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Oncogenic mutations

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https://www.readbyqxmd.com/read/28335073/clinical-characteristics-and-whole-exome-transcriptome-sequencing-of-coexisting-chronic-myeloid-leukemia-and-myelofibrosis
#1
Malathi Kandarpa, Yi-Mi Wu, Dan Robinson, Patrick William Burke, Arul M Chinnaiyan, Moshe Talpaz
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell (HSC) disorders that can be classified on the basis of genetic, clinical, phenotypic features. Genetic lesions such as JAK2 mutations and BCR-ABL translocation are often mutually exclusive in MPN patients and lead to essential thrombocythemia, polycythemia vera or myelofibrosis (ET/PV/MF) or chronic myeloid leukemia, respectively. Nevertheless, coexistence of these genetic aberrations in the same patient has been reported. Whether these aberrations occur in the same stem cell or a different cell is unclear, but an unstable genome in the HSCs seems to be the common antecedent...
March 23, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28334900/cdk12-regulates-alternative-last-exon-mrna-splicing-and-promotes-breast-cancer-cell-invasion
#2
Jerry F Tien, Alborz Mazloomian, S-W Grace Cheng, Christopher S Hughes, Christalle C T Chow, Leanna T Canapi, Arusha Oloumi, Genny Trigo-Gonzalez, Ali Bashashati, James Xu, Vicky C-D Chang, Sohrab P Shah, Samuel Aparicio, Gregg B Morin
CDK12 (cyclin-dependent kinase 12) is a regulatory kinase with evolutionarily conserved roles in modulating transcription elongation. Recent tumor genome studies of breast and ovarian cancers highlighted recurrent CDK12 mutations, which have been shown to disrupt DNA repair in cell-based assays. In breast cancers, CDK12 is also frequently co-amplified with the HER2 (ERBB2) oncogene. The mechanisms underlying functions of CDK12 in general and in cancer remain poorly defined. Based on global analysis of mRNA transcripts in normal and breast cancer cell lines with and without CDK12 amplification, we demonstrate that CDK12 primarily regulates alternative last exon (ALE) splicing, a specialized subtype of alternative mRNA splicing, that is both gene- and cell type-specific...
March 17, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334873/alternative-dna-structure-formation-in-the-mutagenic-human-c-myc-promoter
#3
Imee Marie A Del Mundo, Maha Zewail-Foote, Sean M Kerwin, Karen M Vasquez
Mutation 'hotspot' regions in the genome are susceptible to genetic instability, implicating them in diseases. These hotspots are not random and often co-localize with DNA sequences potentially capable of adopting alternative DNA structures (non-B DNA, e.g. H-DNA and G4-DNA), which have been identified as endogenous sources of genomic instability. There are regions that contain overlapping sequences that may form more than one non-B DNA structure. The extent to which one structure impacts the formation/stability of another, within the sequence, is not fully understood...
February 21, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334865/structure-of-human-pofut1-its-requirement-in-ligand-independent-oncogenic-notch-signaling-and-functional-effects-of-dowling-degos-mutations
#4
Brian J McMillan, Brandon Zimmerman, Emily D Egan, Michael Lofgren, Xiang Xu, Anthony Hesser, Stephen C Blacklow
Protein O-fucosyltransferase-1 (POFUT1), which transfers fucose residues to acceptor sites on serine and threonine residues of epidermal growth factor-like repeats of recipient proteins, is essential for Notch signal transduction in mammals. Here, we examine the consequences of POFUT1 loss on the oncogenic signaling associated with certain leukemia-associated mutations of human Notch1, report the structures of human POFUT1 in free and GDP-fucose bound states, and assess the effects of Dowling-Degos mutations on human POFUT1 function...
March 17, 2017: Glycobiology
https://www.readbyqxmd.com/read/28334384/the-cancer-paradigms-of-mammalian-regeneration-can-mammals-regenerate-as-amphibians
#5
Rachel Sarig, Eldad Tzahor
Regeneration in mammals is restricted to distinct tissues and occurs mainly by expansion and maturation of resident stem cells. During regeneration, even subtle mutations in the proliferating cells may cause a detrimental effect by eliciting abnormal differentiation or malignant transformation. Indeed, cancer in mammals has been shown to arise through deregulation of stem cells maturation, which often leads to a differentiation block and cell transformation. In contrast, lower organisms such as amphibians retain a remarkable regenerative capacity in various organs, which occurs via de- and re-differentiation of mature cells...
March 15, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28334365/effect-of-kit-and-pdgfra-mutations-on-survival-in-patients-with-gastrointestinal-stromal-tumors-treated-with-adjuvant-imatinib-an-exploratory-analysis-of-a-randomized-clinical-trial
#6
Heikki Joensuu, Eva Wardelmann, Harri Sihto, Mikael Eriksson, Kirsten Sundby Hall, Annette Reichardt, Jörg T Hartmann, Daniel Pink, Silke Cameron, Peter Hohenberger, Salah-Eddin Al-Batran, Marcus Schlemmer, Sebastian Bauer, Bengt Nilsson, Raija Kallio, Jouni Junnila, Aki Vehtari, Peter Reichardt
Importance: Little is known about whether the duration of adjuvant imatinib influences the prognostic significance of KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor α (PDGFRA) mutations. Objective: To investigate the effect of KIT and PDGFRA mutations on recurrence-free survival (RFS) in patients with gastrointestinal stromal tumors (GISTs) treated with surgery and adjuvant imatinib. Design, Setting, and Participants: This exploratory study is based on the Scandinavian Sarcoma Group VIII/Arbeitsgemeinschaft Internistische Onkologie (SSGXVIII/AIO) multicenter clinical trial...
March 23, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28334334/p53-and-its-mutants-on-the-slippery-road-from-stemness-to-carcinogenesis
#7
Alina Molchadsky, Varda Rotter
Normal development, tissue homeostasis and regeneration following injury rely on the proper functions of wide repertoire of stem cells (SCs) persisting during embryonic period and throughout the adult life. Therefore, SCs employ robust mechanisms to preserve their genomic integrity and avoid heritage of mutations to their daughter cells. Importantly, propagation of SCs with faulty DNA as well as dedifferentiation of genomically altered somatic cells may result in derivation of cancer SCs, which are considered to be the driving force of the tumorigenic process...
March 15, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28332047/mechanisms-of-resistance-to-target-therapies-in-non-small-cell-lung-cancer
#8
Francesco Facchinetti, Claudia Proto, Roberta Minari, Marina Garassino, Marcello Tiseo
Targeted therapies are revolutionizing the treatment of advanced non-small cell lung cancer (NSCLC). The discovery of key oncogenic events mainly in lung adenocarcinoma, like EGFR mutations or ALK rearrangements, has changed the treatment landscape while improving the prognosis of lung cancer patients. Inevitably, virtually all patients initially treated with targeted therapies develop resistance because of the emergence of an insensitive cellular population, selected by pharmacologic pressure. Diverse mechanisms of resistance, in particular to EGFR, ALK and ROS1 tyrosine-kinase inhibitors (TKIs), have now been discovered and may be classified in three different groups: (1) alterations in the target (such as EGFR T790M and ALK or ROS1 mutations); (2) activation of alternative pathways (i...
March 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28331559/tumor-suppressor-genes-in-familial-adenomatous-polyposis
#9
REVIEW
Nahal Eshghifar, Naser Farrokhi, Tahereh Naji, Mohammadreza Zali
Colorectal cancer (CRC) is mostly due to a series of genetic alterations that are being greatly under the influence of the environmental factors. These changes, mutational or epigenetic modifications at transcriptional forefront and/or post-transcriptional effects via miRNAs, include inactivation and the conversion of proto-oncogene to oncogenes, and/or inactivation of tumor suppressor genes (TSG). Here, a thorough review was carried out on the role of TSGs with the focus on the APC as the master regulator, mutated genes and mal-/dysfunctional pathways that lead to one type of hereditary form of the CRC; namely familial adenomatous polyposis (FAP)...
2017: Gastroenterology and Hepatology From Bed to Bench
https://www.readbyqxmd.com/read/28330468/tumor-burden-monitoring-using-cell-free-tumor-dna-could-be-limited-by-tumor-heterogeneity-in-advanced-breast-cancer-and-should-be-evaluated-together-with-radiographic-imaging
#10
José Angel García-Saenz, Patricia Ayllón, Marion Laig, Daniel Acosta-Eyzaguirre, Marta García-Esquinas, Myriam Montes, Julián Sanz, Miguel Barquín, Fernando Moreno, Vanesa Garcia-Barberan, Eduardo Díaz-Rubio, Trinidad Caldes, Atocha Romero
BACKGROUND: Accurate measurement of tumor burden in breast cancer disease is essential to improve the clinical management of patients. In this study, we evaluate whether the fluctuations in the fraction of PIK3CA mutant allele correlates with tumor response according to RECIST criteria and tumor markers quantification. METHODS: Eighty six plasma samples were analyzed by digital PCR using Rare Mutation Assays for E542K, E545K and H1047R. Mutant cfDNA and tumor markers CA15-3 and CEA were compared with radiographic imaging...
March 22, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28329143/epidermal-growth-factor-receptor-mutations-are-linked-to-skip-n2-lymph-node-metastasis-in-resected-non-small-cell-lung-cancer-adenocarcinomas%C3%A2
#11
Francesco Guerrera, Stéphane Renaud, Fabrizio Tabbó, Anne-Claire Voegeli', Pier Luigi Filosso, Michèle Legrain, Monica Boita, Mickaël Schaeffer, Michèle Beau-Faller, Enrico Ruffini, Pierre-Emmanuel Falcoz, Giorgio Inghirami, Alberto Oliaro, Gilbert Massard
OBJECTIVES: The impact of skip N2 metastases (i.e. N2 lymph node metastases without N1) on survival in surgically resected non-small lung cancer remains an intriguing and rarely investigated topic. The goal of our study was to elucidate (i) skip N2 influence on overall survival (OS) and time to recurrence (TTR) in patients with resected lung adenocarcinoma and (ii) its link with epidermal growth factor receptor ( EGFR ) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations...
December 15, 2016: European Journal of Cardio-thoracic Surgery
https://www.readbyqxmd.com/read/28327577/metabolic-profiling-of-idh-mutation-and-malignant-progression-in-infiltrating-glioma
#12
Llewellyn E Jalbert, Adam Elkhaled, Joanna J Phillips, Evan Neill, Aurelia Williams, Jason C Crane, Marram P Olson, Annette M Molinaro, Mitchel S Berger, John Kurhanewicz, Sabrina M Ronen, Susan M Chang, Sarah J Nelson
Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM)...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28326470/targeted-treatment-of-brain-metastases
#13
REVIEW
Nicole Shonka, Vyshak Alva Venur, Manmeet S Ahluwalia
PURPOSE OF REVIEW: Brain metastases are the most common intracranial tumors in adults. Historically, the median survival after the diagnosis of brain metastases has been dismal and medical therapies had a limited role in the management of these patients. RECENT FINDINGS: The advent of targeted therapy has ushered in an era of increased hope for patients with brain metastases. The most common malignancies that result in brain metastases-melanoma, lung cancer, and breast cancer, often have actionable mutations, which make them good candidates for targeted systemic therapy...
April 2017: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/28325827/sessile-serrated-polyps-and-colon-cancer-prevention
#14
Shahrooz Rashtak, Rafaela Rego, Seth R Sweetser, Frank A Sinicrope
Evidence suggests that up to one fifth of colorectal carcinomas (CRC) develop from serrated polyps, named for their pattern of colonic crypts, and include the sessile serrated adenoma/polyp (SSA/P) that has malignant potential. SSA/Ps are typically located in the proximal colon and have molecular features of hypermethylation of CpG islands in gene promoters and activating point mutations (V600E) in the BRAF oncogene. Both of these features are seen in sporadic CRCs with microsatellite instability (MSI) which is potentially consistent with an origin of these cancers from precursor SSA/Ps...
March 21, 2017: Cancer Prevention Research
https://www.readbyqxmd.com/read/28325298/relevance-of-fusion-genes-in-pediatric-cancers-toward-precision-medicine
#15
REVIEW
Célia Dupain, Anne Catherine Harttrampf, Giorgia Urbinati, Birgit Geoerger, Liliane Massaad-Massade
Pediatric cancers differ from adult tumors, especially by their very low mutational rate. Therefore, their etiology could be explained in part by other oncogenic mechanisms such as chromosomal rearrangements, supporting the possible implication of fusion genes in the development of pediatric cancers. Fusion genes result from chromosomal rearrangements leading to the juxtaposition of two genes. Consequently, an abnormal activation of one or both genes is observed. The detection of fusion genes has generated great interest in basic cancer research and in the clinical setting, since these genes can lead to better comprehension of the biological mechanisms of tumorigenesis and they can also be used as therapeutic targets and diagnostic or prognostic biomarkers...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28325276/limiting-thymic-precursor-supply-increases-the-risk-of-lymphoid-malignancy-in-murine-x-linked-severe-combined-immunodeficiency
#16
Samantha L Ginn, Claus V Hallwirth, Sophia H Y Liao, Erdahl T Teber, Jonathan W Arthur, Jianmin Wu, Hong Ching Lee, Szun S Tay, Min Hu, Roger R Reddel, Matthew P McCormack, Adrian J Thrasher, Marina Cavazzana, Stephen I Alexander, Ian E Alexander
In early gene therapy trials for SCID-X1, using γ-retroviral vectors, T cell leukemias developed in a subset of patients secondary to insertional proto-oncogene activation. In contrast, we have reported development of T cell leukemias in SCID-X1 mice following lentivirus-mediated gene therapy independent of insertional mutagenesis. A distinguishing feature in our study was that only a proportion of transplanted γc-deficient progenitors were transduced and therefore competent for reconstitution. We hypothesized that reconstitution of SCID-X1 mice with limiting numbers of hematopoietic progenitors might be a risk factor for lymphoid malignancy...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28323957/risk-profile-of-the-ret-a883f-germline-mutation-an-international-collaborative-study
#17
Jes Sloth Mathiesen, Mouhammed Amir Habra, John Howard Duncan Bassett, Sirazum Mubin Choudhury, Sabapathy Prakash Balasubramanian, Trevor A Howlett, Bruce G Robinson, Anne-Paule Gimenez-Roqueplo, Frederic Castinetti, Peter Vestergaard, Karin Frank-Raue
Context: The A883F germline mutation of the REarranged during Transfection proto-oncogene causes multiple endocrine neoplasia 2B. In the revised American Thyroid Association (ATA) guidelines for the management of medullary thyroid carcinoma (MTC) the A883F mutation has been reclassified from the highest to high risk level, although no well-defined risk profile for this mutation exists. Objective: To create a risk profile for the A883F mutation for appropriate classification in the ATA risk levels...
March 17, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28323782/controversies-in-intrapatient-melanoma-brafv600e-mutation-status
#18
Erica Riveiro-Falkenbach, Angel Santos-Briz, Juan J Ríos-Martín, José L Rodríguez-Peralto
Therapies targeting the BRAF oncogene have improved the overall and disease-free survival of patients with advanced melanomas. An unresolved issue in clinical practice is the existence (or not) of BRAF-mutated and BRAF-nonmutated tumors in individual patients (intrapatient BRAF mutation heterogeneity), which may serve as a mechanism of resistance to BRAF inhibitors or lead to diagnostic problems. Different research groups have reported differing results after analyzing the BRAF mutation statuses of multiple melanoma tumors...
April 2017: American Journal of Dermatopathology
https://www.readbyqxmd.com/read/28323020/metabolic-reprogramming-in-cancer-cells-consequences-on-ph-and-tumour-progression-integrated-therapeutic-perspectives-with-dietary-lipids-as-adjuvant-to-anticancer-treatment
#19
REVIEW
Jean-François Dumas, Lucie Brisson, Stéphan Chevalier, Karine Mahéo, Gaëlle Fromont, Driffa Moussata, Pierre Besson, Sébastien Roger
While tumours arise from acquired mutations in oncogenes or tumour-suppressor genes, it is clearly established that cancers are metabolic diseases characterized by metabolic alterations in tumour cells, and also non-tumour cells of the host organism resulting in tumour cachexia and patient weakness. In this review, we aimed at delineating details by which metabolic alterations in cancer cells, characterized by mitochondrial bioenergetics deregulations and the preference for aerobic glycolysis, are critical parameters controlling the aggressive progression of tumours...
March 17, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28322182/helicobacter-pylori-as-an-oncogenic-pathogen-revisited
#20
Muhammad Miftahussurur, Yoshio Yamaoka, David Y Graham
Gastric cancer is an inflammation-associated malignancy aetiologically related to infection with the bacterium, Helicobacter pylori, which is considered a necessary but insufficient cause. Unless treated, H. pylori causes life-long acute and chronic gastric inflammation resulting in progressive gastric mucosal damage that may result in gastric cancer. The rate of progression from superficial gastritis, to an atrophic metaplastic mucosa, and ultimately to cancer relates to the virulence of the infecting H. pylori as well as host and environmental factors...
March 21, 2017: Expert Reviews in Molecular Medicine
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