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Apobec

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https://www.readbyqxmd.com/read/29140415/apobec3a-b-deletion-polymorphism-and-cancer-risk
#1
Liv B Gansmo, Paal Romundstad, Kristian Hveem, Lars Vatten, Serena Nik-Zainal, Per Eystein Lønning, Stian Knappskog
Activity of the APOBEC enzymes has been linked to specific mutational processes in human cancer genomes. A germline APOBEC3A/B deletion polymorphism is associated with APOBEC-dependent mutational signatures, and the deletion allele has been reported to confer an elevated risk of some cancers in Asian populations, while the results in European populations, so far, have been conflicting. We genotyped the APOBEC3A/B deletion polymorphism in a large population based sample consisting of 11,106 Caucasian (Norwegian) individuals, including 7,279 incident cancer cases (1,769 breast- , 1,360 lung-, 1,585 colon-, and 2,565 prostate cancer) and a control group of 3,827 matched individuals without cancer (1,918 females and 1,909 males) from the same population...
November 13, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29107330/allele-specific-hla-loss-and-immune-escape-in-lung-cancer-evolution
#2
Nicholas McGranahan, Rachel Rosenthal, Crispin T Hiley, Andrew J Rowan, Thomas B K Watkins, Gareth A Wilson, Nicolai J Birkbak, Selvaraju Veeriah, Peter Van Loo, Javier Herrero, Charles Swanton
Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity...
October 21, 2017: Cell
https://www.readbyqxmd.com/read/29103756/multi-modality-analysis-supports-apobec-as-a-major-source-of-mutations-in-head-and-neck-squamous-cell-carcinoma
#3
Daniel L Faden, Sean Thomas, Paul G Cantalupo, Nishant Agrawal, Jeffrey Myers, Joseph DeRisi
OBJECTIVES: The mutagenic processes underlying head and neck squamous cell carcinoma (HNSCC) are poorly understood. Pan-cancer mutational signature analyses have identified a signature for APOBEC, a cytosine deaminase, in a subset of cancers, including HNSCC. The role of APOBEC activity in HNSCC remains poorly understood. Therefore, we sought to determine the role of APOBEC in HNSCC pathogenesis. MATERIAL AND METHODS: Utilizing bioinformatic approaches we explored the role of APOBEC mediated mutations in tumor exomes, transcriptomes and germline exomes from 511HNSCC patients in the TCGA...
November 2017: Oral Oncology
https://www.readbyqxmd.com/read/29076965/mutational-and-epigenetic-signatures-in-cancer-tissue-linked-to-environmental-exposures-and-lifestyle
#4
Vittorio Perduca, Hanane Omichessan, Laura Baglietto, Gianluca Severi
PURPOSE OF REVIEW: In this article, we describe how recent advances in the study of mutational and epigenetic signatures in tumours provide new opportunities to understand the role of the environment and lifestyle in cancer development. RECENT FINDINGS: Cancer-related mutational events have been investigated for decades but only recently the wide availability of genomic sequences and epigenomic data from thousands of cancer genomes has made it possible to identify numerous distinct mutational and epigenetic signatures through the application of advanced mathematical models...
October 25, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/29044863/identification-of-somatic-genetic-alterations-in-ovarian-clear-cell-carcinoma-with-next-generation-sequencing
#5
Yusuke Shibuya, Hideki Tokunaga, Sakae Saito, Kazurou Shimokawa, Fumiki Katsuoka, Li Bin, Kaname Kojima, Masao Nagasaki, Masayuki Yamamoto, Nobuo Yaegashi, Jun Yasuda
Ovarian clear cell carcinoma (OCCC) is the most refractory subtype of ovarian cancer and more prevalent in Japanese than Caucasians (25% and 5% of all ovarian cancer, respectively). The aim of this study is to discover the genomic alterations that may cause OCCC and effective molecular targets for chemotherapy. Paired genomic DNAs of 48 OCCC tissues and corresponding non-cancerous tissues were extracted from formalin-fixed, paraffin embedded specimens collected between 2007 and 2015 at Tohoku University Hospital...
October 16, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28988769/comprehensive-molecular-characterization-of-muscle-invasive-bladder-cancer
#6
A Gordon Robertson, Jaegil Kim, Hikmat Al-Ahmadie, Joaquim Bellmunt, Guangwu Guo, Andrew D Cherniack, Toshinori Hinoue, Peter W Laird, Katherine A Hoadley, Rehan Akbani, Mauro A A Castro, Ewan A Gibb, Rupa S Kanchi, Dmitry A Gordenin, Sachet A Shukla, Francisco Sanchez-Vega, Donna E Hansel, Bogdan A Czerniak, Victor E Reuter, Xiaoping Su, Benilton de Sa Carvalho, Vinicius S Chagas, Karen L Mungall, Sara Sadeghi, Chandra Sekhar Pedamallu, Yiling Lu, Leszek J Klimczak, Jiexin Zhang, Caleb Choo, Akinyemi I Ojesina, Susan Bullman, Kristen M Leraas, Tara M Lichtenberg, Catherine J Wu, Nicholaus Schultz, Gad Getz, Matthew Meyerson, Gordon B Mills, David J McConkey, John N Weinstein, David J Kwiatkowski, Seth P Lerner
We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology...
October 19, 2017: Cell
https://www.readbyqxmd.com/read/28983111/ifn-%C3%AE-mediated-base-excision-repair-pathway-correlates-with-antiviral-response-against-hepatitis-b-virus-infection
#7
Yong Li, Yuchen Xia, Meifang Han, Guang Chen, Dake Zhang, Wolfgang E Thasler, Ulrike Protzer, Qin Ning
Previous studies identified APOBEC deaminases as enzymes targeting hepatitis B virus (HBV) DNA in the nucleus thus affecting its persistence. Interferon (IFN)-α treated chimpanzees and hepatitis C patients showed elevated APOBEC expression. We thus hypothesized that the responses to IFN-α treatment of chronic hepatitis B (CHB) patients is influenced by IFN-induced base excision repair (BER). CHB-treatment naïve patients, patients treated with PEGylated IFN-α, and patients with sequential treatment of Entecavior and PEGylated IFN-α were recruited...
October 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28981865/enzyme-cycling-contributes-to-efficient-induction-of-genome-mutagenesis-by-the-cytidine-deaminase-apobec3b
#8
Madison B Adolph, Robin P Love, Yuqing Feng, Linda Chelico
The single-stranded DNA cytidine deaminases APOBEC3B, APOBEC3H haplotype I, and APOBEC3A can contribute to cancer through deamination of cytosine to form promutagenic uracil in genomic DNA. The enzymes must access single-stranded DNA during the dynamic processes of DNA replication or transcription, but the enzymatic mechanisms enabling this activity are not known. To study this, we developed a method to purify full length APOBEC3B and characterized it in comparison to APOBEC3A and APOBEC3H on substrates relevant to cancer mutagenesis...
November 16, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28977491/p53-controls-expression-of-the-dna-deaminase-apobec3b-to-limit-its-potential-mutagenic-activity-in-cancer-cells
#9
Manikandan Periyasamy, Anup K Singh, Carolina Gemma, Christian Kranjec, Raed Farzan, Damien A Leach, Naveenan Navaratnam, Hajnalka L Pálinkás, Beata G Vértessy, Tim R Fenton, John Doorbar, Frances Fuller-Pace, David W Meek, R Charles Coombes, Laki Buluwela, Simak Ali
Cancer genome sequencing has implicated the cytosine deaminase activity of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) genes as an important source of mutations in diverse cancers, with APOBEC3B (A3B) expression especially correlated with such cancer mutations. To better understand the processes directing A3B over-expression in cancer, and possible therapeutic avenues for targeting A3B, we have investigated the regulation of A3B gene expression. Here, we show that A3B expression is inversely related to p53 status in different cancer types and demonstrate that this is due to a direct and pivotal role for p53 in repressing A3B expression...
August 16, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28964683/apobec-from-mutator-to-editor
#10
REVIEW
Bei Yang, Xiaosa Li, Liqun Lei, Jia Chen
APOBECs (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) are a family of cytidine deaminases that prefer single-stranded nucleic acids as substrates. Besides their physiological functions, APOBEC family members have been found to cause hypermutations of cancer genomes, which could be correlated with cancer development and poor prognosis. Recently, APOBEC family members have been combined with the versatile CRISPR/Cas9 system to perform targeted base editing or induce hypermutagenesis. This combination improved the CRISPR/Cas9-mediated gene editing at single-base precision, greatly enhancing its usefulness...
August 7, 2017: Journal of Genetics and Genomics, Yi Chuan Xue Bao
https://www.readbyqxmd.com/read/28956761/apobec3a-is-upregulated-by-human-cytomegalovirus-hcmv-in-the-maternal-fetal-interface-acting-as-an-innate-anti-hcmv-effector
#11
Yiska Weisblum, Esther Oiknine-Djian, Zichria Zakay-Rones, Olesya Vorontsov, Ronit Haimov-Kochman, Yuval Nevo, David Stockheim, Simcha Yagel, Amos Panet, Dana G Wolf
Human cytomegalovirus (HCMV) is the leading cause of congenital infection and is associated with a wide range of neurodevelopmental disabilities and intrauterine growth restriction. Yet our current understanding of the mechanisms modulating transplacental HCMV transmission is poor. The placenta, given its critical function in protecting the fetus, has evolved effective yet largely uncharacterized innate immune barriers against invading pathogens. Here we show that the intrinsic cellular restriction factor apolipoprotein B editing catalytic subunit-like 3A (APOBEC3A [A3A]) is profoundly upregulated following ex vivo HCMV infection in human decidual tissues-constituting the maternal aspect of the placenta...
December 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28904067/whole-genome-sequencing-reveals-breast-cancers-with-mismatch-repair-deficiency
#12
Helen Davies, Sandro Morganella, Colin A Purdie, Se Jin Jang, Elin Borgen, Hege Russnes, Dominik Glodzik, Xueqing Zou, Alain Viari, Andrea L Richardson, Anne-Lise Børresen-Dale, Alastair Thompson, Jorunn E Eyfjord, Gu Kong, Michael R Stratton, Serena Nik-Zainal
Mismatch repair (MMR)-deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients...
September 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28878238/apobec3a-is-an-oral-cancer-prognostic-biomarker-in-taiwanese-carriers-of-an-apobec-deletion-polymorphism
#13
Ting-Wen Chen, Chi-Ching Lee, Hsuan Liu, Chi-Sheng Wu, Curtis R Pickering, Po-Jung Huang, Jing Wang, Ian Yi-Feng Chang, Yuan-Ming Yeh, Chih-De Chen, Hsin-Pai Li, Ji-Dung Luo, Bertrand Chin-Ming Tan, Timothy En Haw Chan, Chuen Hsueh, Lichieh Julie Chu, Yi-Ting Chen, Bing Zhang, Chia-Yu Yang, Chih-Ching Wu, Chia-Wei Hsu, Lai-Chu See, Petrus Tang, Jau-Song Yu, Wei-Chao Liao, Wei-Fan Chiang, Henry Rodriguez, Jeffrey N Myers, Kai-Ping Chang, Yu-Sun Chang
Oral squamous cell carcinoma is a prominent cancer worldwide, particularly in Taiwan. By integrating omics analyses in 50 matched samples, we uncover in Taiwanese patients a predominant mutation signature associated with cytidine deaminase APOBEC, which correlates with the upregulation of APOBEC3A expression in the APOBEC3 gene cluster at 22q13. APOBEC3A expression is significantly higher in tumors carrying APOBEC3B-deletion allele(s). High-level APOBEC3A expression is associated with better overall survival, especially among patients carrying APOBEC3B-deletion alleles, as examined in a second cohort (n = 188; p = 0...
September 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28862766/genomic-profiles-of-lung-cancer-associated-with-idiopathic-pulmonary-fibrosis
#14
Ji An Hwang, Deokhoon Kim, Sung-Min Chun, SooHyun Bae, Joon Seon Song, Mi Young Kim, Hyun Jung Koo, Jin Woo Song, Woo Sung Kim, Jae Cheol Lee, Hyeong Ryul Kim, Chang-Min Choi, Se Jin Jang
Little is known on the pathogenesis or molecular profiles of idiopathic pulmonary fibrosis-associated lung cancer (IPF-LC). This study was performed to investigate the genomic profiles of IPF-LC and to explore the possibility of defining potential therapeutic targets in IPF-LC. We assessed genomic profiles of IPF-LC using targeted exome sequencing (OncoPanel version 2) in 35 matched tumor/normal pairs surgically resected between 2004 and 2014. Germline and somatic variant calling was performed using GATK HaplotypeCaller and MuTect with GATK SomaticIndelocator, respectively...
September 1, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28789929/commentary-on-comprehensive-transcriptional-analysis-of-early-stage-urothelial-carcinoma-hedegaard-j-lamy-p-nordentoft-i-algaba-f-h%C3%A3-yer-s-ulh%C3%A3-i-bp-vang-s-reinert-t-hermann-gg-mogensen-k-thomsen-mb-nielsen-mm-marquez-m-segersten-u-aine-m-h%C3%A3-glund-m-birkenkamp
#15
Byron H Lee
Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into 3 major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions...
August 5, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28780131/commentary-on-clonal-evolution-of-chemotherapy-resistant-urothelial-carcinoma-faltas-bm-prandi-d-tagawa-st-molina-am-nanus-dm-sternberg-c-rosenberg-j-mosquera-jm-robinson-b-elemento-o-sboner-a-beltran-h-demichelis-f-rubin-ma-nat-genet-2016-oct-17-http-dx-doi
#16
Byron H Lee
Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights that are as follows: (1) chemotherapy-treated urothelial carcinoma is characterized by intrapatient mutational heterogeneity, and most mutations are not shared; (2) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (3) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell-adhesion molecule and integrin signaling pathways; and (4) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime...
August 2, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28771191/somatic-host-cell-alterations-in-hpv-carcinogenesis
#17
REVIEW
Tamara R Litwin, Megan A Clarke, Michael Dean, Nicolas Wentzensen
High-risk human papilloma virus (HPV) infections cause cancers in different organ sites, most commonly cervical and head and neck cancers. While carcinogenesis is initiated by two viral oncoproteins, E6 and E7, increasing evidence shows the importance of specific somatic events in host cells for malignant transformation. HPV-driven cancers share characteristic somatic changes, including apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC)-driven mutations and genomic instability leading to copy number variations and large chromosomal rearrangements...
August 3, 2017: Viruses
https://www.readbyqxmd.com/read/28753428/clustered-mutation-signatures-reveal-that-error-prone-dna-repair-targets-mutations-to-active-genes
#18
Fran Supek, Ben Lehner
Many processes can cause the same nucleotide change in a genome, making the identification of the mechanisms causing mutations a difficult challenge. Here, we show that clustered mutations provide a more precise fingerprint of mutagenic processes. Of nine clustered mutation signatures identified from >1,000 tumor genomes, three relate to variable APOBEC activity and three are associated with tobacco smoking. An additional signature matches the spectrum of translesion DNA polymerase eta (POLH). In lymphoid cells, these mutations target promoters, consistent with AID-initiated somatic hypermutation...
July 27, 2017: Cell
https://www.readbyqxmd.com/read/28717061/apobec-mediated-genomic-alterations-link-immunity-and-viral-infection-during-human-papillomavirus-driven-cervical-carcinogenesis
#19
Lanting Chen, Xuemin Qiu, Na Zhang, Yan Wang, Mingyan Wang, Dajin Li, Ling Wang, Yan Du
Cervical cancer is one of the most frequently diagnosed cancers and is a major cause of death from gynecologic cancers worldwide; the cancer burden from cervical cancer is especially heavy in less developed countries. Most cases of cervical cancer are caused by persistent infection with carcinogenic human papillomavirus (HPV) genotypes 16 and 18. Non-resolving inflammation caused by HPV infection provides a microenvironment that facilitates cancer development. Molecular alterations during the process of HPV-induced carcinogenesis are characterized by DNA methylation within the HPV genome, promoter hypermethylation of tumor suppressor genes in the host genome, as well as genomic instability caused by viral DNA integrating into the host genome...
July 17, 2017: Bioscience Trends
https://www.readbyqxmd.com/read/28698210/apobec3a-and-apobec3b-activities-render-cancer-cells-susceptible-to-atr-inhibition
#20
Rémi Buisson, Michael S Lawrence, Cyril H Benes, Lee Zou
The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like APOBEC3A and APOBEC3B have emerged as key mutation drivers in cancer. Here, we show that APOBEC3A and APOBEC3B activities impose a unique type of replication stress by inducing abasic sites at replication forks. In contrast to cells under other types of replication stress, APOBEC3A-expressing cells were selectively sensitive to ATR inhibitors (ATRi), but not to a variety of DNA replication inhibitors and DNA-damaging drugs. In proliferating cells, APOBEC3A modestly elicited ATR but not ATM...
September 1, 2017: Cancer Research
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