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Bishoy M Faltas, Davide Prandi, Scott T Tagawa, Ana M Molina, David M Nanus, Cora Sternberg, Jonathan Rosenberg, Juan Miguel Mosquera, Brian Robinson, Olivier Elemento, Andrea Sboner, Himisha Beltran, Francesca Demichelis, Mark A Rubin
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: (i) chemotherapy-treated urothelial carcinoma is characterized by intra-patient mutational heterogeneity, and the majority of mutations are not shared; (ii) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (iii) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell adhesion molecule (L1CAM) and integrin signaling pathways; and (iv) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime...
October 17, 2016: Nature Genetics
Wenjin Liu, Jeff M Snell, William R Jeck, Katherine A Hoadley, Matthew D Wilkerson, Joel S Parker, Nirali Patel, Yohannie B Mlombe, Gift Mulima, N George Liomba, Lindsey L Wolf, Carol G Shores, Satish Gopal, Norman E Sharpless
Esophageal squamous cell carcinoma (ESCC) is endemic in regions of sub-Saharan Africa (SSA), where it is the third most common cancer. Here, we describe whole-exome tumor/normal sequencing and RNA transcriptomic analysis of 59 patients with ESCC in Malawi. We observed similar genetic aberrations as reported in Asian and North American cohorts, including mutations of TP53, CDKN2A, NFE2L2, CHEK2, NOTCH1, FAT1, and FBXW7. Analyses for nonhuman sequences did not reveal evidence for infection with HPV or other occult pathogens...
October 6, 2016: JCI Insight
Lisa Hutchinson
No abstract text is available yet for this article.
October 11, 2016: Nature Reviews. Clinical Oncology
Hanen Ouadani, Imen Ben-Mustapha, Meriem Ben-Ali, Beya Larguèche, Tihana Jovanic, Sylvie Garcia, Benoit Arcangioli, Houda Elloumi-Zghal, Dahmani Fathallah, Mongia Hachicha, Hatem Masmoudi, François Rougeon, Mohamed-Ridha Barbouche
Activation induced cytidine deaminase (AID) is an essential enzyme for class switch recombination (CSR) and somatic hypermutation (SHM) during secondary immune response. Mutations in the AICDA gene are responsible for Hyper IgM 2 syndrome where both CSR and SHM or only CSR are affected. Indeed, triggering either of the two mechanisms requires the DNA deamination activity of AID. Besides, different domains of AID may be differentially involved in CSR and SHM through their interaction with specific cofactors...
October 4, 2016: Molecular Immunology
David W Cescon, Benjamin Haibe-Kains
APOBEC cytidine deaminases have been implicated as major contributors to the mutation burden in many cancers on the basis of their mutational signature. A new experimental study sheds light on the inciting factors, linking APOBEC3B expression to oncogene- and drug-induced replication stress.
September 30, 2016: Genome Biology
(no author information available yet)
SNPs in APOBEC3 alter expression of APOBEC3A/APOBEC3B to affect somatic APOBEC-signature mutations.
September 30, 2016: Cancer Discovery
Gabriel J Starrett, Elizabeth M Luengas, Jennifer L McCann, Diako Ebrahimi, Nuri A Temiz, Robin P Love, Yuqing Feng, Madison B Adolph, Linda Chelico, Emily K Law, Michael A Carpenter, Reuben S Harris
Cytosine mutations within TCA/T motifs are common in cancer. A likely cause is the DNA cytosine deaminase APOBEC3B (A3B). However, A3B-null breast tumours still have this mutational bias. Here we show that APOBEC3H haplotype I (A3H-I) provides a likely solution to this paradox. A3B-null tumours with this mutational bias have at least one copy of A3H-I despite little genetic linkage between these genes. Although deemed inactive previously, A3H-I has robust activity in biochemical and cellular assays, similar to A3H-II after compensation for lower protein expression levels...
September 21, 2016: Nature Communications
Hong Zheng, Wei Dai, Arthur Kwok Leung Cheung, Josephine Mun Yee Ko, Rebecca Kan, Bonnie Wing Yan Wong, Merrin Man Long Leong, Mingdan Deng, Tommy Chin Tung Kwok, Jimmy Yu-Wai Chan, Dora Lai-Wan Kwong, Anne Wing-Mui Lee, Wai Tong Ng, Roger Kai Cheong Ngan, Chun Chung Yau, Stewart Tung, Victor Ho-Fun Lee, Ka-On Lam, Chung Kong Kwan, Wing Sum Li, Stephen Yau, Kwok-Wah Chan, Maria Li Lung
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a unique geographical distribution. The genomic abnormalities leading to NPC pathogenesis remain unclear. In total, 135 NPC tumors were examined to characterize the mutational landscape using whole-exome sequencing and targeted resequencing. An APOBEC cytidine deaminase mutagenesis signature was revealed in the somatic mutations. Noticeably, multiple loss-of-function mutations were identified in several NF-κB signaling negative regulators NFKBIA, CYLD, and TNFAIP3 Functional studies confirmed that inhibition of NFKBIA had a significant impact on NF-κB activity and NPC cell growth...
October 4, 2016: Proceedings of the National Academy of Sciences of the United States of America
Candace D Middlebrooks, A Rouf Banday, Konichi Matsuda, Krizia-Ivana Udquim, Olusegun O Onabajo, Ashley Paquin, Jonine D Figueroa, Bin Zhu, Stella Koutros, Michiaki Kubo, Taro Shuin, Neal D Freedman, Manolis Kogevinas, Nuria Malats, Stephen J Chanock, Montserrat Garcia-Closas, Debra T Silverman, Nathaniel Rothman, Ludmila Prokunina-Olsson
High rates of APOBEC-signature mutations are found in many tumors, but factors affecting this mutation pattern are not well understood. Here we explored the contribution of two common germline variants in the APOBEC3 region. SNP rs1014971 was associated with bladder cancer risk, increased APOBEC3B expression, and enrichment with APOBEC-signature mutations in bladder tumors. In contrast, a 30-kb deletion that eliminates APOBEC3B and creates an APOBEC3A-APOBEC3B chimera was not important in bladder cancer, whereas it was associated with breast cancer risk and enrichment with APOBEC-signature mutations in breast tumors...
September 19, 2016: Nature Genetics
Camilla Lamb, Patrick Arbuthnot
INTRODUCTION: Chronic infection with hepatitis B virus (HBV) is endemic to several populous parts of the world, where resulting complicating cirrhosis and hepatocellular carcinoma occur commonly. Licensed drugs to treat the infection have limited curative efficacy, and development of therapies that eliminate all replication intermediates of HBV is a priority. AREAS COVERED: The recent demonstration that the activation of the innate immune response may eradicate HBV from infected hepatocytes has a promising therapeutic application...
September 7, 2016: Expert Opinion on Biological Therapy
Sachini U Siriwardena, Kang Chen, Ashok S Bhagwat
The AID/APOBEC family enzymes convert cytosines in single-stranded DNA to uracils, causing base substitutions and strand breaks. They are induced by cytokines produced during the body's inflammatory response to infections, and they help combat infections through diverse mechanisms. AID is essential for the maturation of antibodies and causes mutations and deletions in antibody genes through somatic hypermutation (SHM) and class-switch recombination (CSR) processes. One member of the APOBEC family, APOBEC1, edits mRNA for a protein involved in lipid transport...
September 1, 2016: Chemical Reviews
Katia Monteleone, Giuseppe Corano Scheri, Maura Statzu, Carla Selvaggi, Francesca Falasca, Noemi Giustini, Ivano Mezzaroma, Ombretta Turriziani, Gabriella d'Ettorre, Guido Antonelli, Carolina Scagnolari
This study aimed to evaluate the association between the IFNL4 rs368234815 (ΔG/TT) dinucleotide polymorphism and the IFN response during chronic HIV-1 infection. We carried out genotyping analysis and measured the expression of IFN-stimulated genes (ISGs) (myxovirus resistance protein A [MxA], ISG15, ISG56, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like [APOBEC] 3F and APOBEC3G) on peripheral blood mononuclear cells collected from naïve and HAART-treated HIV-1-infected patients. There were no statistically significant differences in endogenous ISGs mRNA levels among HIV-1-positive patients bearing different IFNL4 genotypes, suggesting that ISG expression is independent of the IFNL4 genotype in HIV-1 infection...
November 2016: Archives of Virology
Chanida Vinayanuwattikun, Florence Le Calvez-Kelm, Behnoush Abedi-Ardekani, David Zaridze, Anush Mukeria, Catherine Voegele, Maxime Vallée, Dewajani Purnomosari, Nathalie Forey, Geoffroy Durand, Graham Byrnes, James Mckay, Paul Brennan, Ghislaine Scelo
To examine the diversity of somatic alterations and clonal evolution according to aggressiveness of disease, nineteen tumor-blood pairs of 'formerly bronchiolo-alveolar carcinoma (BAC)' which had been reclassified into preinvasive lesion (adenocarcinoma in situ; AIS), focal invasive lesion (minimally invasive adenocarcinoma; MIA), and invasive lesion (lepidic predominant adenocarcinoma; LPA and non-lepidic predominant adenocarcinoma; non-LPA) according to IASLC/ATS/ERS 2011 classification were explored by whole exome sequencing...
2016: Scientific Reports
Martin Svoboda, Anastasia Meshcheryakova, Georg Heinze, Markus Jaritz, Dietmar Pils, Dan Cacsire Castillo-Tong, Gudrun Hager, Theresia Thalhammer, Erika Jensen-Jarolim, Peter Birner, Ioana Braicu, Jalid Sehouli, Sandrina Lambrechts, Ignace Vergote, Sven Mahner, Philip Zimmermann, Robert Zeillinger, Diana Mechtcheriakova
BACKGROUND: Building up of pathway-/disease-relevant signatures provides a persuasive tool for understanding the functional relevance of gene alterations and gene network associations in multifactorial human diseases. Ovarian cancer is a highly complex heterogeneous malignancy in respect of tumor anatomy, tumor microenvironment including pro-/antitumor immunity and inflammation; still, it is generally treated as single disease. Thus, further approaches to investigate novel aspects of ovarian cancer pathogenesis aiming to provide a personalized strategy to clinical decision making are of high priority...
2016: BMC Genomics
John L Goodier
Retrotransposons have generated about 40 % of the human genome. This review examines the strategies the cell has evolved to coexist with these genomic "parasites", focussing on the non-long terminal repeat retrotransposons of humans and mice. Some of the restriction factors for retrotransposition, including the APOBECs, MOV10, RNASEL, SAMHD1, TREX1, and ZAP, also limit replication of retroviruses, including HIV, and are part of the intrinsic immune system of the cell. Many of these proteins act in the cytoplasm to degrade retroelement RNA or inhibit its translation...
2016: Mobile DNA
Philippe Lamy, Iver Nordentoft, Karin Birkenkamp-Demtröder, Mathilde Borg Houlberg Thomsen, Palle Villesen, Søren Vang, Jakob Hedegaard, Michael Borre, Jørgen Bjerggaard Jensen, Søren Høyer, Jakob Skou Pedersen, Torben F Ørntoft, Lars Dyrskjøt
Greater knowledge concerning tumor heterogeneity and clonality is needed to determine the impact of targeted treatment in the setting of bladder cancer. In this study, we performed whole-exome, transcriptome, and deep-focused sequencing of metachronous tumors from 29 patients initially diagnosed with early-stage bladder tumors (14 with nonprogressive disease and 15 with progressive disease). Tumors from patients with progressive disease showed a higher variance of the intrapatient mutational spectrum and a higher frequency of APOBEC-related mutations...
October 1, 2016: Cancer Research
Robyn A Lindley, Patrick Humbert, Cliff Larner, Eric H Akmeemana, Christopher R R Pendlebury
Evidence already exists that the activation-induced cytidine deaminase (AID/APOBEC) and the adenosine deaminase (ADAR) families of enzymes are implicated as powerful mutagens in oncogenic processes in many somatic tissues. Each deaminase is identified by the DNA or RNA nucleotide sequence ("motif") surrounding the nucleotide targeted for deamination. The primary objective of this study is to develop an in silico approach to identify nucleotide sequence changes of the target motifs of key deaminases during oncogenesis...
September 2016: Cancer Medicine
Hai Hu, Man-Li Luo, Christine Desmedt, Sheida Nabavi, Sina Yadegarynia, Alex Hong, Panagiotis A Konstantinopoulos, Edward Gabrielson, Rebecca Hines-Boykin, German Pihan, Xin Yuan, Christos Sotirious, Dirk P Dittmer, Joyce D Fingeroth, Gerburg M Wulf
Whether the human tumor virus, Epstein-Barr Virus (EBV), promotes breast cancer remains controversial and a potential mechanism has remained elusive. Here we show that EBV can infect primary mammary epithelial cells (MECs) that express the receptor CD21. EBV infection leads to the expansion of early MEC progenitor cells with a stem cell phenotype, activates MET signaling and enforces a differentiation block. When MECs were implanted as xenografts, EBV infection cooperated with activated Ras and accelerated the formation of breast cancer...
July 2016: EBioMedicine
Andrew Feber, Daniel C Worth, Ankur Chakravarthy, Patricia de Winter, Kunal Shah, Manit Arya, Muhammad Saqib, Raj Nigam, Peter R Malone, Wei Shen Tan, Simon Rodney, Alex Freeman, Charles Jameson, Gareth A Wilson, Tom Powles, Stephan Beck, Tim Fenton, Tyson V Sharp, Asif Muneer, John D Kelly
Other than an association with HPV infection, little is known about the genetic alterations determining the development of penile cancer. Although penile cancer is rare in the developed world, it presents a significant burden in developing countries. Here, we report the findings of whole-exome sequencing (WES) to determine the somatic mutational landscape of penile cancer. WES was performed on penile cancer and matched germline DNA from 27 patients undergoing surgical resection. Targeted resequencing of candidate genes was performed in an independent 70 patient cohort...
August 15, 2016: Cancer Research
Jakob Hedegaard, Philippe Lamy, Iver Nordentoft, Ferran Algaba, Søren Høyer, Benedicte Parm Ulhøi, Søren Vang, Thomas Reinert, Gregers G Hermann, Karin Mogensen, Mathilde Borg Houlberg Thomsen, Morten Muhlig Nielsen, Mirari Marquez, Ulrika Segersten, Mattias Aine, Mattias Höglund, Karin Birkenkamp-Demtröder, Niels Fristrup, Michael Borre, Arndt Hartmann, Robert Stöhr, Sven Wach, Bastian Keck, Anna Katharina Seitz, Roman Nawroth, Tobias Maurer, Cane Tulic, Tatjana Simic, Kerstin Junker, Marcus Horstmann, Niels Harving, Astrid Christine Petersen, M Luz Calle, Ewout W Steyerberg, Willemien Beukers, Kim E M van Kessel, Jørgen Bjerggaard Jensen, Jakob Skou Pedersen, Per-Uno Malmström, Núria Malats, Francisco X Real, Ellen C Zwarthoff, Torben Falck Ørntoft, Lars Dyrskjøt
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 three 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...
July 11, 2016: Cancer Cell
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