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somatic mutations

Lies Van Horebeek, Kelly Hilven, Klara Mallants, Annemarie Van Nieuwenhuijze, Tiina Kelkka, Paula Savola, Satu Mustjoki, Susan M Schlenner, Adrian Liston, Bénédicte Dubois, An Goris
The role of somatic variants in diseases beyond cancer is increasingly being recognized, with potential roles in autoinflammatory and autoimmune diseases. However, as mutation rates and allele fractions are lower, studies in these diseases are substantially less tolerant of false positives and bio-informatics algorithms require high replication rates. We developed a pipeline combining two variant callers, MuTect2 and VarScan2, with technical filtering and prioritization. Our pipeline detects somatic variants with allele fractions as low as 0...
December 12, 2018: Human Molecular Genetics
An-Shun Tai, Chien-Hua Peng, Shih-Chi Peng, Wen-Ping Hsieh
Multistage tumorigenesis is a dynamic process characterized by the accumulation of mutations. Thus, a tumor mass is composed of genetically divergent cell subclones. With the advancement of next-generation sequencing (NGS), mathematical models have been recently developed to decompose tumor subclonal architecture from a collective genome sequencing data. Most of the methods focused on single-nucleotide variants (SNVs). However, somatic copy number aberrations (CNAs) also play critical roles in carcinogenesis...
2018: PloS One
Zhi Liu, Xiao Dong, Yixue Li
Accumulating evidence from small-scale studies has suggested that allele-specific expression (ASE) plays an important role in tumor initiation and progression. However, little is known about genome-wide ASE in tumors. In this study, we conducted a comprehensive analysis of ASE in individuals with colorectal cancer (CRC) on a genome-wide scale. We identified 5.4 thousand genome-wide ASEs of single nucleotide variations (SNVs) from tumor and normal tissues of 59 individuals with CRC. We observed an increased ASE level in tumor samples and the ASEs enriched as hotspots on the genome...
2018: Frontiers in Genetics
Clarissa Gerhauser, Francesco Favero, Thomas Risch, Ronald Simon, Lars Feuerbach, Yassen Assenov, Doreen Heckmann, Nikos Sidiropoulos, Sebastian M Waszak, Daniel Hübschmann, Alfonso Urbanucci, Etsehiwot G Girma, Vladimir Kuryshev, Leszek J Klimczak, Natalie Saini, Adrian M Stütz, Dieter Weichenhan, Lisa-Marie Böttcher, Reka Toth, Josephine D Hendriksen, Christina Koop, Pavlo Lutsik, Sören Matzk, Hans-Jörg Warnatz, Vyacheslav Amstislavskiy, Clarissa Feuerstein, Benjamin Raeder, Olga Bogatyrova, Eva-Maria Schmitz, Claudia Hube-Magg, Martina Kluth, Hartwig Huland, Markus Graefen, Chris Lawerenz, Gervaise H Henry, Takafumi N Yamaguchi, Alicia Malewska, Jan Meiners, Daniela Schilling, Eva Reisinger, Roland Eils, Matthias Schlesner, Douglas W Strand, Robert G Bristow, Paul C Boutros, Christof von Kalle, Dmitry Gordenin, Holger Sültmann, Benedikt Brors, Guido Sauter, Christoph Plass, Marie-Laure Yaspo, Jan O Korbel, Thorsten Schlomm, Joachim Weischenfeldt
Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors...
December 10, 2018: Cancer Cell
J H Francis, T Milman, H Grossniklaus, D M Albert, R Folberg, G M Levitin, S E Coupland, F Catalanotti, D Rabady, C Kandoth, K J Busam, D H Abramson
PURPOSE: GNAQ mutations have been identified in port wine stains (both syndromic and non-syndromic) and melanocytic ocular neoplasms. This study investigates the presence of GNAQ mutations in diffuse- (those associated with Sturge-Weber syndrome (SWS)) and solitary choroidal hemangiomas. PARTICIPANTS: Tissue from 11 patients with the following diagnoses: port wine stain (n = 3), diffuse choroidal hemangioma (n = 1), solitary choroidal hemangioma (n = 6), choroidal nevus (n =1) METHODS: Ten specimens were interrogated with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a hybridization capture-based next-generation sequencing assay for targeted deep sequencing of all exons and selected introns of 468 key cancer genes in formalin-fixed, paraffin-embedded tumors...
December 8, 2018: Ophthalmology
Ma Reina Improgo, Bethany Tesar, Josephine L Klitgaard, Reuma Magori-Cohen, Lijian Yu, Siddha Kasar, Divya Chaudhary, Wenyan Miao, Stacey M Fernandes, Kevin Hoang, William F Westlin, Haesook T Kim, Jennifer R Brown
The L265P somatic mutation in the Myeloid Differentiation Primary Response 88 (MYD88) gene is a recurrent mutation in chronic lymphocytic leukaemia (CLL). This mutation has functional effects in various haematological malignancies but its role in CLL remains to be fully elucidated. Here, we report that MYD88 L265P mutations are associated with mutated immunoglobulin heavy-chain gene (IGHV-M) status and that among IGHV-M patients, the presence of MYD88 L265P is associated with younger age at diagnosis. Using microarray and RNA-Seq gene expression analysis, we further observe that the MYD88 L265P mutation is associated with a distinctive gene expression signature that predicts both failure-free survival and overall survival...
December 9, 2018: British Journal of Haematology
Jeffrey L Neul, Timothy A Benke, Eric D Marsh, Steven A Skinner, Jonathan Merritt, David N Lieberman, Shannon Standridge, Timothy Feyma, Peter Heydemann, Sarika Peters, Robin Ryther, Mary Jones, Bernhard Suter, Walter E Kaufmann, Daniel G Glaze, Alan K Percy
Mutations in the X-linked gene MECP2 are associated with a severe neurodevelopmental disorder, Rett syndrome (RTT), primarily in girls. It had been suspected that mutations in Methyl-CpG-binding protein 2 (MECP2) led to embryonic lethality in males, however such males have been reported. To enhance understanding of the phenotypic spectrum present in these individuals, we identified 30 males with MECP2 mutations in the RTT Natural History Study databases. A wide phenotypic spectrum was observed, ranging from severe neonatal encephalopathy to cognitive impairment...
December 7, 2018: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Jason K Sa, Seung Won Choi, Junfei Zhao, Yeri Lee, Jing Zhang, Doo-Sik Kong, Jung Won Choi, Ho Jun Seol, Jung-Il Lee, Antonio Iavarone, Raul Rabadan, Do-Hyun Nam
Hypermutagenesis refers to marked increase in the number of mutations due to continuous mutagenic process. Hypermutated tumors, have being found in several tumor types, are associated with inherited or acquired alterations in DNA repair pathways. Hypermutation has been observed in a subset of adult glioma patients as a direct result of temozolomide(TMZ)-induced mutagenesis. In present study, we have identified a rare subset of treatment-naïve adult gliomas with de novo hypermutator phenotype and explored the evolution of spontaneous and treatment-induced hypermutagenesis...
December 11, 2018: International Journal of Cancer. Journal International du Cancer
Beth K Neilsen, Richard Sleightholm, Rodney McComb, Shakti H Ramkissoon, Jeffrey S Ross, Robert J Corona, Vincent A Miller, Matthew Cooke, Michele R Aizenberg
INTRODUCTION: Glioblastoma (GBM) is heterogeneous and underlying genomic profiles influence evolution, resistance, and therapeutic responses. While extensive knowledge regarding genomic profiling of primary GBM exists, there remains a lack of understanding of genomic differences in recurrent GBM. METHODS: We used the FoundationOne® comprehensive genomic profiling assay (CGP) to analyze ten matched primary and recurrent GBM. Genomic alterations (GA) were compared to the cancer database Catalogue of Somatic Mutations in Cancer (COSMIC)...
December 9, 2018: Journal of Neuro-oncology
Heena Singla, Raman Preet Kaur, Gowhar Shafi, Rajesh Vashistha, Raja Paramjeet Singh Banipal, Vinod Kumar, Anjana Munshi
Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) is an aggressive BC subtype characterized by HER2 overexpression/amplification. Genomic alterations of HER2 and others have been reported to be associated with, HER2 overexpression and prediction of trastuzumab-response. Here, we aimed at identifying germline and somatic alterations associated with HER2+ BC and evaluating their association with clinical outcome in response to trastuzumab therapy given to HER2+ BC patients. Global Sequencing Array (GSA) and polymerase chain reaction-restriction length polymorphism (PCR-RFLP) techniques were used to determine alterations in HER2 and other HER2-interacting as well as signaling-related genes in HER2+ BC...
December 10, 2018: Molecular Biology Reports
Shilpa Nadimpalli Kobren, Mona Singh
Domains are fundamental subunits of proteins, and while they play major roles in facilitating protein-DNA, protein-RNA and other protein-ligand interactions, a systematic assessment of their various interaction modes is still lacking. A comprehensive resource identifying positions within domains that tend to interact with nucleic acids, small molecules and other ligands would expand our knowledge of domain functionality as well as aid in detecting ligand-binding sites within structurally uncharacterized proteins...
December 7, 2018: Nucleic Acids Research
Emily R Rosen, David M Kushner, Aparna M Mahajan, Cara R King
Background: Various ovarian neoplasms may show histological findings that are morphologically indistinguishable from adult granulosa cell tumor (AGCT). Case presentation: A 36 year-old women presented with left lower extremity pain and numbness. Ultrasound revealed a 10 cm left adnexal mass treated with ovarian cystectomy. Histopathology revealed endometriotic cyst with intramural granulosa cell tumor. She underwent a laparoscopic left salpingo-oophorectomy and omental biopsy by Gynecologic Oncology...
February 2019: Gynecologic Oncology Reports
Joon Tae Park, Steven D Leach
Pancreatic cancer constitutes a genetic disease in which somatic mutations in the KRAS proto-oncogene are detected in a majority of tumors. KRAS mutations represent an early event during pancreatic tumorigenesis that crucial for cancer initiation and progression. Here, we established a zebrafish pancreatic cancer model that highly recapitulates human pancreatic intraepithelial neoplasia (PanIN) development. We established a novel system combining CRE/Lox technology with the GAL4/UAS system to express oncogenic KRAS in the ptf1a domain temporarily...
2018: Animal Cells and Systems
Fulvio D'Angelo, Michele Ceccarelli, Tala, Luciano Garofano, Jing Zhang, Véronique Frattini, Francesca P Caruso, Genevieve Lewis, Kristin D Alfaro, Luc Bauchet, Giulia Berzero, David Cachia, Mario Cangiano, Laurent Capelle, John de Groot, Francesco DiMeco, François Ducray, Walid Farah, Gaetano Finocchiaro, Stéphane Goutagny, Carlos Kamiya-Matsuoka, Cinzia Lavarino, Hugues Loiseau, Véronique Lorgis, Carlo E Marras, Ian McCutcheon, Do-Hyun Nam, Susanna Ronchi, Veronica Saletti, Romuald Seizeur, John Slopis, Mariona Suñol, Fanny Vandenbos, Pascale Varlet, Dominique Vidaud, Colin Watts, Viviane Tabar, David E Reuss, Seung-Ki Kim, David Meyronet, Karima Mokhtari, Hector Salvador, Krishna P Bhat, Marica Eoli, Marc Sanson, Anna Lasorella, Antonio Iavarone
Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma)...
December 10, 2018: Nature Medicine
Shinsuke Hirabayashi, Suzuki Misato, Atsushi Manabe
TP53 is a tumor-suppressor gene, and it is the most commonly mutated somatic gene in human cancer. Germline TP53 mutations correlate with a hereditary predisposition to cancer. Comprehensive genetic analysis revealed the role of germline and somatic TP53 gene mutations in hematological malignancies. TP53 mutations affect the prognosis and therapeutic decision-making. Hence, genetic screening and tumor surveillance, including family members, should be performed when a germline TP53 mutation is detected in a patient...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Wenbin Xiao, Maheetha Bharadwaj, Max Levine, Noushin Farnhoud, Friederike Pastore, Bartlomiej M Getta, Anne Hultquist, Christopher Famulare, Juan S Medina, Minal A Patel, Qi Gao, Natasha Lewis, Janine Pichardo, Jeeyeon Baik, Brian Shaffer, Sergio Giralt, Raajit Rampal, Sean Devlin, Robert Cimera, Yanming Zhang, Maria E Arcila, Elli Papaemmanuil, Ross L Levine, Mikhail Roshal
The genetic aberrations that drive mixed phenotype acute leukemia (MPAL) remain largely unknown, with the exception of a small subset of MPALs harboring BCR -ABL1 and MLL translocations. We performed clinicopathologic and genetic evaluation of 52 presumptive MPAL cases at Memorial Sloan Kettering Cancer Center. Only 29 out of 52 (56%) cases were confirmed to be bona fide MPAL according to the 2016 World Heath Organization classification. We identified PHF6 and DNMT3A mutations as the most common recurrent mutations in MPAL, each occurring in 6 out of 26 (23%) cases...
December 11, 2018: Blood Advances
Ian M Frayling, Victor-Felix Mautner, Rick van Minkelen, Roope A Kallionpaa, Safiye Aktaş, Diana Baralle, Shay Ben-Shachar, Alison Callaway, Harriet Cox, Diana M Eccles, Salah Ferkal, Holly LaDuca, Conxi Lázaro, Mark T Rogers, Aaron J Stuenkel, Pia Summerour, Ali Varan, Yoon Sim Yap, Ouidad Zehou, Juha Peltonen, Gareth D Evans, Pierre Wolkenstein, Meena Upadhyaya
BACKGROUND: Neurofibromatosis type 1 (NF1) predisposes to breast cancer (BC), but no genotype-phenotype correlations have been described. METHODS: Constitutional NF1 mutations in 78 patients with NF1 with BC (NF1-BC) were compared with the NF1 Leiden Open Variation Database (n=3432). RESULTS: No cases were observed with whole or partial gene deletions (HR 0.10; 95% CI 0.006 to 1.63; p=0.014, Fisher's exact test). There were no gross relationships with mutation position...
December 10, 2018: Journal of Medical Genetics
Jennifer O'Sullivan, Adam J Mead
Myeloproliferative neoplasms (MPNs) are haematopoietic stem cell-derived clonal disorders characterised by proliferation of some or all myeloid lineages, depending on the subtype. MPNs are classically categorized into three disease subgroups; essential thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis (PMF). The majority (>85%) of patients carry a disease-initiating or driver mutation, the most prevalent occurring in the janus kinase 2 gene (JAK2 V617F), followed by calreticulin (CALR) and myeloproliferative leukaemia virus (MPL) genes...
November 22, 2018: Advances in Biological Regulation
Daniel Kazdal, Alexander Harms, Volker Endris, Roland Penzel, Cristiano Oliveira, Mark Kriegsmann, Rémi Longuespée, Hauke Winter, Marc A Schneider, Thomas Muley, Nicole Pfarr, Wilko Weichert, Albrecht Stenzinger, Arne Warth
OBJECTIVES: The potential role of cancer associated somatic mutations of the mitochondrial genome (mtDNA) is controversial and still poorly understood. Our group and others recently challenged a direct tumorigenic impact and suggested a passenger-like character. In combination with the known increased mutation rate, somatic mtDNA mutations account for an interesting tool to delineate tumor evolution. Here, we comprehensively analyzed the spatial distribution of somatic mtDNA mutations throughout whole tumor sections of pulmonary adenocarcinoma (ADC)...
December 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Meghan Robinson, Ian Fraser, Emily McKee, Kali Scheck, Lillian Chang, Stephanie M Willerth
Cellular transdifferentiation changes mature cells from one phenotype into another by altering their gene expression patterns. Manipulating expression of transcription factors, proteins that bind to DNA promoter regions, regulates the levels of key developmental genes. Viral delivery of transcription factors can efficiently reprogram somatic cells, but this method possesses undesirable side effects, including mutations leading to oncogenesis. Using protein transduction domains (PTDs) fused to transcription factors to deliver exogenous transcription factors serves as an alternative strategy that avoids the issues associated with DNA integration into the host genome...
2018: Frontiers in Bioengineering and Biotechnology
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