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Beryl Royer-Bertrand, Matteo Torsello, Donata Rimoldi, Ikram El Zaoui, Katarina Cisarova, Rosanna Pescini-Gobert, Franck Raynaud, Leonidas Zografos, Ann Schalenbourg, Daniel Speiser, Michael Nicolas, Laureen Vallat, Robert Klein, Serge Leyvraz, Giovanni Ciriello, Nicolò Riggi, Alexandre P Moulin, Carlo Rivolta
Uveal melanoma (UM) is a rare intraocular tumor that, similar to cutaneous melanoma, originates from melanocytes. To gain insights into its genetics, we performed whole-genome sequencing at very deep coverage of tumor-control pairs in 33 samples (24 primary and 9 metastases). Genome-wide, the number of coding mutations was rather low (only 17 variants per tumor on average; range 7-28), thus radically different from cutaneous melanoma, where hundreds of exonic DNA insults are usually detected. Furthermore, no UV light-induced mutational signature was identified...
October 6, 2016: American Journal of Human Genetics
Stephen W Bickler, Eliel Lizardo, David M Cauvi, Antonio De Maio
Urbanization in Africa is associated with an increased incidence of non-communicable diseases, yet the cause and the mechanism remain poorly understood. Here, we propose a role for G protein-coupled receptor (GPCR) signaling in the biological changes that occur with urbanization and suggest a critical area of convergence in GPCR signaling might provide a molecular signature for exposure to environmental factors. As a first step in investing this hypothesis, we examined the expression of the G protein α, β and γ subunit, G protein related kinase, and β-arrestin genes in a rural and urban population living in Morocco (NCBI GSE8847)...
October 2016: Medical Hypotheses
Hildur Helgadottir, Veronica Höiom
Uveal melanoma (UM) is the most common malignant eye tumor in adults affecting ~7,000 individuals per year worldwide. UM is a rare subtype of melanoma with distinct clinical and molecular features as compared to other melanoma subtypes. UMs lack the most typical cutaneous melanoma-associated mutations (BRAF, NRAS, and NF1) and are instead characterized by a different set of genes with oncogenic or loss-of-function mutations. By next-generation sequencing efforts on UM tumors, several driver genes have been detected...
2016: Application of Clinical Genetics
Fadil M Hannan, Valerie N Babinsky, Rajesh V Thakker
The extracellular calcium (Ca(2+) o)-sensing receptor (CaSR) is a family C G protein-coupled receptor, which detects alterations in Ca(2+) o concentrations and modulates parathyroid hormone secretion and urinary calcium excretion. The central role of the CaSR in Ca(2+) o homeostasis has been highlighted by the identification of mutations affecting the CASR gene on chromosome 3q21.1. Loss-of-function CASR mutations cause familial hypocalciuric hypercalcaemia (FHH), whereas gain-of-function mutations lead to autosomal dominant hypocalcaemia (ADH)...
October 2016: Journal of Molecular Endocrinology
Guillaume Carita, Estelle Frisch-Dit-Leitz, Ahmed Dahmani, Chloé Raymondie, Nathalie Cassoux, Sophie Piperno-Neumann, Fariba Némati, Cécile Laurent, Leanne De Koning, Ensar Halilovic, Sebastien Jeay, Andrew Wylie, Caroline Emery, Sergio Roman-Roman, Marie Schoumacher, Didier Decaudin
Uveal melanoma (UM) is the most common cancer of the eye in adults. Many UM patients develop metastases for which no curative treatment has been identified. Novel therapeutic approaches are therefore urgently needed. UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway, leading to the use of PKC inhibitors as a rational strategy to treat UM tumors. Encouraging clinical activity has been noted in UM patients treated with PKC inhibitors. However, it is likely that curative treatment regimens will require a combination of targeted therapeutic agents...
June 7, 2016: Oncotarget
Andrea Palicelli, Maria Giulia Disanto, Gabriele Panzarasa, Claudia Veggiani, Gabriella Galizia, Stefano Dal Cin, Elisa Gruppioni, Renzo Boldorini
AIMS: We provide morphological, immunohistochemical and molecular characterization of the 3rd "intermediate-grade" orbital meningeal melanocytoma, testing for the first time Vysis Melanoma FISH Probe Kit. We reviewed the literature in order to discuss the main differential diagnoses and to provide a better molecular description of these unusual tumors of difficult diagnosis and controversial management. METHODS: Histochemical stains (Haematoxylin and Eosin, Perls, reticulin), immunohistochemistry (HMB45, p16, Melan-A, S100, EMA, Ki67, CD68), polymerase chain reaction amplification and sequence analysis (BRAF, exon 15; NRAS exons 2 and 3; c-KIT, exons 11, 13, 17, 18; GNAQ, exons 4 and 5; GNA11, exons 4 and 5) and fluorescent in situ hybridization (RREB1, 6p25; MYB, 6q23; CCND1, 11q13; CEP 6, 6p11...
July 25, 2016: Pathology, Research and Practice
Xinan Sheng, Yan Kong, Yiqian Li, Qiannan Zhang, Lu Si, Chuanliang Cui, Zhihong Chi, Bixia Tang, Lili Mao, Bin Lian, Xuan Wang, Xieqiao Yan, Siming Li, Jie Dai, Jun Guo
BACKGROUND: Mucosal melanoma (MM) is a rare subtype of melanoma in Caucasians with extremely poor prognosis, and therapy strategy has not been clearly established for MM. We aimed to investigate the genetic aberrations possibly applicable in targeted therapy of MM. We examined the somatic mutations of GNAQ and GNA11 (GNAQ/11, encoding the guanine nucleotide-binding alpha subunits) in MM and evaluated their correlation to clinicopathologic features of MM. METHODS: This study collected samples from primary lesions of 284 MM patients...
September 2016: European Journal of Cancer
Matthew G Field, Michael A Durante, Christina L Decatur, Bercin Tarlan, Kristen M Oelschlager, John F Stone, Jeffim Kuznetsov, Anne M Bowcock, Stefan Kurtenbach, J William Harbour
BACKGROUND: We previously identified PRAME as a biomarker for metastatic risk in Class 1 uveal melanomas. In this study, we sought to define a threshold value for positive PRAME expression (PRAME+) in a large dataset, identify factors associated with PRAME expression, evaluate the prognostic value of PRAME in Class 2 uveal melanomas, and determine whether PRAME expression is associated with aberrant hypomethylation of the PRAME promoter. RESULTS: Among 678 samples analyzed by qPCR, 498 (73...
July 30, 2016: Oncotarget
Young H Lim, Antonella Bacchiocchi, Jingyao Qiu, Robert Straub, Anna Bruckner, Lionel Bercovitch, Deepak Narayan, Jennifer McNiff, Christine Ko, Leslie Robinson-Bostom, Richard Antaya, Ruth Halaban, Keith A Choate
Vascular tumors are among the most common neoplasms in infants and children; 5%-10% of newborns present with or develop lesions within the first 3 months of life. Most are benign infantile hemangiomas that typically regress by 5 years of age; other vascular tumors include congenital tufted angiomas (TAs), kaposiform hemangioendotheliomas (KHEs), and childhood lobular capillary hemangiomas (LCHs). Some of these lesions can become locally invasive and unresponsive to pharmacologic intervention, leading to significant complications...
August 4, 2016: American Journal of Human Genetics
Chang Hun Lee, Hong En Wang, Seung Young Seo, Seong Hun Kim, In Hee Kim, Sang Wook Kim, Soo Teik Lee, Dae Ghon Kim, Myung Kwan Han, Seung Ok Lee
Genome-wide association study in diffusely infiltrating type cholangiocarcinoma (CC) can be limited due to the difficulty of obtaining tumor tissue. We aimed to evaluate the genomic alterations of diffusely infiltrating type CC using next-generation sequencing (NGS) of bile and to compare the variations with those of mass-forming type CC. A total of 24 bile samples obtained during endoscopic retrograde cholangiopancreatography (ERCP) and 17 surgically obtained tumor tissue samples were evaluated. Buffy coat and normal tissue samples were used as controls for a somatic mutation analysis...
August 2016: Experimental and Molecular Pathology
Giulia Angelino, Maria Debora De Pasquale, Luigi De Sio, Annalisa Serra, Luca Massimi, Rita De Vito, Antonio Marrazzo, Laura Lancella, Andrea Carai, Manila Antonelli, Felice Giangaspero, Marco Gessi, Laura Menchini, Laura Scarciolla, Daniela Longo, Angela Mastronuzzi
BACKGROUND: Primary melanocytic neoplasms are rare in the pediatric age. Among them, the pattern of neoplastic meningitis represents a peculiar diagnostic challenge since neuroradiological features may be subtle and cerebrospinal fluid analysis may not be informative. Clinical misdiagnosis of neoplastic meningitis with tuberculous meningitis has been described in few pediatric cases, leading to a significant delay in appropriate management of patients. We describe the case of a child with primary leptomeningeal melanoma (LMM) that was initially misdiagnosed with tuberculous meningitis...
2016: BMC Cancer
Tracy Funk, Young Lim, Ann M Kulungowski, Lori Prok, Timothy M Crombleholme, Keith Choate, Anna L Bruckner
IMPORTANCE: Congenital hemangiomas are uncommon benign vascular tumors that present fully formed at birth. They are rarely associated with transient hematologic abnormalities, which are typically less severe than the Kasabach-Merritt phenomenon associated with kaposiform hemangioendotheliomas. Congenital hemangiomas are typically solitary and have not been reported to occur in a multifocal, generalized pattern. OBJECTIVE: To describe a male infant born with an unusual, large vascular mass complicated by anemia, thrombocytopenia, and disseminated intravascular coagulopathy, as well as innumerable small vascular papules in a generalized cutaneous distribution...
September 1, 2016: JAMA Dermatology
Tianyi Tang, Robert Eldabaje, Lixi Yang
Compared to early-stage melanoma when surgical excision is possible, metastatic disease continues to offer a much grimmer prognosis as traditional chemotherapy treatment regimens offer relatively little survival benefit. This has led to changes in treatment approaches over the preceding two decades as contemporary methods for the treatment of advanced or metastatic melanoma now involve a number of biological modalities, which include immunotherapeutic approaches, targeted therapies and epigenetic modification therapies...
July 2016: Anticancer Research
B R Patel, G G Tall
The heterotrimeric G protein α subunit oncogenes GNAQ or GNA11 carry Q209X or R183X activating mutations and are present with ~90% frequency in human uveal melanomas. Forced expression of GNAQ/11(Q209L) in melanocytes is sufficient to drive metastatic melanoma in immune-compromised mice. No known drugs directly target these oncogenic G proteins. Ric-8A is the molecular chaperone that selectively folds Gαq/i/13 subunits. Targeting Ric-8A serves as a rational, yet unexplored approach to reduce the functional abundance of oncogenic Gαq/11 in order to blunt cancer signaling...
2016: Oncogenesis
Sirpa Tenhola, Raimo Voutilainen, Monica Reyes, Sanna Toiviainen-Salo, Harald Jüppner, Outi Mäkitie
OBJECTIVE: Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 1 is caused by activating mutations in the calcium-sensing receptor (CASR), a G-protein-coupled receptor signaling through α11 (Gα11) and αq (Gαq) subunits. Heterozygous activating mutations in GNA11, the gene encoding Gα11, underlie ADH type 2. This study describes disease characteristics in a family with ADH caused by a gain-of-function mutation in GNA11...
September 2016: European Journal of Endocrinology
Mohammad Atefi, Bjoern Titz, Jennifer Tsoi, Earl Avramis, Allison Le, Charles Ng, Anastasia Lomova, Amanda Lassen, Michael Friedman, Bartosz Chmielowski, Antoni Ribas, Thomas G Graeber
Approximately 75% of melanomas have known driver oncogenic mutations in BRAF, NRAS, GNA11 or GNAQ, while the mutations providing constitutive oncogenic signaling in the remaining melanomas are not known. We established a melanoma cell line from a tumor with none of the common driver mutations. This cell line demonstrated a signaling profile similar to BRAF-mutants, but lacked sensitivity to the BRAF inhibitor vemurafenib. RNA-seq mutation data implicated CRAF R391W as the alternative driver mutation of this melanoma...
2016: Scientific Reports
Ugur M Ayturk, Javier A Couto, Steven Hann, John B Mulliken, Kaitlin L Williams, August Yue Huang, Steven J Fishman, Theonia K Boyd, Harry P W Kozakewich, Joyce Bischoff, Arin K Greene, Matthew L Warman
No abstract text is available yet for this article.
June 2, 2016: American Journal of Human Genetics
Jasmine H Francis, Thomas Wiesner, Tatyana Milman, Helen H Won, Amy Lin, Vivian Lee, Daniel M Albert, Robert Folberg, Michael F Berger, Devron H Char, Brian Marr, David H Abramson
PURPOSE: The aim of this study was to use massively parallel DNA sequencing to identify GNAQ/11, BAP1 and SF3B1 mutations in ophthalmic melanocytoma. PROCEDURES: Six ophthalmic melanocytoma specimens (1 iridociliary and 5 optic nerve) were profiled for genomic alterations in GNAQ/11, BAP1 and SF3B1 using a custom deep sequencing assay. This assay uses solution phase hybridization-based exon capture and deep-coverage massively parallel DNA sequencing to interrogate all protein-coding exons and select introns...
April 2016: Ocular Oncology and Pathology
Nicole Pfarr, Roland Penzel, Frederick Klauschen, Daniel Heim, Regine Brandt, Daniel Kazdal, Moritz Jesinghaus, Esther Herpel, Peter Schirmacher, Arne Warth, Wilko Weichert, Volker Endris, Albrecht Stenzinger
Targeted deep massive parallel sequencing has been implemented in routine molecular diagnostics for high-throughput genetic profiling of formalin-fixed paraffin-embedded (FFPE) cancer samples. This approach is widely used to interrogate simple somatic mutations but experience with the analysis of copy number variations (CNV) is limited. Here, we retrospectively analyzed CNV in 822 cancer cases (135 melanoma, 468 non-small cell lung cancers (NSCLC), 219 colorectal cancers (CRC)). We observed a decreasing frequency of CNV in clinically actionable genes from melanoma to NSCLC to CRC...
November 2016: Genes, Chromosomes & Cancer
Ruchi Mittal, Svetlana Cherepanoff, Sophie Thornton, Helen Kalirai, Bertil Damato, Sarah E Coupland
PURPOSE OF THE STUDY: To describe the clinicopathological features, mutational and chromosomal copy number analysis, and 8-year follow-up of a case of bilateral diffuse uveal melanocytic proliferation (BDUMP) associated with clear-cell carcinoma of the endometrium. METHODS: Histological evaluation, multiplex ligation-dependent probe amplification (MLPA) analysis and GNAQ/11 mutational analysis were performed in a 67-year-old female patient with the diagnosis of BDUMP...
December 2015: Ocular Oncology and Pathology
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