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https://www.readbyqxmd.com/read/28812986/epigenome-aberrations-emerging-driving-factors-of-the-clear-cell-renal-cell-carcinoma
#1
REVIEW
Ali Mehdi, Yasser Riazalhosseini
Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau (VHL) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which the activation of hypoxia inducible factor (HIF) pathway is the best-known function. Constitutive activation of HIF signaling in turn activates hundreds of genes involved in numerous oncogenic pathways, which contribute to the development or progression of ccRCC...
August 16, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28811969/k27m-mutant-histone-3-as-a-novel-target-for-glioma-immunotherapy
#2
Katharina Ochs, Martina Ott, Theresa Bunse, Felix Sahm, Lukas Bunse, Katrin Deumelandt, Jana K Sonner, Melanie Keil, Andreas von Deimling, Wolfgang Wick, Michael Platten
Mutation-specific vaccines have become increasingly important in glioma immunotherapy; however, shared neoepitopes are rare. For diffuse gliomas, a driver mutation in the gene for isocitrate dehydrogenase type-1 has been shown to produce an immunogenic epitope currently targeted in clinical trials. For highly aggressive midline gliomas, a recurrent point mutation in the histone-3 gene (H3F3A) causes an amino acid change from lysine to methionine at position 27 (K27M). Here, we demonstrate that a peptide vaccine against K27M-mutant histone-3 is capable of inducing effective, mutation-specific, cytotoxic T-cell- and T-helper-1-cell-mediated immune responses in a major histocompatibility complex (MHC)-humanized mouse model...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28811315/quantitative-whole-genome-sequencing-of-circulating-tumor-cells-enables-personalized-combination-therapy-of-metastatic-cancer
#3
Natali Gulbahce, Mark Jesus M Magbanua, Robert Chin, Misha R Agarwal, Xuhao Luo, Jia Liu, Daniel M Hayden, Qing Mao, Serban Ciotlos, Zhenyu Li, Yanxiang Chen, Xingpeng Chen, Yuxiang Li, Rebecca Yu Zhang, Katharine Lee, Rick Tearle, Emily Park, Snezana Drmanac, Hope S Rugo, John W Park, Radoje Drmanac, Brock A Peters
Much effort has been dedicated to developing circulating tumor cells (CTC) as a noninvasive cancer biopsy, but with limited success as yet. In this study, we combine a method for isolation of highly pure CTCs using immunomagnetic enrichment/fluorescence-activated cell sorting with advanced whole genome sequencing (WGS), based on long fragment read technology, to illustrate the utility of an accurate, comprehensive, phased, and quantitative genomic analysis platform for CTCs. Whole genomes of 34 CTCs from a patient with metastatic breast cancer were analyzed as 3,072 barcoded subgenomic compartments of long DNA...
August 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28811260/cophylogenetic-analyses-reveal-extensive-host-shift-speciation-in-a-highly-specialized-and-host-specific-symbiont-system
#4
Jorge Doña, Andrew D Sweet, Kevin P Johnson, David Serrano, Sergey Mironov, Roger Jovani
Host-shift speciation and cospeciation are the two major processes driving symbiont macroevolutionary diversification. Cospeciation is expected to be frequent in vertically transmitted and host-specific symbionts, and leads to congruent host-symbiont phylogenies. However, the cophylogenetic dynamics of many groups of highly specialized host-specific symbionts is largely unstudied. Thus, the relevance of cospeciation vs. host-shift speciation remains largely unknown. Here, we investigated this question by performing the largest cophylogenetic study of feather mites to date, using both distance and event-based cophylogenetic methods...
August 12, 2017: Molecular Phylogenetics and Evolution
https://www.readbyqxmd.com/read/28810830/annotating-long-intergenic-non-coding-rnas-under-artificial-selection-during-chicken-domestication
#5
Yun-Mei Wang, Hai-Bo Xu, Ming-Shan Wang, Newton Otieno Otecko, Ling-Qun Ye, Dong-Dong Wu, Ya-Ping Zhang
BACKGROUND: Numerous biological functions of long intergenic non-coding RNAs (lincRNAs) have been identified. However, the contribution of lincRNAs to the domestication process has remained elusive. Following domestication from their wild ancestors, animals display substantial changes in many phenotypic traits. Therefore, it is possible that diverse molecular drivers play important roles in this process. RESULTS: We analyzed 821 transcriptomes in this study and annotated 4754 lincRNA genes in the chicken genome...
August 15, 2017: BMC Evolutionary Biology
https://www.readbyqxmd.com/read/28810144/integrated-genomic-characterization-of-pancreatic-ductal-adenocarcinoma
#6
(no author information available yet)
We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations...
August 14, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28810143/genomic-evolution-of-breast-cancer-metastasis-and-relapse
#7
Lucy R Yates, Stian Knappskog, David Wedge, James H R Farmery, Santiago Gonzalez, Inigo Martincorena, Ludmil B Alexandrov, Peter Van Loo, Hans Kristian Haugland, Peer Kaare Lilleng, Gunes Gundem, Moritz Gerstung, Elli Pappaemmanuil, Patrycja Gazinska, Shriram G Bhosle, David Jones, Keiran Raine, Laura Mudie, Calli Latimer, Elinor Sawyer, Christine Desmedt, Christos Sotiriou, Michael R Stratton, Anieta M Sieuwerts, Andy G Lynch, John W Martens, Andrea L Richardson, Andrew Tutt, Per Eystein Lønning, Peter J Campbell
Patterns of genomic evolution between primary and metastatic breast cancer have not been studied in large numbers, despite patients with metastatic breast cancer having dismal survival. We sequenced whole genomes or a panel of 365 genes on 299 samples from 170 patients with locally relapsed or metastatic breast cancer. Several lines of analysis indicate that clones seeding metastasis or relapse disseminate late from primary tumors, but continue to acquire mutations, mostly accessing the same mutational processes active in the primary tumor...
August 14, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28810139/cliques-and-schisms-of-cancer-genes
#8
Peter J Campbell
With a few exceptions, cancers typically carry more than one driver mutation, sometimes five, ten, or more, and these driver mutations do not necessarily assort randomly. In this issue of Cancer Cell, Mina et al. systematically characterize patterns of co-mutation and mutual exclusivity in 6,456 cancers across 23 tumor types.
August 14, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28809862/gnaq-and-gna11-mutations-and-downstream-yap-activation-in-choroidal-nevi
#9
M J C Vader, M C Madigan, M Versluis, H M Suleiman, G Gezgin, N A Gruis, J J Out-Luiting, W Bergman, R M Verdijk, M J Jager, P A van der Velden
BACKGROUND: Mutations in GNAQ/11 genes are considered an early event in the development of uveal melanoma that may derive from a pre-existing nevus. The Hippo pathway, by way of YAP activation, rather than MAP kinase, has a role in the oncogenic capacity of GNAQ/11 mutations. METHODS: We investigated 16 nevi from 13 human eyes for driver GNAQ/11 mutations using droplet digital PCR and determined whether nevi are clonal by quantifying mutant nevus cell fractions...
August 15, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28807937/hnf1b-loss-exacerbates-the-development-of-chromophobe-renal-cell-carcinomas
#10
Eric Jonasch, Mianen Sun, Pan Tong, Wen Kong, Baijun Dong, Yiran Huang, In Young Park, Lijun Zhou, Xian-De Liu, Zhiyong Ding, Xuesong Zhang, Shanshan Bai, Peter German, Reid Powell, Quan Wang, Xuefei Tong, Nizar M Tannir, Surena F Matin, W Kimryn Rathmell, Gregory N Fuller, Ian E McCutcheon, Cheryl Lyn Walker, Jing Wang
Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of HNF1B loss is unique to ChRCC. We also observed a strong correlation between reduced HNF1B expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell cycle checkpoint proteins RB1 and p27...
August 14, 2017: Cancer Research
https://www.readbyqxmd.com/read/28807780/mgl-1-on-aiy-neurons-translates-starvation-to-reproductive-plasticity-via-neuropeptide-signaling-in-caenorhabditis-elegans
#11
Haelim Jeong, Young-Ki Paik
Reproductive plasticity is the ability of an animal to modulate its reproductive functions in response to environmental changes. For example, Caenorhabditis elegans, a free-living nematode, can adjust the onsets of oogenesis and embryogenesis under harsh environmental conditions, including starvation. However, the molecular mechanisms used to perceive and translate environmental signals into reproductive functional adjustments remain largely uncharacterized. We discovered that in C. elegans, the glutamate receptor homolog MGL-1 initiated reproductive plasticity in response to starvation...
August 11, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28805821/opposing-effects-of-cancer-type-specific-spop-mutants-on-bet-protein-degradation-and-sensitivity-to-bet-inhibitors
#12
Hana Janouskova, Geniver El Tekle, Elisa Bellini, Namrata D Udeshi, Anna Rinaldi, Anna Ulbricht, Tiziano Bernasocchi, Gianluca Civenni, Marco Losa, Tanya Svinkina, Craig M Bielski, Gregory V Kryukov, Luciano Cascione, Sara Napoli, Radoslav I Enchev, David G Mutch, Michael E Carney, Andrew Berchuck, Boris J N Winterhoff, Russell R Broaddus, Peter Schraml, Holger Moch, Francesco Bertoni, Carlo V Catapano, Matthias Peter, Steven A Carr, Levi A Garraway, Peter J Wild, Jean-Philippe P Theurillat
It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants...
August 14, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28805815/aav-mediated-direct-in-vivo-crispr-screen-identifies-functional-suppressors-in-glioblastoma
#13
Ryan D Chow, Christopher D Guzman, Guangchuan Wang, Florian Schmidt, Mark W Youngblood, Lupeng Ye, Youssef Errami, Matthew B Dong, Michael A Martinez, Sensen Zhang, Paul Renauer, Kaya Bilguvar, Murat Gunel, Phillip A Sharp, Feng Zhang, Randall J Platt, Sidi Chen
A causative understanding of genetic factors that regulate glioblastoma pathogenesis is of central importance. Here we developed an adeno-associated virus-mediated, autochthonous genetic CRISPR screen in glioblastoma. Stereotaxic delivery of a virus library targeting genes commonly mutated in human cancers into the brains of conditional-Cas9 mice resulted in tumors that recapitulate human glioblastoma. Capture sequencing revealed diverse mutational profiles across tumors. The mutation frequencies in mice correlated with those in two independent patient cohorts...
August 14, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28803989/mdr65-decreases-toxicity-of-multiple-insecticides-in-drosophila-melanogaster
#14
Haina Sun, Nicolas Buchon, Jeffrey G Scott
ABC transporters are ubiquitous membrane-bound proteins, present in both prokaryotes and eukaryotes. The major function of eukaryotic ABC transporters is to mediate the efflux of a variety of substrates (including xenobiotics) out of cells. ABC transporters have been widely investigated in humans, particularly for their involvement in multidrug resistance (MDR). Considerably less is known about their roles in transport and/or excretion in insects. ABC transporters are only known to function as exporters in insects...
August 10, 2017: Insect Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28803919/therapy-related-clonal-hematopoiesis-in-patients-with-non-hematologic-cancers-is-common-and-associated-with-adverse-clinical-outcomes
#15
Catherine C Coombs, Ahmet Zehir, Sean M Devlin, Ashwin Kishtagari, Aijazuddin Syed, Philip Jonsson, David M Hyman, David B Solit, Mark E Robson, José Baselga, Maria E Arcila, Marc Ladanyi, Martin S Tallman, Ross L Levine, Michael F Berger
Clonal hematopoiesis (CH), as evidenced by recurrent somatic mutations in leukemia-associated genes, commonly occurs among aging human hematopoietic stem cells. We analyzed deep-coverage, targeted, next-generation sequencing (NGS) data of paired tumor and blood samples from 8,810 individuals to assess the frequency and clinical relevance of CH in patients with non-hematologic malignancies. We identified CH in 25% of cancer patients, with 4.5% harboring presumptive leukemia driver mutations (CH-PD). CH was associated with increased age, prior radiation therapy, and tobacco use...
August 9, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28802831/validation-of-a-targeted-rna-sequencing-assay-for-kinase-fusion-detection-in-solid-tumors
#16
Julie W Reeser, Dorrelyn Martin, Jharna Miya, Esko A Kautto, Ezra Lyon, Eliot Zhu, Michele R Wing, Amy Smith, Matthew Reeder, Eric Samorodnitsky, Hannah Parks, Karan R Naik, Joseph Gozgit, Nicholas Nowacki, Kurtis D Davies, Marileila Varella-Garcia, Lianbo Yu, Aharon G Freud, Joshua Coleman, Dara L Aisner, Sameek Roychowdhury
Kinase gene fusions are important drivers of oncogenic transformation and can be inhibited with targeted therapies. Clinical grade diagnostics using RNA sequencing to detect gene rearrangements in solid tumors are limited, and the few that are available require prior knowledge of fusion break points. To address this, we have analytically validated a targeted RNA sequencing assay (OSU-SpARKFuse) for fusion detection that interrogates complete transcripts from 93 kinase and transcription factor genes. From a total of 74 positive and 36 negative control samples, OSU-SpARKFuse had 93...
August 8, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28802078/geographical-features-are-the-predominant-driver-of-molecular-diversification-in-widely-distributed-north-american-whipsnakes
#17
Kyle A O'Connell, Jeffrey W Streicher, Eric N Smith, Matthew K Fujita
Allopatric divergence following the formation of geographical features has been implicated as a major driver of evolutionary diversification. Widespread species complexes provide opportunities to examine allopatric divergence across varying degrees of isolation in both time and space. In North America, several geographical features may play such a role in diversification, including the Mississippi River, Pecos River, Rocky Mountains, Cochise Filter Barrier, Gulf of California, and Isthmus of Tehuantepec. We used thousands of nuclear single nucleotide polymorphisms (SNPs) and mitochondrial DNA from several species of whipsnakes (genera Masticophis and Coluber) distributed across North and Central America to investigate the role that these geographical features have played on lineage divergence...
August 12, 2017: Molecular Ecology
https://www.readbyqxmd.com/read/28800915/transposable-elements-direct-the-coevolution-between-plants-and-microbes
#18
REVIEW
Michael F Seidl, Bart P H J Thomma
Transposable elements are powerful drivers of genome evolution in many eukaryotes. Although they are mostly considered as 'selfish' genetic elements, increasing evidence suggests that they contribute to genetic variability; particularly under stress conditions. Over the past few years, the role of transposable elements during host-microbe interactions has been recognised. It has been proposed that many pathogenic microbes have evolved a 'two-speed' genome with regions that show increased variability and that are enriched in transposable elements and pathogenicity-related genes...
August 8, 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/28797464/relevance-of-chromosomal-band-11q13-in-oral-carcinogenesis-an-update-of-current-knowledge
#19
REVIEW
Pablo Ramos-García, Isabel Ruiz-Ávila, José Antonio Gil-Montoya, Ángela Ayén, Lucía González-Ruiz, Francisco José Navarro-Triviño, Miguel Ángel González-Moles
An important event in oral carcinogenesis is the amplification of chromosomal band 11q13, in which numerous oncogenes and some tumor-suppressor genes are localized and frequently co-amplified during the malignant transformation of oral epithelium. The objectives of this study were to review published data on the involvement of 11q13 amplification in oral cancer, to provide an update on novel concepts and terminology related to gene amplification, and to explore the composition of the 11q13 amplicon in OSCC, including its most relevant amplicon cores and potential drivers...
September 2017: Oral Oncology
https://www.readbyqxmd.com/read/28797453/oncogenic-signalling-pathways-in-benign-odontogenic-cysts-and-tumours
#20
REVIEW
Marina Gonçalves Diniz, Carolina Cavalieri Gomes, Sílvia Ferreira de Sousa, Guilherme Machado Xavier, Ricardo Santiago Gomez
The first step towards the prevention of cancer is to develop an in-depth understanding of tumourigenesis and the molecular basis of malignant transformation. What drives tumour initiation? Why do most benign tumours fail to metastasize? Oncogenic mutations, previously considered to be the hallmark drivers of cancers, are reported in benign cysts and tumours, including those that have an odontogenic origin. Despite the presence of such alterations, the vast majority of odontogenic lesions are benign and never progress to the stage of malignant transformation...
September 2017: Oral Oncology
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