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somatic mutations

Sarah M Choi, Aleodor A Andea, Min Wang, Amir Behdad, Lina Shao, Yanming Zhang, Xinyan Lu, David Dittmann, Juan Castro, Yi-Hua Chen, Juehua Gao
BACKGROUND: Transformation of follicular lymphoma most typically occurs as diffuse large B-cell lymphoma, however other forms of transformation such as classic Hodgkin lymphoma and lymphoblastic transformation can occur. Secondary malignant histiocytosis also represents a rare form of transformation, which is thought to occur due to a process of transdifferentiation whereby the lymphoma cells exhibit lineage plasticity and lose all evidence of B-cell phenotype and instead acquire the phenotype of a histiocytic neoplasm...
October 15, 2018: Diagnostic Pathology
Valeria Pecce, Marialuisa Sponziello, Giuseppe Damante, Francesca Rosignolo, Cosimo Durante, Livia Lamartina, Giorgio Grani, Diego Russo, Cira Rosaria di Gioia, Sebastiano Filetti, Antonella Verrienti
Synonymous mutations continue to be filtered out from most large-scale cancer genome studies, but several lines of evidence suggest they can play driver roles in neoplastic disease. We investigated a case of an aggressive, apparently sporadic medullary thyroid carcinoma (MTC) harboring a somatic RET p.Cys634Arg mutation (a known MTC driver). A germ-line RET substitution (p.Cys630=) had also been found but was considered clinically irrelevant because of its synonymous nature. Next generation sequencing (NGS) of the tumor tissues revealed that the RET mutations were in cis...
October 15, 2018: PLoS Genetics
Amy E Armstrong, David O Walterhouse, Patrick J Leavey, Jennifer Reichek, Amy L Walz
Outcome for patients with metastatic or recurrent/refractory osteosarcoma remains poor. Responses to sorafenib, a multikinase inhibitor, have been seen in recurrent/refractory osteosarcoma, although specific biomarkers of response have not been described. We report a partial response in a 7-year-old with refractory osteosarcoma treated with sorafenib 200 mg twice daily. Toxicities included Common Terminology Criteria for Adverse Events Grade 2 skin toxicities and growth suppression. After 51 months of therapy, he suffered a recurrence...
October 14, 2018: Pediatric Blood & Cancer
Marco Losa, Pietro Mortini, Angela Pagnano, Mario Detomas, Maria Francesca Cassarino, Francesca Pecori Giraldi
PURPOSE: somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been described in patients with Cushing's disease (CD). The aim of the study is to verify whether USP8 mutation may predict early and late outcome of pituitary surgery in patients with CD operated at a single institution. METHODS: We performed a retrospective genetic analysis of 92 adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. Specimens were screened for USP8 hotspot mutations in the exon 14 with Sanger sequencing...
October 12, 2018: Endocrine
Leslie Calapre, Tindaro Giardina, Cleo Robinson, Anna L Reid, Zeyad Al-Ogaili, Michelle R Pereira, Ashleigh C McEvoy, Lydia Warburton, Nicholas K Hayward, Muhammad A Khattak, Tarek M Meniawy, Michael Millward, Benhur Amanuel, Melanie Ziman, Elin S Gray
Circulating tumor DNA (ctDNA) may serve as a surrogate to tissue biopsy for non-invasive identification of mutations across multiple genetic loci and for disease monitoring in melanoma. In this study, we compared the mutation profiles of tumor biopsies and plasma ctDNA from metastatic melanoma patients using custom sequencing panels targeting 30 melanoma-associated genes. Somatic mutations were identified in 20 of 24 melanoma biopsies, and 16 of 20 (70%) matched-patient plasmas had detectable ctDNA. In a subgroup of seven patients for whom matching tumor tissue and plasma were sequenced, 80% of the mutations found in tumor tissue were also detected in ctDNA...
October 12, 2018: Molecular Oncology
Heike Biebermann, Gunnar Kleinau, Dirk Schnabel, Detlef Bockenhauer, Louise C Wilson, Ian Tully, Sarah Kiff, Patrick Scheerer, Monica Reyes, Sarah Paisdzior, John W Gregory, Jeremy Allgrove, Heiko Krude, Michael Mannstadt, Thomas J Gardella, Mehul Dattani, Harald Jüppner, Annette Grüters
Context: The alpha-subunit of the stimulatory G-protein (Gαs) links numerous receptors to adenylyl cyclase. Gαs, encoded by GNAS, is expressed predominantly from the maternal allele in certain tissues. Thus, maternal heterozygous loss-of-function mutations cause hormonal resistance, as in pseudohypoparathyroidism type Ia, while somatic gain-of-function mutations cause hormone-independent endocrine stimulation, as in McCune-Albright Syndrome. Objective: We here report two unrelated boys presenting with a new combination of clinical findings that suggest both gain and loss of Gαs function...
October 11, 2018: Journal of Clinical Endocrinology and Metabolism
Xiaonan Zhao, Yongwei Zhang, Kenneth Wilkins, Winfried Edelmann, Karen Usdin
The Fragile X-related disorders (FXDs) are Repeat Expansion Diseases resulting from an expansion of a CGG-repeat tract at the 5' end of the FMR1 gene. The mechanism responsible for this unusual mutation is not fully understood. We have previously shown that mismatch repair (MMR) complexes, MSH2/MSH3 (MutSβ) and MSH2/MSH6 (MutSα), together with Polβ, a DNA polymerase important for base excision repair (BER), are important for expansions in a mouse model of these disorders. Here we show that MLH1/MLH3 (MutLγ), a protein complex that can act downstream of MutSβ in MMR, is also required for all germ line and somatic expansions...
October 12, 2018: PLoS Genetics
Michael F Walsh, Deborah I Ritter, Chimene Kesserwan, Dmitriy Sonkin, Debyani Chakravarty, Elizabeth Chao, Rajarshi Ghosh, Yelena Kemel, Gang Wu, Kristy Lee, Shashikant Kulkarni, Dale Hedges, Diana Mandelker, Ozge Ceyhan-Birsoy, Minjie Luo, Michael Drazer, Liying Zhang, Kenneth Offit, Sharon E Plon
In its landmark paper about Standards and Guidelines for the Interpretation of Sequence Variants, the American College of Medical Genetics and Genomics (ACMG), and Association for Molecular Pathology (AMP) did not address how to use tumor data when assessing the pathogenicity of germline variants. The Clinical Genome Resource (ClinGen) established a multidisciplinary working group, the Germline/Somatic Variant Subcommittee (GSVS) with this focus. The GSVS implemented a survey to determine current practices of integrating somatic data when classifying germline variants in cancer predisposition genes...
November 2018: Human Mutation
Dehua Zhu, Jianping Zhou, Jinbo Zhao, Guiyang Jiang, Xiupeng Zhang, Yong Zhang, Ming Dong
ZC3H13 is a canonical CCCH zinc finger protein, which harbors a somatic frame-shift mutation in colorectal cancer (CRC). However, its expression and biological function were still uncertain. In the current study, we found that ZC3H13 was served as a tumor suppressor in CRC cells, which decreased the expression of Snail, Cyclin D1, and Cyclin E1, and increased the expression of Occludin and Zo-1 through inactivating Ras-ERK signaling pathway. Furthermore, reduction of ZC3H13 associated with advanced TNM stage (p = 0...
October 12, 2018: Journal of Cellular Physiology
Martin P Nilsson, Erik D Nilsson, Åke Borg, Yvonne Brandberg, Barbro Silfverberg, Niklas Loman
PURPOSE: In the BRCAsearch study, unselected breast cancer patients were prospectively offered germline BRCA1/2 mutation testing through a simplified testing procedure. The purpose of the present study was to evaluate satisfaction with the BRCAsearch testing procedure and, furthermore, to report on uptake rates of prophylactic surgeries among mutation carriers. METHODS: Pre-test information was provided by a standardized invitation letter instead of in-person genetic counseling...
October 11, 2018: Breast Cancer Research and Treatment
Miho Kono, Takeo Fujii, Naoko Matsuda, Kenichi Harano, Huiqin Chen, Chetna Wathoo, Aron Y Joon, Debu Tripathy, Funda Meric-Bernstam, Naoto T Ueno
Background: Bone is the most common site of metastasis of breast cancer. Biological mechanisms of metastasis to bone may be different from mechanisms of metastasis to non-bone sites, and identification of distinct signaling pathways and somatic mutations may provide insights on biology and rational targets for treatment and prevention of bone metastasis. The aims of this study were to compare and contrast somatic mutations, clinicopathologic characteristics, and survival in breast cancer patients with bone-only versus non-bone sites of first metastasis...
2018: Journal of Cancer
Chenfei Zhou, Xiaojing Feng, Fei Yuan, Jun Ji, Min Shi, Yingyan Yu, Zhenggang Zhu, Jun Zhang
Objective: The aim of this study was to compare the molecular profiling, including somatic mutation and somatic copy number variation (SCNV), between human epidermal growth factor receptor 2 (HER2)-positive (HER2+) and HER2-negative (HER2-) gastric cancer patients. Patients and methods: Tumor samples were collected from 15 gastric cancer patients, including 10 HER2+ samples and five HER2- samples, which were diagnosed by immunohistochemistry. Whole-genome sequencing was performed by Illumina HiSeq PE150 instrument, along with somatic single nucleotide variant (SNV), somatic structural variation (SV) and SCNV analyses...
2018: Cancer Management and Research
Bogdan I Fedeles, John M Essigmann
In a multicellular organism, somatic mutations represent a permanent record of the past chemical and biochemical perturbations experienced by a cell in its local microenvironment. Akin to a perpetual recording device, with every replication, genomic DNA accumulates mutations in patterns that reflect: i) the sequence context-dependent formation of DNA damage, due to environmental or endogenous reactive species, including spontaneous processes; ii) the activity of DNA repair pathways, which, depending on the type of lesion, can erase, ignore or exacerbate the mutagenic consequences of that DNA damage; and iii) the choice of replication machinery that synthesizes the nascent genomic copy...
August 25, 2018: DNA Repair
R Wendel Naumann, Jacob C Morris, David L Tait, Robert V Higgins, Erin K Crane, Lane K Drury, Lisa Amacker-North, Megan Templin, Jubilee Brown
OBJECTIVES: To compare the outcomes after intraperitoneal (IP) chemotherapy in patients with and without pathogenic BRCA mutations. METHODS: Patients with high grade ovarian cancer who were treated with adjuvant IP chemotherapy in the initial setting between 2005 and 2016 were identified. Outcomes were compared between patients with pathogenic mutations in BRCA (BRCA+) and those who tested negative or were unknown (BRCA-). RESULTS: A total of 100 eligible patients were identified...
October 8, 2018: Gynecologic Oncology
Jong-Lyul Park, Seon-Kyu Kim, Jeong-Hwan Kim, Seok Joong Yun, Wun-Jae Kim, Won Tae Kim, Pildu Jeong, Ho Won Kang, Seon-Young Kim
Because castration-resistant prostate cancer (CRPC) does not respond to androgen deprivation therapy and has a very poor prognosis, it is critical to identify a prognostic indicator for predicting high-risk patients who will develop CRPC. Here, we report a dataset of whole genomes from four pairs of primary prostate cancer (PC) and CRPC samples. The analysis of the paired PC and CRPC samples in the whole-genome data showed that the average number of somatic mutations per patients was 7,927 in CRPC tissues compared with primary PC tissues (range, 1,691 to 21,705)...
September 2018: Genomics & Informatics
Sankaran Sandhya, Aditi Maulik, Malyasree Giri, Mahavir Singh
BAF250a and BAF250b are subunits of the SWI/SNF chromatin-remodeling complex that recruit the complex to chromatin allowing transcriptional activation of several genes. Despite being the central subunits of the SWI/SNF complex, the structural and functional annotation of BAF250a/b remains poorly understood. BAF250a (nearly 2200 residues protein) harbors an N-terminal DNA binding ARID (~110 residues) and a C-terminal folded region (~250 residues) of unknown structure and function, recently annotated as BAF250_C...
2018: PloS One
William L Hwang, Rachel L Wolfson, Andrzej Niemierko, Karen J Marcus, Steven G DuBois, Daphne Haas-Kogan
Background: Neuroblastoma is the most common pediatric extracranial solid tumor. Within conventional risk groups, there is considerable heterogeneity in outcomes, indicating the need for improved risk stratification. Methods: In this study we analyzed the somatic mutational burden of 515 primary, untreated neuroblastoma tumors from three independent cohorts. Mutations in coding regions were determined by whole-exome/genome sequencing of tumor samples compared to matched blood leukocytes...
October 10, 2018: Journal of the National Cancer Institute
James F Powers, Brent Cochran, James D Baleja, Hadley D Sikes, Xue Zhang, Inna Lomakin, Troy Langford, Kassi Taylor Stein, Arthur S Tischler
We describe a unique patient-derived xenograft (PDX) and cell culture model of succinate dehydrogenase-deficient gastrointestinal stromal tumor (SDH-deficient GIST), a rare mesenchymal tumor that can occur in association with paragangliomas in hereditary and non-hereditary syndromes. This model is potentially important for what it might reveal specifically pertinent to this rare tumor type and, more broadly, to other types of SDH-deficient tumors. The primary tumor and xenografts show a very high proliferative fraction, and distinctive morphology characterized by tiny cells with marked autophagic activity...
November 1, 2018: Endocrine-related Cancer
Ellena Cotton, David Ray
A young woman carrying germline DICER1 mutation was discovered to have a pituitary microprolactinoma when she became amenorrhoic. The mutation was identified as a result of family screening following the early death of the patient’s daughter with ovarian cancer. The patient was in follow-up screening for thyroid disease, and investigations were initiated when she became amenorrhoic. MR scan revealed a 6 mm diameter pituitary microadenoma and raised prolactin. The prolactin was efficiently suppressed with low-dose cabergoline, and her menstrual cycles resumed...
September 25, 2018: Endocrinology, Diabetes & Metabolism Case Reports
Jonathan W Nyce
The activation of TP53 is well known to exert tumor suppressive effects. We have detected a primate-specific adrenal androgen-mediated tumor suppression system in which circulating DHEAS is converted to DHEA specifically in cells in which TP53 has been inactivated. DHEA is an uncompetitive inhibitor of glucose-6-phosphate dehydrogenase (G6PD), an enzyme indispensable for maintaining reactive oxygen species within limits survivable by the cell. Uncompetitive inhibition is otherwise unknown in natural systems because it becomes irreversible in the presence of high concentrations of substrate and inhibitor...
November 1, 2018: Endocrine-related Cancer
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