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Clinical molecular genetics

Mariella G Filbin, Dominik Sturm
Gliomas are the most common primary central nervous system (CNS) neoplasms in children and adolescents and are thought to arise from their glial progenitors or stem cells. Although the exact cells of origin for most pediatric gliomas remain to be identified, our current understanding is that specific cell populations during CNS development are susceptible to particular oncogenic events during certain time windows and thus give rise to pediatric gliomas with distinct histological, molecular, and clinical features...
February 2018: Seminars in Neurology
Elizabeth R Gerstner, Kristian W Pajtler
Ependymoma can arise throughout the whole neuraxis. In children, tumors predominantly occur intracranially, whereas the spine is the most prevalent location in adults. Significant variance in the grade II versus grade III distinction of ependymomas has led to the acknowledgment that the clinical utility of histopathological classification is limited. Epigenomic profiling efforts have identified molecularly distinct groups of ependymomas that adequately reflect the biological, clinical, and histopathological heterogeneities across anatomical compartments, age groups, and grades...
February 2018: Seminars in Neurology
Zachary J Reitman, Frank Winkler, Andrew E H Elia
Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system. The current standard of care for GBM is maximal resection followed by postoperative radiation with concomitant and adjuvant temozolomide. Despite this multimodality treatment, the median survival for GBM remains marginally better than 1 year. In the past decade, genome-wide analyses have uncovered new molecular features of GBM that have refined its classification and provided new insights into the molecular basis for GBM pathogenesis...
February 2018: Seminars in Neurology
Maria Martinez-Lage, Felix Sahm
The updated 2016 WHO classification of Central Nervous System tumors introduced a novel concept of neuropathology diagnostics. Molecular parameters are now included into the definition of several entities. This evolution from a previously purely histology-based classification to an integrated approach of histology and genetic characteristics has implications in daily diagnostic and clinical practice. Both the spectrum of diagnostic workup demanded from the neuropathologist and the range of relevant markers to be considered by clinicians and clinical investigators have increased...
February 2018: Seminars in Neurology
Michael Karsy, Jian Guan, L Eric Huang
OBJECTIVE Gliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from α-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis...
March 16, 2018: Journal of Neurosurgery
Michael B Ranke, Jan M Wit
Growth hormone (GH) research and its clinical application for the treatment of growth disorders span more than a century. During the first half of the 20th century, clinical observations and anatomical and biochemical studies formed the basis of the understanding of the structure of GH and its various metabolic effects in animals. The following period (1958-1985), during which pituitary-derived human GH was used, generated a wealth of information on the regulation and physiological role of GH - in conjunction with insulin-like growth factors (IGFs) - and its use in children with GH deficiency (GHD)...
March 16, 2018: Nature Reviews. Endocrinology
Xiangfeng Wang, Hu Fang, Yong Cheng, Lin Li, Xiaohui Sun, Tao Fu, Peide Huang, Anping Zhang, Zhimin Feng, Chunxue Li, Xuanlin Huang, Guangyan Li, Peina Du, Huanming Yang, Xiaodong Fang, Fan Li, Qiang Gao, Baohua Liu
Synchronous colorectal cancers (syCRCs), which present two or more lesions at diagnosis, are rare and pose a great challenge for clinical management. Although some predisposing factors associated with syCRCs have been studied with limited accession, the full repertoire of genomic events among the lesions within an individual and the causes of syCRCs remain unclear. We performed whole-exome sequencing of 40 surgical tumour samples of paired lesions from 20 patients to characterize the genetic alterations. Lesions from same patient showed distinct landscapes of somatic aberrations and shared few mutations, which suggests that they originate and develop independently although they shared the similar genetic background...
March 13, 2018: Carcinogenesis
Vincent Plagnol, Samuel Woodhouse, Karen Howarth, Stefanie Lensing, Matt Smith, Michael Epstein, Mikidache Madi, Sarah Smalley, Catherine Leroy, Jonathan Hinton, Frank de Kievit, Esther Musgrave-Brown, Colin Herd, Katherine Baker-Neblett, Will Brennan, Peter Dimitrov, Nathan Campbell, Clive Morris, Nitzan Rosenfeld, James Clark, Davina Gale, Jamie Platt, John Calaway, Greg Jones, Tim Forshew
Circulating tumor DNA (ctDNA) analysis is being incorporated into cancer care; notably in profiling patients to guide treatment decisions. Responses to targeted therapies have been observed in patients with actionable mutations detected in plasma DNA at variant allele fractions (VAFs) below 0.5%. Highly sensitive methods are therefore required for optimal clinical use. To enable objective assessment of assay performance, detailed analytical validation is required. We developed the InVisionFirst™ assay, an assay based on enhanced tagged amplicon sequencing (eTAm-Seq™) technology to profile 36 genes commonly mutated in non-small cell lung cancer (NSCLC) and other cancer types for actionable genomic alterations in cell-free DNA...
2018: PloS One
Martina Baneckova, Abbas Agaimy, Simon Andreasen, Tomas Vanecek, Petr Steiner, David Slouka, Tomas Svoboda, Marketa Miesbauerova, Michael Michal, Alena Skálová
Secretory carcinoma, originally described as mammary analog secretory carcinoma (MASC), is a low-grade salivary gland tumor characterized by a t(12;15)(p13;q25) translocation, resulting in an ETV6-NTRK3 gene fusion. Most MASCs are localized to the parotid gland and intraoral minor salivary glands. Moreover, ETV6-rearranged carcinomas with secretory features have been reported recently in the thyroid (with and without a history of radiation exposure), skin, and in very rare instances in the sinonasal tract. Here, we describe 2 cases of primary MASC in the sinonasal tract and provide a detailed clinical and histopathologic characterization of their morphology, immunohistochemical profile, and genetic background and highlight features allowing for its separation from its recently described molecular mimicker, ETV6-rearranged low-grade sinonasal adenocarcinoma...
March 14, 2018: American Journal of Surgical Pathology
Dafina Ilijazi, Mohammad Abufaraj, Melanie R Hassler, Iris E Ertl, David D'Andrea, Shahrokh F Shariat
Bladder cancer (BCa) is the fifth most frequently diagnosed cancer worldwide and is, in fact, the most expensive cancer on a per-patient to treat basis. There is a critical need to implement new tests into clinical practice to improve the quality of clinical care, decrease unnecessary invasive therapies and ultimately save costs. Currently, no molecular or genetic biomarker has been widely integrated into daily clinical practice. However, major milestones have been achieved in our understanding of the molecular alterations in BCa that will provide the basis for integrating molecular and genetic biomarkers into clinical decision making to guide management...
March 15, 2018: Expert Review of Molecular Diagnostics
Hiroshi Maeda, Mahin Khatami
For over six decades reductionist approaches to cancer chemotherapies including recent immunotherapy for solid tumors produced outcome failure-rates of 90% (±5) according to governmental agencies and industry. Despite tremendous public and private funding and initial enthusiasm about missile-therapy for site-specific cancers, molecular targeting drugs for specific enzymes such as kinases or inhibitors of growth factor receptors, the outcomes are very bleak and disappointing. Major scientific reasons for repeated failures of such therapeutic approaches are attributed to reductionist approaches to research and infinite numbers of genetic mutations in chaotic molecular environment of solid tumors that are bases of drug development...
March 1, 2018: Clinical and Translational Medicine
Ibtessam R Hussein, Rima S Bader, Adeel G Chaudhary, Randa Bassiouni, Maha Alquaiti, Fai Ashgan, Hans-Juergen Schulten, Mohammad H Al Qahtani
Congenital heart defects (CHDs) are the most common birth defects in neonatal life. CHDs could be presented as isolated defects or associated with developmental delay (DD) and/or other congenital malformations. A small proportion of cardiac defects are caused by chromosomal abnormalities or single gene defects; however, in a large proportion of cases no genetic diagnosis could be achieved by clinical examination and conventional genetic analysis. The development of genome wide array-Comparative Genomic Hybridization technique (array-CGH) allowed for the detection of cryptic chromosomal imbalances and pathogenic copy number variants (CNVs) not detected by conventional techniques...
March 14, 2018: Pediatric Cardiology
Jingyi Li, Jie Xu, Lynne V Abruzzo, Guilin Tang, Shaoying Li, M James You, Gary Lu, Elias J Jabbour, Qi Deng, Carlos E Bueso-Ramos, L Jeffrey Medeiros, C Cameron Yin
We describe the clinical, morphologic, immunophenotypic and molecular genetic features of 15 cases of acute myeloid leukemia (AML) with t(4;12)(q12;p13). There were 9 men and 6 women, with a median age of 50 years (range, 17-76). Most patients had hypercellular bone marrow with a median blast count of 58% and multilineage dysplasia. Flow cytometry analysis showed myeloid lineage with blasts positive for CD13, CD33, CD34, CD38, CD117 and HLA-DR. Interestingly, aberrant CD7 expression was detected in 12/14 cases, and myeloperoxidase was either negative (3/15) or positive in only a small subset of the blasts (12/15)...
February 16, 2018: Oncotarget
Weiwei Ruan, Li Cao, Zhonghua Chen, Mingxiang Kong, Qing Bi
Hereditary multiple osteochondroma (HMO) is an autosomal dominant genetic disorder characterized by multiple outgrowing bony tumors capped by cartilage, generally affecting the metaphyses. The disease is known as hereditary multiple exostoses, familial exostosis, multiple cartilaginous exostoses or hereditary malformation of cartilage. The prevalence of HMO in Europe and the Unites States is ~1:100,000, although it has not been reported in China. The disease is often accompanied by pain, asymmetry and skeletal malformations, including forearm and leg bending deformities, limb length discrepancies, and knee internal and external rotation abnormalities...
April 2018: Oncology Letters
Cun-Zhi Lin, Gui-Ling Xiang, Xin-Hong Zhu, Lu-Lu Xiu, Jia-Xing Sun, Xiao-Yuan Zhang
Cancer virotherapy mediated by oncolytic viruses (OV), has emerged as a novel and effective strategy in cancer therapeutics. Preclinical models have demonstrated anticancer activity against numerous types of cancer. Currently, a number of recombinant viruses are in late phase clinical trials, many of which have demonstrated promising results regarding the safety and reliability of the treatments, particularly when combined with standard antineoplastic therapies. In addition to molecular-targeted therapeutics, genetic engineering of the viruses allows functional complementation to chemotherapy or radiotherapy agents...
April 2018: Oncology Letters
Germano Orrù, Mauro Giovanni Carta
Background: Bipolar Disorder (BD), along with depression and schizophrenia, is one of the most serious mental illnesses, and one of the top 20 causes of severe impairment in everyday life. Recent molecular studies, using both traditional approaches and new procedures such as Whole-Genome Sequencing (WGS), have suggested that genetic factors could significantly contribute to the development of BD, with heritability estimates of up to 85%. However, it is assumed that BD is a multigenic and multifactorial illness with environmental factors that strongly contribute to disease development/progression, which means that progress in genetic knowledge of BD might be difficult to interpret in clinical practice...
2018: Clinical Practice and Epidemiology in Mental Health: CP & EMH
Sylvie Jaillard, Elena J Tucker, Linda Akloul, Marion Beaumont, Mathilde Domin, Laurent Pasquier, Guilhem Jouve, Sylvie Odent, Marc-Antoine Belaud-Rotureau, Célia Ravel
Ovarian reserve represents the number of available follicles/oocytes within ovaries and it can be assessed by follicle stimulating hormone levels, anti-Müllerian hormone levels, and/or antral follicle count determined by ultrasounds. A low ovarian reserve is defined by an abnormal ovarian reserve test. This condition can be considered premature if it occurs before the age of 40, leading to premature ovarian insufficiency. Despite the growing knowledge concerning the genetic basis of ovarian deficiency, the majority of cases remain without a genetic diagnosis...
March 14, 2018: Journal of Human Genetics
Roy Morello
Osteogenesis imperfecta, or brittle bone disease, is a congenital disease that primarily causes low bone mass and bone fractures but it can negatively affect other organs. It is usually inherited in an autosomal dominant fashion, although rarer recessive and X-chromosome-linked forms of the disease have been identified. In addition to type I collagen, mutations in a number of other genes, often involved in type I collagen synthesis or in the differentiation and function of osteoblasts, have been identified in the last several years...
March 11, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
Guillaume Bataillon, Laetitia Fuhrmann, Elodie Girard, Emanuelle Menet, Marick Laé, Mathieu Capovilla, Isabelle Treilleux, Laurent Arnould, Frederique Penault-Llorca, Roman Rouzier, Caterina Marchiò, Ivan Bieche, Anne Vincent-Salomon
Low-grade adenosquamous carcinoma of the breast (LGASC) is a rare variant of metaplastic carcinoma characterized by a favorable outcome and histologically composed of glandular and squamous elements in a spindle cell background typically associated with a lymphocytic stromal reaction. Due to its rarity, the immunophenoptypical and genetic profile LGASC has not been sufficiently characterized. The aim of this study was to gain insight into the molecular and phenotypic characteristics of LGASC. We reviewed the clinical, morphological features and detailed the immunohistochemical characteristics of a retrospective series of 13 LGASCs...
March 14, 2018: Histopathology
Ping Hu, Fengchang Qiao, Yan Wang, Lulu Meng, Xiuqing Ji, Chunyu Luo, Tianhui Xu, Ran Zhou, Jingjing Zhang, Bin Yu, Leilei Wang, Ting Wang, Qiong Pan, Dingyuan Ma, Dong Liang, Zhengfeng Xu
OBJECTIVES: This study aimed to determine the diagnostic yield of targeted next-generation sequencing (NGS) in prenatal diagnosis of congenital heart defects (CHDs) and for investigating the possible genetic etiology of prenatal CHD cases. METHODS: Forty-four fetuses with CHDs and normal molecular karyotypes underwent targeted NGS in this study. Fetal genomic DNA was directly extracted from amniotic fluid cells in each prenatal case. A customized targeted NGS panel containing 77 CHD-associated genes was designed to detect variants in the coding regions and the splicing sites of these genes...
March 13, 2018: Ultrasound in Obstetrics & Gynecology
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