom
R-loops are stable nucleic acid structures that have important physiological functions, but which also pose a significant threat to genomic stability. Increased R-loops cause replication stress and chromosome fragility and have been associated with diseases such as neurodegeneration and cancer. Although excessive R-loops are a feature of cells that are defective in RNA processing, what causes them to form is unclear. Here, we demonstrate that DHX9 (RNA helicase A) promotes the formation of pathological and non-pathological R-loops...
October 19, 2018: Nature Communications
Camila D M Campos, Sachindra S T Gamage, Joshua M Jackson, Malgorzata A Witek, Daniel S Park, Michael C Murphy, Andrew K Godwin, Steven A Soper
Cell-free DNA (cfDNA) is a liquid biopsy marker that can carry signatures (i.e., mutations) associated with certain pathological conditions. Therefore, the extraction of cfDNA from a variety of clinical samples can be an effective and minimally invasive source of markers for disease detection and subsequent management. In the oncological diseases, circulating tumor DNA (ctDNA), a cfDNA sub-class, can carry clinically actionable mutations and coupled with next generation sequencing or other mutation detection methods provide a venue for effective in vitro diagnostics...
October 19, 2018: Lab on a Chip
Emmanuel S Antonarakis, Farah Shaukat, Pedro Isaacsson Velho, Harsimar Kaur, Eugene Shenderov, Drew M Pardoll, Tamara L Lotan
Mismatch repair (MMR) gene mutations are rare in prostate cancer, and their histological and clinical characteristics are largely unknown. We conducted a retrospective study to explore disease characteristics and treatment outcomes of men with metastatic prostate cancer harboring germline and/or somatic MMR mutations detected using clinical-grade genomic assays. Thirteen patients with a deleterious MMR gene mutation were identified. Median age was 64 yr, 75% had grade group 5 (Gleason sum 9 or 10), 23% had intraductal histology, 46% had metastatic disease at initial diagnosis, and 31% had visceral metastases...
October 15, 2018: European Urology
Hong-Mei Zhao, Yong-Jia Yang, Jia-Qi Duan, Hong-Juan Ouyang, Li Liu, Li-Chun Yi, Thomas M Attard, Ding-You Li, Jie-Yu You
OBJECTIVES: The present study aims to identify the genotype-phenotype correlation in children with Peutz-Jeghers Syndrome (PJS) through the analysis of STK11 gene mutations in the context of clinical and pathological characteristics. METHOD: In this observational cohort study, the clinical characteristics of 18 families diagnosed with pediatric PJS were collected. Genomic DNA from the peripheral blood of affected children and their family members was collected. The coding region of STK11 was amplified by PCR and screened for mutation by Sanger sequencing...
October 16, 2018: Journal of Pediatric Gastroenterology and Nutrition
Kai Gao, Yujia Zhang, Ling Zhang, Weijing Kong, Han Xie, Jingmin Wang, Ye Wu, Xiru Wu, Xiaoyan Liu, Yuehua Zhang, Feng Zhang, Albert Cheung-Hoi Yu, Yuwu Jiang
Epilepsy is one of the most common complex neurological diseases. It is frequently associated with intellectual and developmental disabilities (ID/DD). In recent years, copy number variation (CNV), especially microdeletion, was proven to be a potential key factor of genetic epilepsy. In this paper, the authors tested the hypothesis that the large de novo rare CNV is an important cause of epilepsy with ID/DD. We performed a custom array comparative genomic hybridization (aCGH) to detect the CNVs of 96 Chinese epileptic patients with ID/DD...
2018: Advances in Neurobiology
Xue Zhang, Fei Gao, Dongdong Wang, Chao Li, Yi Fu, Wei He, Jianmin Zhang
Tau protein-a member of the microtubule-associated protein family-is a key protein involved in many neurodegenerative diseases. Tau pathology in neurodegenerative diseases is characterized by pathological tau aggregation in neurofibrillary tangles (NFTs). Diseases with this typical pathological feature are called tauopathies. Parkinson's disease (PD) was not initially considered to be a typical tauopathy. However, recent studies have demonstrated increasing evidence of tau pathology in PD. A genome-wide association (GWA) study indicated a potential association between tauopathy and sporadic PD...
2018: Frontiers in Neurology
Habiba Elfandy, Joshua Armenia, Filippo Pederzoli, Eli Pullman, Nelma Pértega-Gomes, Nikolaus Schultz, Kartik Viswanathan, Aram Vosoughi, Mirjam Blattner, Konrad H Stopsack, Giorgia Zadra, Kathryn L Penney, Juan Miguel Mosquera, Svitlana Tyekucheva, Lorelei A Mucci, Christopher Barbieri, Massimo Loda
Among prostate cancers (PCa) containing Gleason pattern 4, cribriform morphology is associated with unfavorable clinico-pathologic factors, but its genetic features and association with long-term outcomes are incompletely understood. In this study, genetic, transcriptional and epigenetic features of invasive cribriform carcinoma (ICC) tumors were compared to non-cribriform Gleason 4 (NC4) in The Cancer Genome Atlas (TCGA) cohort. ICC (n=164) had distinctive molecular features when compared to NC4 (n=102). These include: 1) Increased somatic copy number variations, specifically deletions at 6q, 8p which encompassed PTEN and MAP3K7 losses and gains at 3q; 2) Increased SPOPmut and ATMmut; 3) Enrichment for mTORC1 and MYC pathways by gene expression; 4) Increased methylation of selected genes...
October 17, 2018: Molecular Cancer Research: MCR
Jun-Ting Ren, Mei-Xia Wang, Yi Su, Lu-Ying Tang, Ze-Fang Ren
BACKGROUND: DNA methylation (DNAm) age was found to be an indicator for all-cause mortality, cancer incidence, and longevity, but no study has involved in the associations of DNAm age with the prognosis of breast cancer. METHODS: We retrieved information of 1076 breast cancer patients from Genomic Data Commons (GDC) data portal on March 30, 2017, including breast cancer DNAm profiling, demographic features, clinicopathological parameters, recurrence, and all-cause fatality...
October 17, 2018: BMC Cancer
Oscar Teijido, Ramón Cacabelos
Cerebrovascular and neurodegenerative disorders affect one billion people around the world and result from a combination of genomic, epigenomic, metabolic, and environmental factors. Diagnosis at late stages of disease progression, limited knowledge of gene biomarkers and molecular mechanisms of the pathology, and conventional compounds based on symptomatic rather than mechanistic features, determine the lack of success of current treatments, including current FDA-approved conventional drugs. The epigenetic approach opens new avenues for the detection of early presymptomatic pathological events that would allow the implementation of novel strategies in order to stop or delay the pathological process...
October 16, 2018: International Journal of Molecular Sciences
Jean-Marie Tan, Lisa N Tom, H Peter Soyer, Mitchell S Stark
Melanocytic naevi are common melanocytic proliferations that may simulate the appearance of cutaneous melanoma. Naevi commonly harbour somatic mutations implicated in melanomagenesis but in most cases lack the necessary genomic alterations required for melanoma development. While the mitogen-activated protein kinase pathway and ultraviolet radiation strongly contribute to naevogenesis, the somatic mutational landscape of dermoscopic naevus subsets distinguishes some of the molecular hallmarks of naevi in relation to melanoma...
October 17, 2018: Dermatology: International Journal for Clinical and Investigative Dermatology
Marion Classe, Hui Yao, Roger Mouawad, Chad J Creighton, Alice Burgess, Frederick Allanic, Michel Wassef, Xavier Leroy, Benjamin Verillaud, Geoffrey Mortuaire, Franck Bielle, Christophe Le Tourneau, Jean-Emmanuel Kurtz, David Khayat, Xiaoping Su, Gabriel G Malouf
Esthesioneuroblastoma (ENB) is a rare cancer of the olfactory mucosa, with no established molecular stratification to date. We report similarities of ENB with tumors arising in the neural crest and perform integrative analysis of these tumors. We propose a molecular-based subtype classification of ENB as basal or neural, both of which have distinct pathological, transcriptomic, proteomic, and immune features. Among the basal subtype, we uncovered an IDH2 R172 mutant-enriched subgroup (∼35%) harboring a CpG island methylator phenotype reminiscent of IDH2 mutant gliomas...
October 16, 2018: Cell Reports
Daphne W Bell, Lora Hedrick Ellenson
Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States. Endometrioid endometrial carcinomas constitute approximately 85% of newly diagnosed cases; serous carcinomas represent approximately 3-10% of diagnoses; clear cell carcinoma accounts for <5% of diagnoses; and uterine carcinosarcomas are rare, biphasic tumors. Longstanding molecular observations implicate PTEN inactivation as a major driver of endometrioid carcinomas; TP53 inactivation as a major driver of most serous carcinomas, some high-grade endometrioid carcinomas, and many uterine carcinosarcomas; and inactivation of either gene as drivers of some clear cell carcinomas...
October 17, 2018: Annual Review of Pathology
Ye Zhu, Xiang Gu, Chao Xu
BACKGROUND: Nuclear genes or family-based mitochondrial screening have been the focus of genetic studies into essential hypertension. Studies into the role of mitochondria in sporadic Chinese hypertensives are lacking. The objective of the study was to explore the relationship between mitochondrial DNA (mtDNA) variations and the development of maternally inherited essential hypertension (MIEH) in China. METHODS: Yangzhou residents who were outpatients or in-patients at the Department of Cardiology in Northern Jiangsu People's Hospital (Jiangsu, China) from June 2009 to June 2015 were recruited in a 1:1 case control study of 600 gender-matched Chinese MIEH subjects and controls...
October 16, 2018: BMC Medical Genomics
Xiao Chang, Leandro de Araujo Lima, Yichuan Liu, Jin Li, Qingqin Li, Patrick M A Sleiman, Hakon Hakonarson
Hundreds of genomic loci have been identified with the recent advances of schizophrenia in genome-wide association studies (GWAS) and sequencing studies. However, the functional interactions among those genes remain largely unknown. We developed a network-based approach to integrate multiple genetic risk factors, which lead to the discovery of new susceptibility genes and causal sub-networks, or pathways in schizophrenia. We identified significantly and consistently over-represented pathways in the largest schizophrenia GWA studies, which are highly relevant to synaptic plasticity, neural development and signaling transduction, such as long-term potentiation, neurotrophin signaling pathway, and the ERBB signaling pathway...
2018: Frontiers in Genetics
N Green, A Al-Allak, C Fowler
INTRODUCTION: Decisions regarding adjuvant chemotherapy in women with oestrogen receptor positive, human epidermal growth factor receptor 2 negative, node negative, early invasive breast cancer are unclear. The Recurrence Score® (RS) from Oncotype DX® (ODX) testing guides decisions based on individual cancer genomics. The aim of this study was to evaluate the impact of introducing ODX results on adjuvant treatment decisions and its potential economic benefits. METHODS: Patients offered the test were identified from the ODX requesting system...
October 16, 2018: Annals of the Royal College of Surgeons of England
Houda Benhelli-Mokrani, Zeyni Mansuroglu, Alban Chauderlier, Benoit Albaud, David Gentien, Sabrina Sommer, Claire Schirmer, Lucie Laqueuvre, Thibaut Josse, Luc Buée, Bruno Lefebvre, Marie-Christine Galas, Sylvie Souès, Eliette Bonnefoy
Tauopathies such as Alzheimer's Disease (AD) are neurodegenerative disorders for which there is presently no cure. They are named after the abnormal oligomerization/aggregation of the neuronal microtubule-associated Tau protein. Besides its role as a microtubule-associated protein, a DNA-binding capacity and a nuclear localization for Tau protein has been described in neurons. While questioning the potential role of Tau-DNA binding in the development of tauopathies, we have carried out a large-scale analysis of the interaction of Tau protein with the neuronal genome under physiological and heat stress conditions using the ChIP-on-chip technique that combines Chromatin ImmunoPrecipitation (ChIP) with DNA microarray (chip)...
October 13, 2018: Nucleic Acids Research
Lisa L Koorneef, José K van den Heuvel, Jan Kroon, Mariëtte R Boon, Peter A C 't Hoen, Kristina M Hettne, Nienke M van de Velde, Kelsey B Kolenbrander, Trea C M Streefland, Isabel M Mol, Hetty C M Sips, Szymon M Kielbasa, Hailiang Mei, Joseph K Belanoff, Alberto M Pereira, Maaike H Oosterveer, Hazel Hunt, Patrick C N Rensen, Onno C Meijer
Non-alcoholic fatty liver disease (NAFLD) medication is an unmet need. Glucocorticoid stress hormones (GC) drive fat metabolism in the liver, but both full blockade and full stimulation of GC signaling aggravate NAFLD pathology. We investigated the efficacy of selective glucocorticoid receptor (GR) modulator CORT118335, that recapitulates only a subset of GC actions, in reducing liver lipid accumulation in mice. Male C57BL/6J mice received low-fat diet, or high-fat diet mixed with vehicle or CORT118335. Livers were analyzed histologically and for genome-wide mRNA expression...
October 12, 2018: Endocrinology
Denis A Baird, Daniel S Evans, Frederick K Kamanu, Jennifer S Gregory, Fiona R Saunders, Claudiu V Giuraniuc, Rebecca J Barr, Richard M Aspden, Deborah Jenkins, Douglas P Kiel, Eric S Orwoll, Steven R Cummings, Nancy E Lane, Benjamin H Mullin, Frances Mk Williams, J Brent Richards, Scott G Wilson, Tim D Spector, Benjamin G Faber, Deborah A Lawlor, Elin Grundberg, Claes Ohlsson, Ulrika Pettersson-Kymmer, Terence D Capellini, Daniel Richard, Thomas J Beck, David M Evans, Lavinia Paternoster, David Karasik, Jonathan H Tobias
We aimed to report the first genome-wide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modelling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed-sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS) and Study of Osteoporotic Fractures (SOF; females) (total n = 15,934)...
October 15, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
You-Cheng Shao, Xiao-Cui Nie, Guo-Qing Song, Yan Wei, Pu Xia, Xiao-Yan Xu
Breast cancer is one of the most frequently diagnosed types of cancer with a high mortality and malignancy rate in women worldwide. The Dickkopf (DKK) protein family, as a canonical Wnt/β-catenin pathway antagonist, has been implicated in both physiological and pathological processes. This study aimed to comprehensively characterize the prognostic value and elucidate the mechanisms of DKKs in breast cancer and its subtypes. Firstly, DKK mRNA expression and corresponding outcome were analyzed by means of the Gene Expression-Based Outcome for Breast Cancer Online (GOBO) platform based on PAM50 intrinsic breast cancer subtypes...
October 9, 2018: International Journal of Oncology
Simone de Jong, Mateus Jose Abdalla Diniz, Andiara Saloma, Ary Gadelha, Marcos L Santoro, Vanessa K Ota, Cristiano Noto, Charles Curtis, Stephen J Newhouse, Hamel Patel, Lynsey S Hall, Paul F O Reilly, Sintia I Belangero, Rodrigo A Bressan, Gerome Breen
Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree ( n  ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations...
2018: Communications biology
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