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1. RNA editing of AZIN1 induces the malignant progression of non-small-cell lung cancers

Author

Xueda Hu, Jingyi Chen, Xiaoshun Shi, Fenglan Feng, King Wai Lau, Yaoqi Chen, Yusong Chen, Long Jiang, Fei Cui, Yalei Zhang, Xin Xu, and Jin Li

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

RNA editing is a widespread post-transcriptional mechanism that confers specific and reproducible nucleotide changes in selected RNA transcripts and plays a critical role in many human cancers. However, little is known about how RNA editing operates in non-small-cell lung cancers. Here, we measured the sequence and expression level of genes of antizyme inhibitor 1 and adenosine deaminase acting on RNA family in 30 non-small-cell lung cancer patient samples and 13 cell lines and revealed RNA editing S367G in antizyme inhibitor 1 is a high-frequent molecular events. We determined overexpression of antizyme inhibitor 1 with RNA editing, implying the oncogenic function of this alteration. We also detected the association of adenosine deaminase acting on RNA overexpression with RNA editing occurred in antizyme inhibitor 1 . Furthermore, the RNA editing could cause a cytoplasmic-to-nuclear translocation of antizyme inhibitor 1 protein and conferred the malignant phenotype of non-small-cell lung cancer cells. The in vivo experiment confirmed that this RNA editing confers higher capacity of tumor migration as well. In conclusion, antizyme inhibitor 1 RNA editing and its involvement in tumorigenesis of non-small-cell lung cancer pave a new way for potential clinical management of non-small-cell lung cancer.

Published
2017
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2. Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection

Author

David Adlam, Timothy M. Olson, Nicolas Combaret, Jason C. Kovacic, Siiri E. Iismaa, Abtehale Al-Hussaini, Megan M. O'Byrne, Sara Bouajila, Adrien Georges, Ketan Mishra, Peter S. Braund, Valentina d’Escamard, Siying Huang, Marios Margaritis, Christopher P. Nelson, Mariza de Andrade, Daniella Kadian-Dodov, Catherine A. Welch, Stephani Mazurkiewicz, Xavier Jeunemaitre, Claire Mei Yi Wong, Eleni Giannoulatou, Michael Sweeting, David Muller, Alice Wood, Lucy McGrath-Cadell, Diane Fatkin, Sally L. Dunwoodie, Richard Harvey, Cameron Holloway, Jean-Philippe Empana, Xavier Jouven, Jeffrey W. Olin, Rajiv Gulati, Marysia S. Tweet, Sharonne N. Hayes, Nilesh J. Samani, Robert M. Graham, Pascal Motreff, Nabila Bouatia-Naji, Loïc Belle, Patrick Dupouy, Pierre Barnay, Nicolas Meneveau, Martine Gilard, Gilles Rioufol, Grégoire Range, Philippe Brunel, Nicolas Delarche, Emmanuelle Filippi, Louis Le Bivic, Brahim Harbaoui, Hakim Benamer, Guillaume Cayla, Olivier Varenne, Stephane Peggy Manzo-Silberman, Johanne Silvain, Christian Spaulding, Christophe Caussin, Edouard Gerbaud, Yann Valy, René Koning, Thibault Lhermusier, Stanislas Champin, Emmanuel Salengro, Arnaud Fluttaz, Amer Zabalawi, Yves Cottin, Emmanuel Teiger, Christophe Saint-Etienne, Grégory Ducrocq, Stéphanie Marliere, Emmanuel Boiffard, Pierre Aubry, Jean Louis Georges, Didier Bresson, Fabien De Poli, Gaëtan Karrillon, Vincent Roule, Laurent Bali, Mathieu Valla, Antoine Gerbay, David Houpe, Olivier Dubreuil, Arsène Monnier, Norbert Mayaud, Aurélie Manchuelle, Philippe Commeau, Marc Bedossa, Majid Nikpay, Anuj Goel, Hong-Hee Won, Leanne M. Hall, Christina Willenborg, Stavroula Kanoni, Danish Saleheen, Theodosios Kyriakou, Jemma C. Hopewell, Thomas R. Webb, Lingyao Zeng, Abbas Dehghan, Maris Alver, Sebastian M. Armasu, Kirsi Auro, Andrew Bjonnes, Daniel I. Chasman, Shufeng Chen, Ian Ford, Nora Franceschini, Christian Gieger, Christopher Grace, Stefan Gustafsson, Jie Huang, Shih-Jen Hwang, Yun Kyoung Kim, Marcus E. Kleber, King Wai Lau, Xiangfeng Lu, Yingchang Lu, Leo P. Lyytikäinen, Evelin Mihailov, Alanna Morrison, Natalia Pervjakova, Liming Qu, Lynda M. Rose, Elias Salfati, Richa Saxena, Markus Scholz, Albert V. Smith, Emmi Tikkanen, Andre Uitterlinden, Xueli Yang, Weihua Zhang, Wei Zhao, Paul S. de Vries, Natalie R. van Zuydam, Sonia S. Anand, Lars Bertram, Frank Beutner, George Dedoussis, Philippe Frossard, Dominique Gauguier, Alison H. Goodall, Omri Gottesman, Marc Haber, Bok-Ghee Han, Jianfeng Huang, Shapour Jalilzadeh, Thorsten Kessler, Inke R. König, Lars Lannfelt, Wolfgang Lieb, Lars Lind, Cecilia M. Lindgren, Maisa Lokki, Patrik K. Magnusson, Nadeem H. Mallick, Narinder Mehra, Thomas Meitinger, Fazal-ur-Rehman Memon, Andrew P. Morris, Markku S. Nieminen, Nancy L. Pedersen, Annette Peters, Loukianos S. Rallidis, Asif Rasheed, Maria Samuel, Svati H. Shah, Juha Sinisalo, Kathleen E. Stirrups, Stella Trompet, Laiyuan Wang, Khan S. Zaman, Diego Ardissino, Eric Boerwinkle, Ingrid B. Borecki, Erwin P. Bottinger, Julie E. Buring, John C. Chambers, Rory Collins, L Adrienne Cupples, John Danesh, Ilja Demuth, Roberto Elosua, Stephen E. Epstein, Tõnu Esko, Mary F. Feitosa, Oscar H. Franco, Maria Grazia Franzosi, Christopher B. Granger, Dongfeng Gu, Vilmundur Gudnason, Alistair S. Hall, Anders Hamsten, Tamara B. Harris, Stanley L. Hazen, Christian Hengstenberg, Albert Hofman, Erik Ingelsson, Carlos Iribarren, J Wouter Jukema, Pekka J. Karhunen, Bong-Jo Kim, Jaspal S. Kooner, Iftikhar J. Kullo, Terho Lehtimäki, Ruth J. Loos, Olle Melander, Andres Metspalu, Winfried März, Colin N. Palmer, Markus Perola, Thomas Quertermous, Daniel J. Rader, Paul M. Ridker, Samuli Ripatti, Robert Roberts, Veikko Salomaa, Dharambir K. Sanghera, Stephen M. Schwartz, Udo Seedorf, Alexandre F. Stewart, David J. Stott, Joachim Thiery, Pierre A. Zalloua, Christopher J. O'Donnell, Muredach P. Reilly, Themistocles L. Assimes, John R. Thompson, Jeanette Erdmann, Robert Clarke, Hugh Watkins, Sekar Kathiresan, Ruth McPherson, Panos Deloukas, Heribert Schunkert, Martin Farrall, Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, Mayo Clinic [Rochester], Service de Cardiologie Maladies Vasculaires [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Victor Chang Cardiac Research Institute, University of New South Wales [Sydney] (UNSW), St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Service de génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Department of Cardiovascular Medicine, Mayo Clinic, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), and Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)

Subjects
Adult, Male, medicine.medical_specialty, Myocardial infarction, Coronary Vessel Anomalies, Fibromuscular dysplasia, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Prevalence, Fibromuscular Dysplasia, Humans, 030212 general & internal medicine, Vascular Diseases, Artery dissection, MESH: Australia, United Kingdom, USA, Coronary Vessel Anomalies / epidemiology, Endothelin-1 / genetics, Microfilament proteins / genetics, Genetic association, Aged, Endothelin-1, business.industry, Microfilament Proteins, Australia, Cardiovascular disease in women, Middle Aged, medicine.disease, R1, United States, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, Case-Control Studies, Cardiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, France, Cardiology and Cardiovascular Medicine, Scad, business
Abstract

Background: \ud Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.\ud \ud Objectives: \ud This study sought to test the association between the rs9349379 genotype and SCAD.\ud \ud Methods: \ud Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.\ud \ud Results: \ud The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.\ud \ud Conclusions: \ud The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

Published
2019

3. RNA editing of AZIN1 induces the malignant progression of non-small-cell lung cancers

Author

Fenglan Feng, Xin Xu, King Wai Lau, Xiaoshun Shi, Yusong Chen, Long Jiang, Yalei Zhang, Jin Li, Xueda Hu, Fei Cui, Yaoqi Chen, and Jingyi Chen

Subjects
0301 basic medicine, Adult, Male, Carcinogenesis, Biology, medicine.disease_cause, 03 medical and health sciences, Carcinoma, Non-Small-Cell Lung, medicine, Humans, Gene, RC254-282, Antizyme inhibitor 1, Aged, Cell Proliferation, RNA, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, General Medicine, Middle Aged, Non-coding RNA, Molecular biology, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, RNA silencing, 030104 developmental biology, RNA editing, Cancer research, biology.protein, Disease Progression, Female, RNA Editing, Carrier Proteins, Small nuclear RNA
Abstract

RNA editing is a widespread post-transcriptional mechanism that confers specific and reproducible nucleotide changes in selected RNA transcripts and plays a critical role in many human cancers. However, little is known about how RNA editing operates in non-small-cell lung cancers. Here, we measured the sequence and expression level of genes of antizyme inhibitor 1 and adenosine deaminase acting on RNA family in 30 non-small-cell lung cancer patient samples and 13 cell lines and revealed RNA editing S367G in antizyme inhibitor 1 is a high-frequent molecular events. We determined overexpression of antizyme inhibitor 1 with RNA editing, implying the oncogenic function of this alteration. We also detected the association of adenosine deaminase acting on RNA overexpression with RNA editing occurred in antizyme inhibitor 1. Furthermore, the RNA editing could cause a cytoplasmic-to-nuclear translocation of antizyme inhibitor 1 protein and conferred the malignant phenotype of non-small-cell lung cancer cells. The in vivo experiment confirmed that this RNA editing confers higher capacity of tumor migration as well. In conclusion, antizyme inhibitor 1 RNA editing and its involvement in tumorigenesis of non-small-cell lung cancer pave a new way for potential clinical management of non-small-cell lung cancer.

Published
2017

4. No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis

Author

Pierre Zalloua, King Wai Lau, Andrew Bjonnes, Marcus E. Kleber, Christina Willenborg, Veikko Salomaa, Elias Salfati, Robert Clarke, Sonia S. Anand, Yingchang Lu, Anders Hamsten, Pekka J. Karhunen, Theodosios Kyriakou, Frank Beutner, Alexandre F.R. Stewart, George Dedoussis, Patrik K. E. Magnusson, John C. Chambers, Christopher P. Nelson, Stavroula Kanoni, Svati H. Shah, Lars Lind, Ruth J. F. Loos, Carlos Iribarren, Reijo Laaksonen, Nilesh J. Samani, Inke R. König, Dominique Gauguier, Christina Loley, Tõnu Esko, Mika Kähönen, Jeanette Erdmann, Panos Deloukas, Loukianos S. Rallidis, John R. Thompson, Vilmantas Giedraitis, Martin Farrall, Stanley A Hazen, Dharambir K. Sanghera, Erik Ingelsson, Eirini Marouli, S. Ripatti, Kjell Nikus, Taru Tukiainen, Maris Alver, Joachim Thiery, Nancy L. Pedersen, Anuj Goel, Jemma C. Hopewell, Themistocles L. Assimes, Winfried März, Stefan Gustafsson, Markku Eskola, Lingyao Zeng, Weihua Zhang, Hong-Hee Won, Jussi Hernesniemi, Majid Nikpay, Ruth McPherson, Leo-Pekka Lyytikäinen, Liming Qu, Andres Metspalu, Muredach P. Reilly, Hugh Watkins, Erwin P. Bottinger, Evelin Mihailov, Terho Lehtimäki, Sekar Kathiresan, Ron Do, Heribert Schunkert, Alistair S. Hall, Rory Collins, Markus Scholz, Jie Huang, Andrew P. Morris, Cecilia M. Lindgren, Jaspal S. Kooner, Christopher B. Granger, Clinicum, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, Department of Public Health, Biostatistics Helsinki, and Complex Disease Genetics

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Internationality, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biology, Logistic regression, Bioinformatics, GENOTYPE IMPUTATION, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, GENOME-WIDE ASSOCIATION, X chromosome, Genetic association, Medicinsk genetik, Genetics, Chromosomes, Human, X, Science & Technology, Multidisciplinary, Autosome, Random effects model, Multidisciplinary Sciences, 030104 developmental biology, Meta-analysis, Science & Technology - Other Topics, Medical genetics, Female, INACTIVATION, SEX, 3111 Biomedicine, Medical Genetics
Abstract

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

Published
2016

5. Systematic identification of genomic markers of drug sensitivity in cancer cells

Author

Xeni Mitropoulos, Jae Won Chang, Daniel A. Haber, Jeffrey Settleman, Wanjuan Yang, I. Richard Thompson, Julio Saez-Rodriguez, Nathanael S. Gray, Olivier Delattre, Jeffrey A. Engelman, Qingsong Liu, Sonja J. Heidorn, José Baselga, Michael R. Stratton, Karl P. Lawrence, Helen Davies, Stephen R. Lutz, Li Chen, Helen Thi, Graham R. Bignell, Randy J. Milano, Anne McLaren-Douglas, Anahita Dastur, Sridhar Ramaswamy, Sreenath V. Sharma, Jesse A. Stevenson, Patricia Greninger, Jessica L. Boisvert, King Wai Lau, Xi Luo, Tatiana Mironenko, Xianming Deng, Christopher Greenman, Fiona Kogera, P. Andrew Futreal, Tinghu Zhang, Patrick O’Brien, Syd Barthorpe, F Jewitt, Ultan McDermott, Hwan Geun Choi, Mathew J. Garnett, Ivan Stamenkovic, Francesco Iorio, Wooyoung Hur, Stacey Price, Jorge Soares, Laura Richardson, Wenjun Zhou, Cyril H. Benes, Ah Ting Tam, Adam Butler, Elena J. Edelman, and Didier Surdez

Subjects
Genetic Markers, Indoles, Oncogene Proteins, Fusion, Cell Survival, Sarcoma, Ewing, Poly(ADP-ribose) Polymerase Inhibitors, Biology, Bioinformatics, Poly (ADP-Ribose) Polymerase Inhibitor, Piperazines, Article, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Neoplasms, Humans, Biomarker discovery, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Genome, Human, Proto-Oncogene Protein c-fli-1, Genomics, Oncogene Addiction, Human genetics, 3. Good health, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Pharmacogenetics, 030220 oncology & carcinogenesis, Pharmacogenomics, Cancer cell, Cancer research, Phthalazines, Human genome, Drug Screening Assays, Antitumor, RNA-Binding Protein EWS, Genes, Neoplasm
Abstract

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.

Published
2012

6. The Life History of 21 Breast Cancers

Author

Richard Rance, Sancha Martin, Michael R. Stratton, Anita Langerød, Stuart McLaren, Lucy Stebbings, Samuel Aparicio, Serena Nik-Zainal, Kenric Leung, Göran Jönsson, Elli Papaemmanuil, David J. McBride, King Wai Lau, Christopher Greenman, Catherine Leroy, Adam Butler, Odette Mariani, Anieta M. Sieuwerts, Jon W. Teague, Susanna L. Cooke, Peter Van Loo, Patrick S. Tarpey, Gilles Thomas, Peter J. Campbell, Andrew Tutt, Anne Vincent Salomon, Keiran Raine, Laura Mudie, Sandrine Boyault, Manasa Ramakrishna, Helen Davies, Ignacio Varela, Andrea L. Richardson, Adam Shlien, Anne Lise Børresen-Dale, Åke Borg, Mingming Jia, John L. Marshall, Philip J. Stephens, Aquila Fatima, Penelope Miron, Ludmil B. Alexandrov, Stephen J. Gamble, Andrew Menzies, David T. Jones, P. Andrew Futreal, Jonathan Hinton, David C. Wedge, and Graham R. Bignell

Subjects
Oncology, medicine.medical_specialty, Lineage (genetic), Cell, Breast Neoplasms, Biology, medicine.disease_cause, Somatic evolution in cancer, General Biochemistry, Genetics and Molecular Biology, Article, Metastasis, Clonal Evolution, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, Humans, Point Mutation, Life history, 030304 developmental biology, Genetics, Chromosome Aberrations, 0303 health sciences, Mutation, Biochemistry, Genetics and Molecular Biology(all), Point mutation, Cancer, medicine.disease, 3. Good health, medicine.anatomical_structure, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Kataegis, Female, Algorithms
Abstract

Summary Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis. PaperClip, Graphical Abstract Highlights ► Genome-wide analyses of mutations emerging through time in 21 breast cancers ► Minimal expansion of subclones occurs until thousands of mutations have accumulated ► Cancer-specific signatures of point mutations and genomic instability emerge late ► ERBB2 amplification begins early but continues to evolve over long molecular time, Newly developed algorithms allow the reconstruction of the genomic history of different breast cancers, tracing the temporal evolution of each tumor and the emergence of the dominant subclones that will eventually trigger diagnosis.

Published
2012

7. A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Author

Emmi Tikkanen, Elias Salfati, Majid Nikpay, Sonia S. Anand, Heribert Schunkert, Thomas Quertermous, George Dedoussis, Abbas Dehghan, Evelin Mihailov, Danish Saleheen, Lars Lannfelt, M. De Andrade, Daniel I. Chasman, Stanley L. Hazen, Vilmundur Gudnason, Christopher Grace, Christina Willenborg, Xueli Yang, Paul M. Ridker, Panos Deloukas, Hwang S-J., Eric Boerwinkle, Sekar Kathiresan, Lars Bertram, Kim B-J., Yun Kyoung Kim, Lokki M-L., Philippe M. Frossard, Adil Rasheed, Marc Haber, Alistair S. Hall, Kathleen Stirrups, Daniel J. Rader, Christopher B. Granger, Ingrid B. Borecki, Weihua Zhang, Thomas Meitinger, Liming Qu, Maris Alver, Wei Zhao, Samuli Ripatti, Andres Metspalu, Diego Ardissino, Memon F-U-R., Themistocles L. Assimes, Sebastian M. Armasu, Won H-H., L. A. Cupples, Tõnu Esko, Stephen M. Schwartz, Dongfeng Gu, Alanna C. Morrison, Han B-G., Nancy L. Pedersen, Tom R. Webb, Joachim Thiery, Marcus E. Kleber, Ligui Wang, J W Jukema, Thorsten Kessler, Xiangfeng Lu, Frank Beutner, Alison H. Goodall, Loukianos S. Rallidis, Natalia Pervjakova, Loos Rjf., Stavroula Kanoni, Leanne M. Hall, Patrik K. E. Magnusson, John C. Chambers, Christian Hengstenberg, Svati H. Shah, Olle Melander, Richa Saxena, Markus Perola, Alexandre F.R. Stewart, Jeanette Erdmann, Nadeem Hayyat Mallick, N. R. van Zuydam, Omri Gottesman, Jemma C. Hopewell, Hugh Watkins, John R. Thompson, Carlos Iribarren, Anders Hamsten, Rory Collins, Theodosios Kyriakou, Markus Scholz, Dharambir K. Sanghera, Jie Huang, Julie E. Buring, Christopher J. O'Donnell, Anuj Goel, Lynda M. Rose, Martin Farrall, Albert V. Smith, Lyytikäinen L-P., Winfried März, Muredach P. Reilly, Mary F. Feitosa, Andrew Bjonnes, Stella Trompet, John Danesh, Robert Roberts, Stefan Gustafsson, Christian Gieger, Ian Ford, Lingyao Zeng, Lars Lind, David J. Stott, Erik Ingelsson, Colin N. A. Palmer, Markku S. Nieminen, M Samuel, Annette Peters, Kirsi Auro, Dominique Gauguier, Narinder K. Mehra, Khan Shah Zaman, P. De Vries, Nilesh J. Samani, Inke R. König, Juha Sinisalo, Ilja Demuth, Pekka J. Karhunen, Wolfgang Lieb, Andrew P. Morris, Nora Franceschini, Veikko Salomaa, Robert Clarke, Erwin P. Bottinger, Roberto Elosua, Yingchang Lu, André G. Uitterlinden, Shapour Jalilzadeh, Cecilia M. Lindgren, Shufeng Chen, Terho Lehtimäki, Jaspal S. Kooner, Tamara B. Harris, Stephen E. Epstein, Udo Seedorf, Oscar H. Franco, Pierre Zalloua, King Wai Lau, Iftikhar J. Kullo, Albert Hofman, Christopher P. Nelson, MariaGrazia Franzosi, Ruth McPherson, Epidemiology, Hematology, Internal Medicine, Ophthalmology, and CARDIoGRAMplusC4D Consortium

Subjects
EXPRESSION, Genome-wide association study, Single-nucleotide polymorphism, HEART-DISEASE, Coronary Artery Disease, Biology, CELL-MIGRATION, MICE LACKING, Article, GENETIC-VARIANTS, Genetics, Genetic predisposition, CARDIoGRAMplusC4D Consortium, Humans, 1000 Genomes Project, SUSCEPTIBILITY LOCUS, IDENTIFIES 13, Genetics & Heredity, RISK, Science & Technology, Genome, Human, Haplotype, 11 Medical And Health Sciences, 06 Biological Sciences, Genetic architecture, 3. Good health, Minor allele frequency, Phenotype, MYOCARDIAL-INFARCTION, CARDIOVASCULAR-DISEASE, Allelic heterogeneity, Life Sciences & Biomedicine, Genome-Wide Association Study, Developmental Biology
Abstract

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

Published
2015

8. Mutational processes molding the genomes of 21 breast cancers

Author

Andrea L. Richardson, John D Marshall, Adam Shlien, Philip J. Stephens, Anne Lise Børresen-Dale, Judy Garber, Andrew Tutt, Adam Butler, Laura Mudie, John Gamble, Jon W. Teague, Aquila Fatima, Åke Borg, Manasa Ramakrishna, Peter J. Campbell, Elli Papaemmanuil, Peter Van Loo, Michael S. Neuberger, Susanna L. Cooke, Ignacio Varela, Mark Maddison, Sancha Martin, Keiran Raine, Graham R. Bignell, Göran Jönsson, Kenric Leung, Helen Davies, Daniel P. Silver, Richard Rance, David T. Jones, John W.M. Martens, Gilles Thomas, Stuart McLaren, Lina Chen, David J. McBride, Penelope Miron, King Wai Lau, Christopher Greenman, David C. Wedge, Ian Whitmore, Sandrine Boyault, P. Andrew Futreal, Samuel Aparicio, Jonathan Hinton, Catherine Leroy, Anne Vincent Salomon, Lucy Stebbings, Michael R. Stratton, Anita Langerød, Patrick S. Tarpey, Serena Nik-Zainal, Ludmil B. Alexandrov, Andrew Menzies, Cardiology, Medical Oncology, and Radiotherapy

Subjects
APOBEC, Genetics, 0303 health sciences, Biochemistry, Genetics and Molecular Biology(all), Point mutation, Somatic hypermutation, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, SDG 3 - Good Health and Well-being, 030220 oncology & carcinogenesis, Kataegis, DNA Mutational Analysis, APOBEC Deaminases, APOBEC3A, 030304 developmental biology
Abstract

SummaryAll cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed “kataegis,” was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.PaperClip

Published
2012

9. Massive genomic rearrangement acquired in a single catastrophic event during cancer development

Author

Michael R. Stratton, David J. McBride, Stuart McLaren, Catherine Leroy, Laura Morsberger, Graham R. Bignell, David Beare, Peter J. Campbell, King Wai Lau, Christopher Greenman, Philip J. Stephens, Christine A. Iacobuzio-Donahue, Mingming Jia, Erin Pleasance, Adam Butler, Beiyuan Fu, Lucy Stebbings, Jon W. Teague, George A. Follows, Harold Swerdlow, Andrew Menzies, Meng-Lay Lin, Michael A. Quail, Nigel P. Carter, Fengtang Yang, Adrienne M. Flanagan, Serena Nik-Zainal, Anthony R. Green, John Burton, P. Andrew Futreal, Ignacio Varela, and Laura Mudie

Subjects
medicine.medical_specialty, education, Bone Neoplasms, Genomics, Biology, General Biochemistry, Genetics and Molecular Biology, Chromosome Painting, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Neoplasms, medicine, Humans, health care economics and organizations, 030304 developmental biology, Sequence (medicine), Chromosome Aberrations, Gene Rearrangement, Genetics, 0303 health sciences, Chromothripsis, Biochemistry, Genetics and Molecular Biology(all), Point mutation, Cancer, Gene rearrangement, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, 030220 oncology & carcinogenesis, Kataegis, Medical genetics, Female
Abstract

Cancer is driven by somatically acquired point mutations and chromosomal rearrangements, conventionally thought to accumulate gradually over time. Using next-generation sequencing, we characterize a phenomenon, which we term chromothripsis, whereby tens to hundreds of genomic rearrangements occur in a one-off cellular crisis. Rearrangements involving one or a few chromosomes crisscross back and forth across involved regions, generating frequent oscillations between two copy number states. These genomic hallmarks are highly improbable if rearrangements accumulate over time and instead imply that nearly all occur during a single cellular catastrophe. The stamp of chromothripsis can be seen in at least 2%¿3% of all cancers, across many subtypes, and is present in ~25% of bone cancers. We find that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis. This phenomenon has important implications for the origins of genomic remodeling and temporal emergence of cancer., This work was supported by the Wellcome Trust (grant reference 077012/Z/ 05/Z) and the Chordoma Foundation. P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship (grant reference WT088340MA). I.V. is supported by a fellowship from The International Human Frontier Science Program Organization.

Published
2011

10. RNA editing of AZIN 1 induces the malignant progression of non-small-cell lung cancers.

Author

Xueda Hu, Jingyi Chen, Xiaoshun Shi, Fenglan Feng, King Wai Lau, Yaoqi Chen, Yusong Chen, Long Jiang, Fei Cui, Yalei Zhang, Xin Xu, and Jin Li

Subjects
NON-small-cell lung carcinoma, ADENOSINE deaminase, CANCER patients, RNA editing, NEOPLASTIC cell transformation
Abstract

RNA editing is a widespread post-transcriptional mechanism that confers specific and reproducible nucleotide changes in selected RNA transcripts and plays a critical role in many human cancers. However, little is known about how RNA editing operates in non-small-cell lung cancers. Here, we measured the sequence and expression level of genes of antizyme inhibitor 1 and adenosine deaminase acting on RNA family in 30 non-small-cell lung cancer patient samples and 13 cell lines and revealed RNA editing S367G in antizyme inhibitor 1 is a high-frequent molecular events. We determined overexpression of antizyme inhibitor 1 with RNA editing, implying the oncogenic function of this alteration. We also detected the association of adenosine deaminase acting on RNA overexpression with RNA editing occurred in antizyme inhibitor 1. Furthermore, the RNA editing could cause a cytoplasmic-to-nuclear translocation of antizyme inhibitor 1 protein and conferred the malignant phenotype of non-small-cell lung cancer cells. The in vivo experiment confirmed that this RNA editing confers higher capacity of tumor migration as well. In conclusion, antizyme inhibitor 1 RNA editing and its involvement in tumorigenesis of non-small-cell lung cancer pave a new way for potential clinical management of non-small-cell lung cancer. [ABSTRACT FROM AUTHOR]

Published
2017
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11. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma.

Author

Varela, Ignacio, Tarpey, Patrick, Raine, Keiran, Huang, Dachuan, Ong, Choon Kiat, Stephens, Philip, Davies, Helen, Jones, David, Meng-Lay Lin, Teague, Jon, Bignell, Graham, Butler, Adam, Cho, Juok, Dalgliesh, Gillian L., Galappaththige, Danushka, Greenman, Chris, Hardy, Claire, Mingming Jia, Latimer, Calli, and King Wai Lau

Subjects
RENAL cell carcinoma, TUMOR suppressor genes, SUPPRESSOR cells, CANCER genes, POLYMERASE chain reaction, LYSINE, SOMATIC cells, METHYLATION
Abstract

The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology. [ABSTRACT FROM AUTHOR]

Published
2011
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12. Complex landscapes of somatic rearrangement in human breast cancer genomes.

Author

Stephens, Philip J., McBride, David J., Meng-Lay Lin, Varela, Ignacio, Pleasance, Erin D., Simpson, Jared T., Stebbings, Lucy A., Leroy, Catherine, Edkins, Sarah, Mudie, Laura J., Greenman, Chris D., Mingming Jia, Latimer, Calli, Teague, Jon W., King Wai Lau, Burton, John, Quail, Michael A., Swerdlow, Harold, Churcher, Carol, and Natrajan, Rachael

Subjects
GENOMES, GENOMICS, GENES, CANCER genes, CANCER genetics, GENETICS, DNA repair, HEREDITY, DNA
Abstract

Multiple somatic rearrangements are often found in cancer genomes; however, the underlying processes of rearrangement and their contribution to cancer development are poorly characterized. Here we use a paired-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. There are more rearrangements in some breast cancers than previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicate that these have been mediated by non-homologous end-joining DNA repair, although varying sequence patterns indicate that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. The study provides a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development. [ABSTRACT FROM AUTHOR]

Published
2009
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13. Estimation of rearrangement phylogeny for cancer genomes.

Author

Greenman, Chris D., Pleasance, Erin D., Newman, Scott, Fengtang Yang, Beiyuan Fu, Nik-Zainal, Serena, Jones, David, King Wai Lau, Carter, Nigel, Edwards, Paul A.W., Futreal, P. Andrew, Stratton, Michael R., and Campbell, Peter J.

Subjects
*CANCER, *GENOMES, *GENES, *SOMATIC cells, *CATALOGS
Abstract

Cancer genomes are complex, carrying thousands of somatic mutations including base substitutions, insertions and deletions, rearrangements, and copy number changes that have been acquired over decades. Recently, technologies have been introduced that allow generation of high-resolution, comprehensive catalogs of somatic alterations in cancer genomes. However, analyses of these data sets generally do not indicate the order in which mutations have occurred, or the resulting karyotype. Here, we introduce a mathematical framework that begins to address this problem. By using samples with accurate data sets, we can reconstruct relatively complex temporal sequences of rearrangements and provide an assembly of genomic segments into digital karyotypes. For cancer genes mutated in rearranged regions, this information can provide a chronological examination of the selective events that have taken place. [ABSTRACT FROM AUTHOR]

Published
2012
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