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https://www.readbyqxmd.com/read/27713405/molecular-analysis-of-aggressive-renal-cell-carcinoma-with-unclassified-histology-reveals-distinct-subsets
#1
Ying-Bei Chen, Jianing Xu, Anders Jacobsen Skanderup, Yiyu Dong, A Rose Brannon, Lu Wang, Helen H Won, Patricia I Wang, Gouri J Nanjangud, Achim A Jungbluth, Wei Li, Virginia Ojeda, A Ari Hakimi, Martin H Voss, Nikolaus Schultz, Robert J Motzer, Paul Russo, Emily H Cheng, Filippo G Giancotti, William Lee, Michael F Berger, Satish K Tickoo, Victor E Reuter, James J Hsieh
Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%)...
October 7, 2016: Nature Communications
https://www.readbyqxmd.com/read/27698142/enhancer-priming-by-h3k4-methyltransferase-mll4-controls-cell-fate-transition
#2
Chaochen Wang, Ji-Eun Lee, Binbin Lai, Todd S Macfarlan, Shiliyang Xu, Lenan Zhuang, Chengyu Liu, Weiqun Peng, Kai Ge
Transcriptional enhancers control cell-type-specific gene expression. Primed enhancers are marked by histone H3 lysine 4 (H3K4) mono/di-methylation (H3K4me1/2). Active enhancers are further marked by H3K27 acetylation (H3K27ac). Mixed-lineage leukemia 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase with functional redundancy with MLL3 (KMT2C). However, its role in cell fate maintenance and transition is poorly understood. Here, we show in mouse embryonic stem cells (ESCs) that MLL4 associates with, but is surprisingly dispensable for the maintenance of, active enhancers of cell-identity genes...
October 18, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27632392/the-contribution-of-mosaic-variants-to-autism-spectrum-disorder
#3
Donald Freed, Jonathan Pevsner
De novo mutation is highly implicated in autism spectrum disorder (ASD). However, the contribution of post-zygotic mutation to ASD is poorly characterized. We performed both exome sequencing of paired samples and analysis of de novo variants from whole-exome sequencing of 2,388 families. While we find little evidence for tissue-specific mosaic mutation, multi-tissue post-zygotic mutation (i.e. mosaicism) is frequent, with detectable mosaic variation comprising 5.4% of all de novo mutations. We identify three mosaic missense and likely-gene disrupting mutations in genes previously implicated in ASD (KMT2C, NCKAP1, and MYH10) in probands but none in siblings...
September 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27626165/mutational-burdens-and-evolutionary-ages-of-thyroid-follicular-adenoma-are-comparable-to-those-of-follicular-carcinoma
#4
Seung-Hyun Jung, Min Sung Kim, Chan Kwon Jung, Hyun-Chun Park, So Youn Kim, Jieying Liu, Ja-Seong Bae, Sung Hak Lee, Tae-Min Kim, Sug Hyung Lee, Yeun-Jun Chung
Follicular thyroid adenoma (FTA) precedes follicular thyroid carcinoma (FTC) by definition with a favorable prognosis compared to FTC. However, the genetic mechanism of FTA to FTC progression remains unknown. For this, it is required to disclose FTA and FTC genomes in mutational and evolutionary perspectives. We performed whole-exome sequencing and copy number profiling of 14 FTAs and 13 FTCs, which exhibited previously-known gene mutations (NRAS, HRAS, BRAF, TSHR and EIF1AX) and copy number alterations (CNAs) (22q loss and 1q gain) in follicular tumors...
September 9, 2016: Oncotarget
https://www.readbyqxmd.com/read/27491809/genetic-events-in-the-progression-of-adenoid-cystic-carcinoma-of-the-breast-to-high-grade-triple-negative-breast-cancer
#5
Nicola Fusco, Felipe C Geyer, Maria R De Filippo, Luciano G Martelotto, Charlotte K Y Ng, Salvatore Piscuoglio, Elena Guerini-Rocco, Anne M Schultheis, Laetitia Fuhrmann, Lu Wang, Achim A Jungbluth, Kathleen A Burke, Raymond S Lim, Anne Vincent-Salomon, Masamichi Bamba, Suzuko Moritani, Sunil S Badve, Shu Ichihara, Ian O Ellis, Jorge S Reis-Filho, Britta Weigelt
Adenoid cystic carcinoma of the breast is a rare histological type of triple-negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple-negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and intronic regions of 488 genes...
November 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/27340278/whole-exome-sequencing-of-salivary-gland-mucoepidermoid-carcinoma
#6
Hyunseok Kang, Marietta Tan, Justin A Bishop, Siân Jones, Mark Sausen, Patrick K Ha, Nishant Agrawal
PURPOSE: Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. To explore the genetic origins of MEC, we performed systematic genomic analyses of these tumors. EXPERIMENTAL DESIGN: Whole-exome sequencing and gene copy number analyses were performed for 18 primary cancers with matched normal tissue. Fluorescence in situ hybridization (FISH) was used to determine the presence or absence of the MECT1-MAML2 translocation in 17 tumors. RESULTS: TP53 was the most commonly mutated gene in MEC (28%), and mutations were found only in intermediate- and high-grade tumors...
June 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27280393/reduced-expression-of-histone-methyltransferases-kmt2c-and-kmt2d-correlates-with-improved-outcome-in-pancreatic-ductal-adenocarcinoma
#7
Joshua B N Dawkins, Jun Wang, Eleni Maniati, James A Heward, Lola Koniali, Hemant M Kocher, Sarah A Martin, Claude Chelala, Frances R Balkwill, Jude Fitzgibbon, Richard P Grose
Genes encoding the histone H3 lysine 4 methyltransferases KMT2C and KMT2D are subject to deletion and mutation in pancreatic ductal adenocarcinoma (PDAC), where these lesions identify a group of patients with a more favorable prognosis. In this study, we demonstrate that low KMT2C and KMT2D expression in biopsies also defines better outcome groups, with median survivals of 15.9 versus 9.2 months (P = 0.029) and 19.9 versus 11.8 months (P = 0.001), respectively. Experiments with eight human pancreatic cell lines showed attenuated cell proliferation when these methyltransferases were depleted, suggesting that this improved outcome may reflect a cell-cycle block with diminished progression from G0-G1 RNA-seq analysis of PDAC cell lines following KMT2C or KMT2D knockdown identified 31 and 124 differentially expressed genes, respectively, with 19 genes in common...
August 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27260798/copy-number-analysis-of-whole-genome-data-using-bic-seq2-and-its-application-to-detection-of-cancer-susceptibility-variants
#8
Ruibin Xi, Semin Lee, Yuchao Xia, Tae-Min Kim, Peter J Park
Whole-genome sequencing data allow detection of copy number variation (CNV) at high resolution. However, estimation based on read coverage along the genome suffers from bias due to GC content and other factors. Here, we develop an algorithm called BIC-seq2 that combines normalization of the data at the nucleotide level and Bayesian information criterion-based segmentation to detect both somatic and germline CNVs accurately. Analysis of simulation data showed that this method outperforms existing methods. We apply this algorithm to low coverage whole-genome sequencing data from peripheral blood of nearly a thousand patients across eleven cancer types in The Cancer Genome Atlas (TCGA) to identify cancer-predisposing CNV regions...
July 27, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27195705/analysis-of-paired-primary-metastatic-hormone-receptor-positive-breast-tumors-hrpbc-uncovers-potential-novel-drivers-of-hormonal-resistance
#9
Luis Manso, Silvana Mourón, Michael Tress, Gonzalo Gómez-López, Manuel Morente, Eva Ciruelos, Miriam Rubio-Camarillo, Jose Luis Rodriguez-Peralto, Miguel A Pujana, David G Pisano, Miguel Quintela-Fandino
We sought to identify genetic variants associated with disease relapse and failure to hormonal treatment in hormone-receptor positive breast cancer (HRPBC). We analyzed a series of HRPBC with distant relapse, by sequencing pairs (n = 11) of tumors (primary and metastases) at >800X. Comparative genomic hybridization was performed as well. Top hits, based on the frequency of alteration and severity of the changes, were tested in the TCGA series. Genes determining the most parsimonious prognostic signature were studied for their functional role in vitro, by performing cell growth assays in hormonal-deprivation conditions, a setting that mimics treatment with aromatase inhibitors...
2016: PloS One
https://www.readbyqxmd.com/read/27171244/subsets-of-visceral-adipose-tissue-nuclei-with-distinct-levels-of-5-hydroxymethylcytosine
#10
Ping Yu, Lexiang Ji, Kevin J Lee, Miao Yu, Chuan He, Suresh Ambati, Elizabeth C McKinney, Crystal Jackson, Clifton A Baile, Robert J Schmitz, Richard B Meagher
The reprogramming of cellular memory in specific cell types, and in visceral adipocytes in particular, appears to be a fundamental aspect of obesity and its related negative health outcomes. We explored the hypothesis that adipose tissue contains epigenetically distinct subpopulations of adipocytes that are differentially potentiated to record cellular memories of their environment. Adipocytes are large, fragile, and technically difficult to efficiently isolate and fractionate. We developed fluorescence nuclear cytometry (FNC) and fluorescence activated nuclear sorting (FANS) of cellular nuclei from visceral adipose tissue (VAT) using the levels of the pan-adipocyte protein, peroxisome proliferator-activated receptor gamma-2 (PPARg2), to distinguish classes of PPARg2-Positive (PPARg2-Pos) adipocyte nuclei from PPARg2-Negative (PPARg2-Neg) leukocyte and endothelial cell nuclei...
2016: PloS One
https://www.readbyqxmd.com/read/27057633/genetic-profile-of-gnaq-mutated-blue-melanocytic-neoplasms-reveals-mutations-in-genes-linked-to-genomic-instability-and-the-pi3k-pathway
#11
Mileidys Pérez-Alea, Ana Vivancos, Ginevra Caratú, Judit Matito, Berta Ferrer, Javier Hernandez-Losa, Javier Cortés, Eva Muñoz, Vicente Garcia-Patos, Juan A Recio
Melanomas arising in association with a common or cellular blue nevus (MABN) comprise a relatively rare and heterogeneous group of lethal melanomas. Although GNAQ is known to be frequently mutated in common blue nevus, cellular blue nevus (CBN) and MABN and these malignant lesions present gross chromosome alterations harboring BAP1 mutations, little is known about other mutations that contribute to the development and progression of these neoplasms. Thus, the genetic profile of these tumors is important to increase the number of intervention and treatment modalities...
May 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27023146/colorectal-cancer-genetic-heterogeneity-delineated-by-multi-region-sequencing
#12
You-Wang Lu, Hui-Feng Zhang, Rui Liang, Zhen-Rong Xie, Hua-You Luo, Yu-Jian Zeng, Yu Xu, La-Mei Wang, Xiang-Yang Kong, Kun-Hua Wang
Intratumor heterogeneity (ITH) leads to an underestimation of the mutational landscape portrayed by a single needle biopsy and consequently affects treatment precision. The extent of colorectal cancer (CRC) genetic ITH is not well understood in Chinese patients. Thus, we conducted deep sequencing by using the OncoGxOne™ Plus panel, targeting 333 cancer-specific genes in multi-region biopsies of primary and liver metastatic tumors from three Chinese CRC patients. We determined that the extent of ITH varied among the three cases...
2016: PloS One
https://www.readbyqxmd.com/read/27009459/genetic-investigation-of-uterine-carcinosarcoma-case-report-and-cohort-analysis
#13
Timothy N Hembree, Jamie K Teer, Ardeshir Hakam, Alberto A Chiappori
BACKGROUND: Uterine carcinosarcoma, a rare gynecological malignancy, often presents at the advanced stage with a poor prognosis because current therapies have not improved rates of survival. Genetic characterization of this tumor may lead to novel, specifically targeted drug targets to provide better treatment options for patients with this malignancy. METHODS: We present a case of a woman aged 61 years with uterine carcinosarcoma and retrospectively analyzed 100 study patients with uterine carcinosarcoma...
January 2016: Cancer Control: Journal of the Moffitt Cancer Center
https://www.readbyqxmd.com/read/26620301/contribution-of-rare-germline-copy-number-variations-and-common-susceptibility-loci-in-lynch-syndrome-patients-negative-for-mutations-in-the-mismatch-repair-genes
#14
Rolando A R Villacis, Priscila M Miranda, Israel Gomy, Erika M M Santos, Dirce M Carraro, Maria I Achatz, Benedito M Rossi, Silvia R Rogatto
In colorectal carcinoma (CRC), 35% of cases are known to have a hereditary component, while a lower proportion (∼ 5%) can be explained by known genetic factors. In this study, copy number variations (CNVs) were evaluated in 45 unrelated patients with clinical hypothesis of Lynch syndrome (Amsterdam or Bethesda criteria); negative for MLH1, MSH2, MSH6, PMS2, CHEK2*1100delC and TP53 pathogenic mutations; aiming to reveal new predisposing genes. Analyses with two different microarray platforms (Agilent 180K and Affymetrix CytoScan HD) revealed 35 rare CNVs covering 67 known genes in 22 patients...
April 15, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/26592504/uterine-adenosarcomas-are-mesenchymal-neoplasms
#15
Salvatore Piscuoglio, Kathleen A Burke, Charlotte K Y Ng, Anastasios D Papanastasiou, Felipe C Geyer, Gabriel S Macedo, Luciano G Martelotto, Ino de Bruijn, Maria R De Filippo, Anne M Schultheis, Rafael A Ioris, Douglas A Levine, Robert A Soslow, Brian P Rubin, Jorge S Reis-Filho, Britta Weigelt
Uterine adenosarcomas (UAs) are biphasic lesions composed of a malignant mesenchymal (ie stromal) component and an epithelial component. UAs are generally low-grade and have a favourable prognosis, but may display sarcomatous overgrowth (SO), which is associated with a worse outcome. We hypothesized that, akin to breast fibroepithelial lesions, UAs are mesenchymal neoplasms in which clonal somatic genetic alterations are restricted to the mesenchymal component. To characterize the somatic genetic alterations in UAs and to test this hypothesis, we subjected 20 UAs to a combination of whole-exome (n = 6), targeted capture (n = 13) massively parallel sequencing (MPS) and/or RNA sequencing (n = 6)...
February 2016: Journal of Pathology
https://www.readbyqxmd.com/read/26551667/the-mutational-landscape-of-cutaneous-t-cell-lymphoma-and-s%C3%A3-zary-syndrome
#16
COMPARATIVE STUDY
Ana Carolina da Silva Almeida, Francesco Abate, Hossein Khiabanian, Estela Martinez-Escala, Joan Guitart, Cornelis P Tensen, Maarten H Vermeer, Raul Rabadan, Adolfo Ferrando, Teresa Palomero
Sézary syndrome is a leukemic and aggressive form of cutaneous T cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4(+) T cells. Here we performed whole-exome sequencing of tumor-normal sample pairs from 25 patients with Sézary syndrome and 17 patients with other CTCLs. These analyses identified a distinctive pattern of somatic copy number alterations in Sézary syndrome, including highly prevalent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A and CDKN1B tumor suppressors...
December 2015: Nature Genetics
https://www.readbyqxmd.com/read/26350096/ras-signaling-and-anti-ras-therapy-lessons-learned-from-genetically-engineered-mouse-models-human-cancer-cells-and-patient-related-studies
#17
REVIEW
Bingliang Fang
Activating mutations of oncogenic RAS genes are frequently detected in human cancers. The studies in genetically engineered mouse models (GEMMs) reveal that Kras-activating mutations predispose mice to early onset tumors in the lung, pancreas, and gastrointestinal tract. Nevertheless, most of these tumors do not have metastatic phenotypes. Metastasis occurs when tumors acquire additional genetic changes in other cancer driver genes. Studies on clinical specimens also demonstrated that KRAS mutations are present in premalignant tissues and that most of KRAS mutant human cancers have co-mutations in other cancer driver genes, including TP53, STK11, CDKN2A, and KMT2C in lung cancer; APC, TP53, and PIK3CA in colon cancer; and TP53, CDKN2A, SMAD4, and MED12 in pancreatic cancer...
January 2016: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/26282282/serine-arginine-rich-splicing-factor-3-srsf3-regulates-homologous-recombination-mediated-dna-repair
#18
Xiaolong He, Pei Zhang
BACKGROUND: Our previous work found that serine/arginine-rich splicing factor 3 (SRSF3) was overexpressed in human ovarian cancer and the overexpression of SRSF3 was required for ovarian cancer cell growth and survival. The mechanism underlying the role of SRSF3 in ovarian cancer remains to be addressed. METHODS: We conducted microarray analysis to profile the gene expression and splicing in SRSF3-knockdown cells and employed quantitative PCR and western blotting to validate the profiling results...
August 19, 2015: Molecular Cancer
https://www.readbyqxmd.com/read/26077434/disrupted-intricacy-of-histone-h3k4-methylation-in-neurodevelopmental-disorders
#19
REVIEW
Christina N Vallianatos, Shigeki Iwase
Methylation of histone H3 lysine 4 (H3K4me) is an intricately regulated posttranslational modification, which is broadly associated with enhancers and promoters of actively transcribed genomic loci. Recent advances in next-generation sequencing have identified a number of H3K4me regulators mutated in neurodevelopmental disorders including intellectual disabilities, autism spectrum disorders, and schizophrenia. Here, we aim to summarize the molecular function of H3K4me-regulating enzymes in brain development and function...
2015: Epigenomics
https://www.readbyqxmd.com/read/25794446/the-cancer-compass-navigating-the-functions-of-mll-complexes-in-cancer
#20
REVIEW
David J Ford, Andrew K Dingwall
The mixed-lineage leukemia family of histone methyltransferases (MLL1-4, or KMT2A-D) were previously linked to cancer through the founding member, MLL1/KMT2A, which is often involved in translocation-associated gene fusion events in childhood leukemias. However, in recent years, a multitude of tumor exome sequencing studies have revealed that orthologues MLL3/KMT2C and MLL2/KMT2D are mutated in a significant percentage of a large variety of malignancies, particularly solid tumors. These unexpected findings necessitate a deeper inspection into the activities and functional differences between the MLL/KMT2 family members...
May 2015: Cancer Genetics
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