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Pauline Funchain, Ahmad A Tarhini
Rapidly advancing genomic sequencing technologies are changing all areas of cancer, from diagnosis to surveillance, and prognostication to treatment. The role of genomic testing in melanoma is expanding, and multiple genomically based tests are available, including somatic tumor sequencing for actionable genetic alterations and tumor mutational burden, prognostic gene expression profiling from tumor tissue, and germline genetic testing from blood. The available testing options have varying levels of supporting data, from robust to preliminary...
March 15, 2018: Oncology (Williston Park, NY)
Julie J Miller, Wolfgang Wick
The majority of World Health Organization grade II and grade III gliomas harbor heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1), and tumors with an IDH wild-type status show molecular features of a glioblastoma and simply may constitute a separate disease entity. This discovery has led to a profound shift in the way that gliomas are classified and, consequently, how treatment decisions are made. We will review the current understanding of IDH- mutant gliomagenesis and the preclinical models being used to investigate the underlying biology of these tumors and to explore new therapeutic options for these patients...
February 2018: Seminars in Neurology
Antonella Sferra, Fabiana Fattori, Teresa Rizza, Elsabetta Flex, Emanuele Bellacchio, Alessandro Bruselles, Stefania Petrini, Serena Cecchetti, Massimo Teson, Fabrizia Restaldi, Andrea Ciolfi, Filippo M Santorelli, Ginevra Zanni, Sabina Barresi, Claudia Castiglioni, Marco Tartaglia, Enrico Bertini
Microtubules participate in fundamental cellular processes, including chromosomal segregation and cell division, migration, and intracellular trafficking. Their proper function is required for correct central nervous system development and operative preservation, and mutations in genes coding tubulins, the constituting units of microtubules, underlie a family of neurodevelopmental and neurodegenerative diseases, collectively known as "tubulinopathies", characterized by a wide range of neuronal defects resulting from defective proliferation, migration, and function...
March 14, 2018: Human Molecular Genetics
Zhanfeng Si, Hui Liu, Jiankun Zhu, Jiedan Chen, Qiong Wang, Lei Fang, Fengkai Gao, Yue Tian, Yali Chen, Lijing Chang, Bingliang Liu, Zegang Han, Baoliang Zhou, Yan Hu, Xianzhong Huang, Tianzhen Zhang
In cotton, the formation of fruiting branches affects both plant architecture and fiber yield. Here, we report map-based cloning of the Gossypium barbadense axillary flowering (GbAF) mutation gene, which causes bolls to be borne directly on the main plant stem, and of the G. hirsutum clustered boll (cl1) mutation gene. Both mutant alleles were found to represent point mutations at the Cl1 locus of the corresponding species, and therefore we propose that the GbAF mutation be referred to as cl1b. These Cl1 loci correspond to homologs of tomato SELF-PRUNING (SP), i...
March 14, 2018: Journal of Experimental Botany
Vassilis E Papadopoulos, Georgia Nikolopoulou, Ivi Antoniadou, Antonia Karachaliou, Giovanna Arianoglou, Evangelia Emmanouilidou, S Pablo Sardi, Leonidas Stefanis, Kostas Vekrellis
Glucocerebrosidase gene (GBA) mutations are the most common genetic contributor to Parkinson's Disease (PD) and are associated with decreased Glucocerebrosidase (GCase) enzymatic activity in PD. PD patients without GBA mutations also exhibit lower levels of GCase activity in the central nervous system (CNS) suggesting a potential contribution of the enzyme activity in disease pathogenesis, possibly by alteration of lysosomal function. α-synuclein, a protein with a central role in PD pathogenesis, has been shown to be secreted partly in association with exosomes...
March 14, 2018: Human Molecular Genetics
Shana J Kim, Tomasz Huzarski, Jacek Gronwald, Christian F Singer, Pål Møller, Henry T Lynch, Susan Armel, Beth Y Karlan, William D Foulkes, Susan L Neuhausen, Leigha Senter, Andrea Eisen, Charis Eng, Seema Panchal, Tuya Pal, Olufunmilayo Olopade, Dana Zakalik, Jan Lubinski, Steven A Narod, Joanne Kotsopoulos
Background: Although evidence suggests that larger body size in early life confers lifelong protection from developing breast cancer, few studies have investigated the relationship between body size and breast cancer risk among BRCA mutation carriers. Therefore, we conducted a prospective evaluation of body size and the risk of breast cancer among BRCA mutation carriers. Methods: Current height and body mass index (BMI) at age 18 were determined from baseline questionnaires...
March 13, 2018: International Journal of Epidemiology
Yilun Deng, Yuejuan Qin, Subramanya Srikantan, Anqi Luo, Zi-Ming Cheng, Shahida K Flores, Kris S Vogel, Exing Wang, Patricia L M Dahia
The TMEM127 tumor suppressor gene encodes a transmembrane protein of unknown function mutated in pheochromocytomas and, rarely, in renal cancers. Tumors with inactivating TMEM127 mutations have increased mTORC1 signaling by undefined mechanisms. Here we report that TMEM127 interacts with the lysosome-anchored complex comprised of Rag GTPases, the LAMTOR pentamer (or 'ragulator') and vATPase, which controls amino acid-mediated mTORC1 activation. We found that in nutrient-rich conditions TMEM127 expression reduces mTORC1 recruitment to Rags...
March 14, 2018: Human Molecular Genetics
Claudia Kruger, Susan J Burke, J Jason Collier, Trang-Tiffany Nguyen, J Michael Salbaum, Krisztian Stadler
Early podocyte loss is characteristic of chronic kidney diseases (CKD) in obesity and diabetes. Since treatments for hyperglycemia and hypertension do not prevent podocyte loss, there must be additional factors causing podocyte depletion. The role of oxidative stress has been implicated in CKD but it is not known how exactly free radicals affect podocyte physiology. To assess this relationship, we investigated the effects of lipid radicals on podocytes, as lipid peroxidation is a major form of oxidative stress in diabetes...
March 6, 2018: Redox Biology
Zahraa Haidar, Nadine Jalkh, Sandra Corbani, Ali Fawaz, Eliane Chouery, André Mégarbané
Pyridoxine dependent epilepsy (PDE) is a rare autosomal recessive neurometabolic disorder. In the classical form, seizures are observed within the first month of life, while in the atypical form seizures appear later in life, sometimes as late as at the age of 3 years of life. Both types are unresponsive to conventional anticonvulsant therapy, but can be controlled with pyridoxine monotherapy. Mutations in the ALDH7A1 gene, encoding α-aminoadipic semialdehyde dehydrogenase have been reported to cause this disease in most patients...
March 10, 2018: Seizure: the Journal of the British Epilepsy Association
Sophie Outh-Gauer, Marie Alt, Christophe Le Tourneau, Jérémy Augustin, Chloé Broudin, Cassandre Gasne, Thomas Denize, Haitham Mirghani, Elizabeth Fabre, Madeleine Ménard, Florian Scotte, Eric Tartour, Cécile Badoual
Cancer occurrence can be understood as the result of dysfunctions in immune tumoral microenvironment. Here we review the recent understandings of those microenvironment changes, regarding their causes and prognostic significance in head and neck (HN) carcinoma. We will focus on HN squamous cell cancer (SCC) and nasopharyngeal carcinomas (NPC). Their overall poor prognosis may be improved with immunotherapy in a subset of patients, as supported by current clinical trials. However, finding reliable markers of therapeutic response is crucial for patient selection, due to potential severe adverse reactions and high costs...
March 1, 2018: Cancer Treatment Reviews
Yang Zou, Jiang-Yan Zhou, Jiu-Bai Guo, Li-Qun Wang, Yong Luo, Zi-Yu Zhang, Fa-Ying Liu, Jun Tan, Feng Wang, Ou-Ping Huang
Endometriosis is a potential premalignant disorder. The underlying molecular aberrations, however, are not fully understood. A recent exome sequencing study found that 25% (10/39) of deep infiltrating endometriosis harbored cancer driver gene mutations. However, it is unclear whether these mutations also exist in ovarian endometriosis. Here, a total of 101 ovarian endometriosis samples were analyzed for the presence of these gene mutations, including KRAS, PPP2R1A, PIK3CA and ARID1A. In addition, 6 other cancer-associated genes (BRAF, NRAS, HRAS, ERK1, ERK2 and PTEN) were also analyzed...
March 9, 2018: Mutation Research
Tales Rocha de Moura, Sina Mozaffari-Jovin, Csaba Zoltán Kibédi Szabó, Jana Schmitzová, Olexandr Dybkov, Constantin Cretu, Michael Kachala, Dmitri Svergun, Henning Urlaub, Reinhard Lührmann, Vladimir Pena
Human nineteen complex (NTC) acts as a multimeric E3 ubiquitin ligase in DNA repair and splicing. The transfer of ubiquitin is mediated by Prp19-a homotetrameric component of NTC whose elongated coiled coils serve as an assembly axis for two other proteins called SPF27 and CDC5L. We find that Prp19 is inactive on its own and have elucidated the structural basis of its autoinhibition by crystallography and mutational analysis. Formation of the NTC core by stepwise assembly of SPF27, CDC5L, and PLRG1 onto the Prp19 tetramer enables ubiquitin ligation...
March 15, 2018: Molecular Cell
Celine Tasset, Avilash Singh Yadav, Sridevi Sureshkumar, Rupali Singh, Lennard van der Woude, Maxim Nekrasov, David Tremethick, Martijn van Zanten, Sureshkumar Balasubramanian
Ambient temperature affects plant growth and even minor changes can substantially impact crop yields. The underlying mechanisms of temperature perception and response are just beginning to emerge. Chromatin remodeling, via the eviction of the histone variant H2A.Z containing nucleosomes, is a critical component of thermal response in plants. However, the role of histone modifications remains unknown. Here, through a forward genetic screen, we identify POWERDRESS (PWR), a SANT-domain containing protein known to interact with HISTONE DEACETYLASE 9 (HDA9), as a novel factor required for thermomorphogenesis in Arabidopsis thaliana...
March 16, 2018: PLoS Genetics
Nicola L D Overton, Axel A Brakhage, Andreas Thywißen, David W Denning, Paul Bowyer
Allergic bronchopulmonary aspergillosis (ABPA) in asthma is a severe, life-affecting disease that potentially affects over 4.8 million people globally. In the UK, ABPA is predominantly caused by the fungus Aspergillus fumigatus. Phagocytosis is important in clearance of this fungus, and Early Endosome Antigen 1 (EEA1) has been demonstrated to be involved in phagocytosis of fungi. We sought to investigate the role of EEA1 mutations and phagocytosis in ABPA. We used exome sequencing to identify variants in EEA1 associated with ABPA...
2018: PloS One
Davina Gale, Andrew R J Lawson, Karen Howarth, Mikidache Madi, Bradley Durham, Sarah Smalley, John Calaway, Shannon Blais, Greg Jones, James Clark, Peter Dimitrov, Michelle Pugh, Samuel Woodhouse, Michael Epstein, Ana Fernandez-Gonzalez, Alexandra S Whale, Jim F Huggett, Carole A Foy, Gerwyn M Jones, Hadas Raveh-Amit, Karin Schmitt, Alison Devonshire, Emma Green, Tim Forshew, Vincent Plagnol, Nitzan Rosenfeld
INTRODUCTION: Detection and monitoring of circulating tumor DNA (ctDNA) is rapidly becoming a diagnostic, prognostic and predictive tool in cancer patient care. A growing number of gene targets have been identified as diagnostic or actionable, requiring the development of reliable technology that provides analysis of multiple genes in parallel. We have developed the InVision™ liquid biopsy platform which utilizes enhanced TAm-Seq™ (eTAm-Seq™) technology, an amplicon-based next generation sequencing method for the identification of clinically-relevant somatic alterations at low frequency in ctDNA across a panel of 35 cancer-related genes...
2018: PloS One
Yuval B Simons, Kevin Bullaughey, Richard R Hudson, Guy Sella
Human genome-wide association studies (GWASs) are revealing the genetic architecture of anthropomorphic and biomedical traits, i.e., the frequencies and effect sizes of variants that contribute to heritable variation in a trait. To interpret these findings, we need to understand how genetic architecture is shaped by basic population genetics processes-notably, by mutation, natural selection, and genetic drift. Because many quantitative traits are subject to stabilizing selection and because genetic variation that affects one trait often affects many others, we model the genetic architecture of a focal trait that arises under stabilizing selection in a multidimensional trait space...
March 16, 2018: PLoS Biology
Suzanne M Mahon
People with multiple polyps may have a germline mutation that places them at higher risk for developing colorectal, gastrointestinal, and other cancers. Genetic testing can often identify the specific polyposis syndrome and provide insight into appropriate recommendations for cancer prevention and early detection. Individuals with hereditary polyposis syndromes often begin developing polyps in their teenage years and require aggressive gastrointestinal surveillance to remove polyps. For some, the polyp burden will be too high to manage endoscopically and will require risk-reducing colectomies...
April 1, 2018: Clinical Journal of Oncology Nursing
Hanrui Zhang
PURPOSE OF REVIEW: Lysosomal acid lipase (LAL), encoded by the LIPA gene, is an essential lysosomal enzyme that hydrolyzes cholesteryl ester and triglyceride delivered to the lysosome. This review highlights the novel pathophysiological role of LAL, the functional genomic discoveries of LIPA as a risk locus for coronary heart diseases (CHD), and the clinical advance in therapies for LAL deficiency. RECENT FINDINGS: The essential role of LAL in lipid metabolism has been confirmed in human and mice with LAL deficiency...
March 15, 2018: Current Opinion in Lipidology
Masha M Rosenberg, Alfred G Redfield, Mary Roberts, Lizbeth Hedstrom
The ability of enzymes to modulate the dynamics of bound substrates and cofactors is a critical feature of catalysis, but the role of dynamics has largely been approached from the perspective of the protein. Here we use an underappreciated NMR technique, subtesla high resolution field cycling31 P NMR relaxometry, to interrogate the dynamics of enzyme bound substrates and cofactors in guanosine-5'-monophosphate reductase (GMPR). These experiments reveal distinct binding modes and dynamic profiles associated with the31 P nuclei in the Michaelis complexes for the deamination and hydride transfer steps of the catalytic cycle...
March 16, 2018: Biochemistry
David Williams, Joanne L Fothergill, Benjamin Evans, Jessica Caples, Sam Haldenby, Martin J Walshaw, Michael A Brockhurst, Craig Winstanley, Steve Paterson
Pseudomonas aeruginosa chronic infections of cystic fibrosis (CF) airways are a paradigm for within-host evolution with abundant evidence for rapid evolutionary adaptation and diversification. Recently emerged transmissible strains have spread globally, with the Liverpool Epidemic Strain (LES) the most common strain infecting the UK CF population. Previously we have shown that highly divergent lineages of LES can be found within a single infection, consistent with super-infection among a cross-sectional cohort of patients...
March 16, 2018: Microbial Genomics
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