ALBERT

Description: The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF 〈/= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755714/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755714/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Hou-Feng -- Forgetta, Vincenzo -- Hsu, Yi-Hsiang -- Estrada, Karol -- Rosello-Diez, Alberto -- Leo, Paul J -- Dahia, Chitra L -- Park-Min, Kyung Hyun -- Tobias, Jonathan H -- Kooperberg, Charles -- Kleinman, Aaron -- Styrkarsdottir, Unnur -- Liu, Ching-Ti -- Uggla, Charlotta -- Evans, Daniel S -- Nielson, Carrie M -- Walter, Klaudia -- Pettersson-Kymmer, Ulrika -- McCarthy, Shane -- Eriksson, Joel -- Kwan, Tony -- Jhamai, Mila -- Trajanoska, Katerina -- Memari, Yasin -- Min, Josine -- Huang, Jie -- Danecek, Petr -- Wilmot, Beth -- Li, Rui -- Chou, Wen-Chi -- Mokry, Lauren E -- Moayyeri, Alireza -- Claussnitzer, Melina -- Cheng, Chia-Ho -- Cheung, Warren -- Medina-Gomez, Carolina -- Ge, Bing -- Chen, Shu-Huang -- Choi, Kwangbom -- Oei, Ling -- Fraser, James -- Kraaij, Robert -- Hibbs, Matthew A -- Gregson, Celia L -- Paquette, Denis -- Hofman, Albert -- Wibom, Carl -- Tranah, Gregory J -- Marshall, Mhairi -- Gardiner, Brooke B -- Cremin, Katie -- Auer, Paul -- Hsu, Li -- Ring, Sue -- Tung, Joyce Y -- Thorleifsson, Gudmar -- Enneman, Anke W -- van Schoor, Natasja M -- de Groot, Lisette C P G M -- van der Velde, Nathalie -- Melin, Beatrice -- Kemp, John P -- Christiansen, Claus -- Sayers, Adrian -- Zhou, Yanhua -- Calderari, Sophie -- van Rooij, Jeroen -- Carlson, Chris -- Peters, Ulrike -- Berlivet, Soizik -- Dostie, Josee -- Uitterlinden, Andre G -- Williams, Stephen R -- Farber, Charles -- Grinberg, Daniel -- LaCroix, Andrea Z -- Haessler, Jeff -- Chasman, Daniel I -- Giulianini, Franco -- Rose, Lynda M -- Ridker, Paul M -- Eisman, John A -- Nguyen, Tuan V -- Center, Jacqueline R -- Nogues, Xavier -- Garcia-Giralt, Natalia -- Launer, Lenore L -- Gudnason, Vilmunder -- Mellstrom, Dan -- Vandenput, Liesbeth -- Amin, Najaf -- van Duijn, Cornelia M -- Karlsson, Magnus K -- Ljunggren, Osten -- Svensson, Olle -- Hallmans, Goran -- Rousseau, Francois -- Giroux, Sylvie -- Bussiere, Johanne -- Arp, Pascal P -- Koromani, Fjorda -- Prince, Richard L -- Lewis, Joshua R -- Langdahl, Bente L -- Hermann, A Pernille -- Jensen, Jens-Erik B -- Kaptoge, Stephen -- Khaw, Kay-Tee -- Reeve, Jonathan -- Formosa, Melissa M -- Xuereb-Anastasi, Angela -- Akesson, Kristina -- McGuigan, Fiona E -- Garg, Gaurav -- Olmos, Jose M -- Zarrabeitia, Maria T -- Riancho, Jose A -- Ralston, Stuart H -- Alonso, Nerea -- Jiang, Xi -- Goltzman, David -- Pastinen, Tomi -- Grundberg, Elin -- Gauguier, Dominique -- Orwoll, Eric S -- Karasik, David -- Davey-Smith, George -- AOGC Consortium -- Smith, Albert V -- Siggeirsdottir, Kristin -- Harris, Tamara B -- Zillikens, M Carola -- van Meurs, Joyce B J -- Thorsteinsdottir, Unnur -- Maurano, Matthew T -- Timpson, Nicholas J -- Soranzo, Nicole -- Durbin, Richard -- Wilson, Scott G -- Ntzani, Evangelia E -- Brown, Matthew A -- Stefansson, Kari -- Hinds, David A -- Spector, Tim -- Cupples, L Adrienne -- Ohlsson, Claes -- Greenwood, Celia M T -- UK10K Consortium -- Jackson, Rebecca D -- Rowe, David W -- Loomis, Cynthia A -- Evans, David M -- Ackert-Bicknell, Cheryl L -- Joyner, Alexandra L -- Duncan, Emma L -- Kiel, Douglas P -- Rivadeneira, Fernando -- Richards, J Brent -- G1000143/Medical Research Council/United Kingdom -- K01 AR062655/AR/NIAMS NIH HHS/ -- MC_UU_12013/3/Medical Research Council/United Kingdom -- R01 AG005394/AG/NIA NIH HHS/ -- R01 AG005407/AG/NIA NIH HHS/ -- R01 AG027574/AG/NIA NIH HHS/ -- R01 AG027576/AG/NIA NIH HHS/ -- R01 AR035582/AR/NIAMS NIH HHS/ -- R01 AR035583/AR/NIAMS NIH HHS/ -- RC2 AR058973/AR/NIAMS NIH HHS/ -- U01 AG018197/AG/NIA NIH HHS/ -- U01 AG042140/AG/NIA NIH HHS/ -- U01 AG042143/AG/NIA NIH HHS/ -- U01 AR045580/AR/NIAMS NIH HHS/ -- U01 AR045583/AR/NIAMS NIH HHS/ -- U01 AR045614/AR/NIAMS NIH HHS/ -- U01 AR045632/AR/NIAMS NIH HHS/ -- U01 AR045647/AR/NIAMS NIH HHS/ -- U01 AR045654/AR/NIAMS NIH HHS/ -- U01 AR066160/AR/NIAMS NIH HHS/ -- England -- Nature. 2015 Oct 1;526(7571):112-7. doi: 10.1038/nature14878. Epub 2015 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal H3A 1A2, Canada. ; Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal H3T 1E2, Canada. ; Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA. ; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA. ; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, USA. ; The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia. ; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA. ; Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York 10021, USA. ; Rheumatology Divison, Hospital for Special Surgery New York, New York 10021, USA. ; School of Clinical Science, University of Bristol, Bristol BS10 5NB, UK. ; MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK. ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Department of Research, 23andMe, Mountain View, California 94041, USA. ; Department of Population Genomics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. ; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; California Pacific Medical Center Research Institute, San Francisco, California 94158, USA. ; Department of Public Health and Preventive Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Bone &Mineral Unit, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK. ; Departments of Pharmacology and Clinical Neurosciences, Umea University, Umea S-901 87, Sweden. ; Department of Public Health and Clinical Medicine, Umea University, Umea SE-901 87, Sweden. ; Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; McGill University and Genome Quebec Innovation Centre, Montreal H3A 0G1, Canada. ; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Oregon Clinical and Translational Research Institute, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Department of Medical and Clinical Informatics, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK. ; Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. ; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA. ; Department of Human Genetics, McGill University, Montreal H3A 1B1, Canada. ; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands. ; Center for Musculoskeletal Research, University of Rochester, Rochester, New York 14642, USA. ; Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal H3G 1Y6, Canada. ; Department of Computer Science, Trinity University, San Antonio, Texas 78212, USA. ; Musculoskeletal Research Unit, University of Bristol, Bristol BS10 5NB, UK. ; Department of Radiation Sciences, Umea University, Umea S-901 87, Sweden. ; School of Public Health, University of Wisconsin, Milwaukee, Wisconsin 53726, USA. ; School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK. ; Department of Statistics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam 1007 MB, The Netherlands. ; Department of Human Nutrition, Wageningen University, Wageningen 6700 EV, The Netherlands. ; Department of Internal Medicine, Section Geriatrics, Academic Medical Center, Amsterdam 1105, The Netherlands. ; Nordic Bioscience, Herlev 2730, Denmark. ; Cordeliers Research Centre, INSERM UMRS 1138, Paris 75006, France. ; Institute of Cardiometabolism and Nutrition, University Pierre &Marie Curie, Paris 75013, France. ; Departments of Medicine (Cardiovascular Medicine), Centre for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA. ; Department of Genetics, University of Barcelona, Barcelona 08028, Spain. ; U-720, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona 28029, Spain. ; Department of Human Molecular Genetics, The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain. ; Women's Health Center of Excellence Family Medicine and Public Health, University of California - San Diego, San Diego, California 92093, USA. ; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. ; Osteoporosis &Bone Biology Program, Garvan Institute of Medical Research, Sydney 2010, Australia. ; School of Medicine Sydney, University of Notre Dame Australia, Sydney 6959, Australia. ; St. Vincent's Hospital &Clinical School, NSW University, Sydney 2010, Australia. ; Musculoskeletal Research Group, Institut Hospital del Mar d'Investigacions Mediques, Barcelona 08003, Spain. ; Cooperative Research Network on Aging and Fragility (RETICEF), Institute of Health Carlos III, 28029, Spain. ; Department of Internal Medicine, Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona 08193, Spain. ; Neuroepidemiology Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Icelandic Heart Association, Kopavogur IS-201, Iceland. ; Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland. ; Genetic epidemiology unit, Department of Epidemiology, Erasmus MC, Rotterdam 3000CA, The Netherlands. ; Department of Orthopaedics, Skane University Hospital Malmo 205 02, Sweden. ; Department of Medical Sciences, University of Uppsala, Uppsala 751 85, Sweden. ; Department of Surgical and Perioperative Sciences, Umea Unviersity, Umea 901 85, Sweden. ; Department of Molecular Biology, Medical Biochemistry and Pathology, Universite Laval, Quebec City G1V 0A6, Canada. ; Axe Sante des Populations et Pratiques Optimales en Sante, Centre de recherche du CHU de Quebec, Quebec City G1V 4G2, Canada. ; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Australia. ; Department of Medicine, University of Western Australia, Perth 6009, Australia. ; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C 8000, Denmark. ; Department of Endocrinology, Odense University Hospital, Odense C 5000, Denmark. ; Department of Endocrinology, Hvidovre University Hospital, Hvidovre 2650, Denmark. ; Clinical Gerontology Unit, University of Cambridge, Cambridge CB2 2QQ, UK. ; Medicine and Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. ; Institute of Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK. ; Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida MSD 2080, Malta. ; Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmo, Lund University, 205 02, Sweden. ; Department of Medicine and Psychiatry, University of Cantabria, Santander 39011, Spain. ; Department of Internal Medicine, Hospital U.M. Valdecilla- IDIVAL, Santander 39008, Spain. ; Department of Legal Medicine, University of Cantabria, Santander 39011, Spain. ; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK. ; Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA. ; Department of Medicine and Physiology, McGill University, Montreal H4A 3J1, Canada. ; Department of Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13010, Israel. ; Laboratory of Epidemiology, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ; School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia. ; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece. ; Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, Rhode Island 02903, USA. ; deCODE Genetics, Reykjavik IS-101, Iceland. ; Framingham Heart Study, Framingham, Massachusetts 01702, USA. ; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal H3A 1A2, Canada. ; Department of Oncology, Gerald Bronfman Centre, McGill University, Montreal H2W 1S6, Canada. ; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210, USA. ; The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA. ; Department of Diabetes and Endocrinology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26367794" target="_blank"〉PubMed〈/a〉

Description: Defects in the availability of haem substrates or the catalytic activity of the terminal enzyme in haem biosynthesis, ferrochelatase (Fech), impair haem synthesis and thus cause human congenital anaemias. The interdependent functions of regulators of mitochondrial homeostasis and enzymes responsible for haem synthesis are largely unknown. To investigate this we used zebrafish genetic screens and cloned mitochondrial ATPase inhibitory factor 1 (atpif1) from a zebrafish mutant with profound anaemia, pinotage (pnt (tq209)). Here we describe a direct mechanism establishing that Atpif1 regulates the catalytic efficiency of vertebrate Fech to synthesize haem. The loss of Atpif1 impairs haemoglobin synthesis in zebrafish, mouse and human haematopoietic models as a consequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, redox potential, [2Fe-2S] clusters and Fech activity, we used genetic complementation studies of Fech constructs with or without [2Fe-2S] clusters in pnt, as well as pharmacological agents modulating mitochondrial pH and redox potential. The presence of [2Fe-2S] cluster renders vertebrate Fech vulnerable to perturbations in Atpif1-regulated mitochondrial pH and redox potential. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize haem, resulting in anaemia. The identification of mitochondrial Atpif1 as a regulator of haem synthesis advances our understanding of the mechanisms regulating mitochondrial haem homeostasis and red blood cell development. An ATPIF1 deficiency may contribute to important human diseases, such as congenital sideroblastic anaemias and mitochondriopathies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504625/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504625/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shah, Dhvanit I -- Takahashi-Makise, Naoko -- Cooney, Jeffrey D -- Li, Liangtao -- Schultz, Iman J -- Pierce, Eric L -- Narla, Anupama -- Seguin, Alexandra -- Hattangadi, Shilpa M -- Medlock, Amy E -- Langer, Nathaniel B -- Dailey, Tamara A -- Hurst, Slater N -- Faccenda, Danilo -- Wiwczar, Jessica M -- Heggers, Spencer K -- Vogin, Guillaume -- Chen, Wen -- Chen, Caiyong -- Campagna, Dean R -- Brugnara, Carlo -- Zhou, Yi -- Ebert, Benjamin L -- Danial, Nika N -- Fleming, Mark D -- Ward, Diane M -- Campanella, Michelangelo -- Dailey, Harry A -- Kaplan, Jerry -- Paw, Barry H -- K01 DK085217/DK/NIDDK NIH HHS/ -- P01 HL032262/HL/NHLBI NIH HHS/ -- P30 DK072437/DK/NIDDK NIH HHS/ -- R01 DK052380/DK/NIDDK NIH HHS/ -- R01 DK070838/DK/NIDDK NIH HHS/ -- R01 DK096051/DK/NIDDK NIH HHS/ -- R01 HL082945/HL/NHLBI NIH HHS/ -- T32 GM007223/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 22;491(7425):608-12. doi: 10.1038/nature11536. Epub 2012 Nov 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23135403" target="_blank"〉PubMed〈/a〉

Description: 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 approximately 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030920/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030920/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Varela, Ignacio -- Tarpey, Patrick -- Raine, Keiran -- Huang, Dachuan -- Ong, Choon Kiat -- Stephens, Philip -- Davies, Helen -- Jones, David -- Lin, Meng-Lay -- Teague, Jon -- Bignell, Graham -- Butler, Adam -- Cho, Juok -- Dalgliesh, Gillian L -- Galappaththige, Danushka -- Greenman, Chris -- Hardy, Claire -- Jia, Mingming -- Latimer, Calli -- Lau, King Wai -- Marshall, John -- McLaren, Stuart -- Menzies, Andrew -- Mudie, Laura -- Stebbings, Lucy -- Largaespada, David A -- Wessels, L F A -- Richard, Stephane -- Kahnoski, Richard J -- Anema, John -- Tuveson, David A -- Perez-Mancera, Pedro A -- Mustonen, Ville -- Fischer, Andrej -- Adams, David J -- Rust, Alistair -- Chan-on, Waraporn -- Subimerb, Chutima -- Dykema, Karl -- Furge, Kyle -- Campbell, Peter J -- Teh, Bin Tean -- Stratton, Michael R -- Futreal, P Andrew -- 077012/Wellcome Trust/United Kingdom -- 077012/Z/05/Z/Wellcome Trust/United Kingdom -- 088340/Wellcome Trust/United Kingdom -- 093867/Wellcome Trust/United Kingdom -- R01 CA113636/CA/NCI NIH HHS/ -- R01 CA134759/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Jan 27;469(7331):539-42. doi: 10.1038/nature09639. Epub 2011 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21248752" target="_blank"〉PubMed〈/a〉

Description: Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376394/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376394/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perez-Mancera, Pedro A -- Rust, Alistair G -- van der Weyden, Louise -- Kristiansen, Glen -- Li, Allen -- Sarver, Aaron L -- Silverstein, Kevin A T -- Grutzmann, Robert -- Aust, Daniela -- Rummele, Petra -- Knosel, Thomas -- Herd, Colin -- Stemple, Derek L -- Kettleborough, Ross -- Brosnan, Jacqueline A -- Li, Ang -- Morgan, Richard -- Knight, Spencer -- Yu, Jun -- Stegeman, Shane -- Collier, Lara S -- ten Hoeve, Jelle J -- de Ridder, Jeroen -- Klein, Alison P -- Goggins, Michael -- Hruban, Ralph H -- Chang, David K -- Biankin, Andrew V -- Grimmond, Sean M -- Australian Pancreatic Cancer Genome Initiative -- Wessels, Lodewyk F A -- Wood, Stephen A -- Iacobuzio-Donahue, Christine A -- Pilarsky, Christian -- Largaespada, David A -- Adams, David J -- Tuveson, David A -- 13031/Cancer Research UK/United Kingdom -- 2P50CA101955/CA/NCI NIH HHS/ -- CA106610/CA/NCI NIH HHS/ -- CA122183/CA/NCI NIH HHS/ -- CA128920/CA/NCI NIH HHS/ -- CA62924/CA/NCI NIH HHS/ -- K01 CA122183/CA/NCI NIH HHS/ -- K01 CA122183-05/CA/NCI NIH HHS/ -- P50 CA101955/CA/NCI NIH HHS/ -- P50CA62924/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2012 Apr 29;486(7402):266-70. doi: 10.1038/nature11114.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22699621" target="_blank"〉PubMed〈/a〉

Description: PPARgamma is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARgamma-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARgamma by Cdk5. Here we describe novel synthetic compounds that have a unique mode of binding to PPARgamma, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARgamma drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARgamma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179551/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179551/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choi, Jang Hyun -- Banks, Alexander S -- Kamenecka, Theodore M -- Busby, Scott A -- Chalmers, Michael J -- Kumar, Naresh -- Kuruvilla, Dana S -- Shin, Youseung -- He, Yuanjun -- Bruning, John B -- Marciano, David P -- Cameron, Michael D -- Laznik, Dina -- Jurczak, Michael J -- Schurer, Stephan C -- Vidovic, Dusica -- Shulman, Gerald I -- Spiegelman, Bruce M -- Griffin, Patrick R -- 1RC4DK090861/DK/NIDDK NIH HHS/ -- DK31405/DK/NIDDK NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- R01 GM084041/GM/NIGMS NIH HHS/ -- R01 GM084041-03/GM/NIGMS NIH HHS/ -- R01-GM084041/GM/NIGMS NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- R37 DK031405-30/DK/NIDDK NIH HHS/ -- R37 DK031405-31/DK/NIDDK NIH HHS/ -- RC4 DK090861/DK/NIDDK NIH HHS/ -- RC4 DK090861-01/DK/NIDDK NIH HHS/ -- S10 RR027270/RR/NCRR NIH HHS/ -- U24 DK059635/DK/NIDDK NIH HHS/ -- U54 MH074404/MH/NIMH NIH HHS/ -- U54 MH074404-01/MH/NIMH NIH HHS/ -- U54-MH074404/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Sep 4;477(7365):477-81. doi: 10.1038/nature10383.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21892191" target="_blank"〉PubMed〈/a〉

Description: Despite the high prevalence and poor outcome of patients with metastatic lung cancer the mechanisms of tumour progression and metastasis remain largely uncharacterized. Here we modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS and inactivation of the p53 pathway, using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras(LSL-G12D/+);p53(flox/flox) mice initiates lung adenocarcinoma development. Although tumours are initiated synchronously by defined genetic alterations, only a subset becomes malignant, indicating that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK2-related homeobox transcription factor Nkx2-1 (also called Ttf-1 or Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1 negativity is pathognomonic of high-grade poorly differentiated tumours. Gain- and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1-regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically restricted chromatin regulator Hmga2. Whereas focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability and increased metastatic proclivity. Thus, the oncogenic and suppressive functions of Nkx2-1 in the same tumour type substantiate its role as a dual function lineage factor.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088778/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088778/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Winslow, Monte M -- Dayton, Talya L -- Verhaak, Roel G W -- Kim-Kiselak, Caroline -- Snyder, Eric L -- Feldser, David M -- Hubbard, Diana D -- DuPage, Michel J -- Whittaker, Charles A -- Hoersch, Sebastian -- Yoon, Stephanie -- Crowley, Denise -- Bronson, Roderick T -- Chiang, Derek Y -- Meyerson, Matthew -- Jacks, Tyler -- K08 CA154784/CA/NCI NIH HHS/ -- K99-CA151968/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30 CA014051-36/CA/NCI NIH HHS/ -- P30 CA014051-37/CA/NCI NIH HHS/ -- P30 CA014051-38/CA/NCI NIH HHS/ -- P30 CA014051-39/CA/NCI NIH HHS/ -- P30 CA014051-40/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R00 CA151968/CA/NCI NIH HHS/ -- R01 CA109038/CA/NCI NIH HHS/ -- T32-HL007627/HL/NHLBI NIH HHS/ -- U01 CA084306/CA/NCI NIH HHS/ -- U01 CA084306-11/CA/NCI NIH HHS/ -- U01 CA084306-12/CA/NCI NIH HHS/ -- U01 CA084306-13/CA/NCI NIH HHS/ -- U01-CA84306/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 May 5;473(7345):101-4. doi: 10.1038/nature09881. Epub 2011 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21471965" target="_blank"〉PubMed〈/a〉

Description: Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288636/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288636/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Xiaochong -- Northcott, Paul A -- Dubuc, Adrian -- Dupuy, Adam J -- Shih, David J H -- Witt, Hendrik -- Croul, Sidney -- Bouffet, Eric -- Fults, Daniel W -- Eberhart, Charles G -- Garzia, Livia -- Van Meter, Timothy -- Zagzag, David -- Jabado, Nada -- Schwartzentruber, Jeremy -- Majewski, Jacek -- Scheetz, Todd E -- Pfister, Stefan M -- Korshunov, Andrey -- Li, Xiao-Nan -- Scherer, Stephen W -- Cho, Yoon-Jae -- Akagi, Keiko -- MacDonald, Tobey J -- Koster, Jan -- McCabe, Martin G -- Sarver, Aaron L -- Collins, V Peter -- Weiss, William A -- Largaespada, David A -- Collier, Lara S -- Taylor, Michael D -- K01CA122183/CA/NCI NIH HHS/ -- NS055089/NS/NINDS NIH HHS/ -- R01 CA108622/CA/NCI NIH HHS/ -- R01 CA113636/CA/NCI NIH HHS/ -- R01 CA148699/CA/NCI NIH HHS/ -- R01 CA148699-03/CA/NCI NIH HHS/ -- R01 NS055089/NS/NINDS NIH HHS/ -- R01CA148699/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2012 Feb 15;482(7386):529-33. doi: 10.1038/nature10825.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Arthur and Sonia Labatt Brain Tumour Research Center, Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22343890" target="_blank"〉PubMed〈/a〉

Description: Developing a vaccine for human immunodeficiency virus (HIV) may be aided by a complete understanding of those rare cases in which some HIV-infected individuals control replication of the virus. Most of these elite controllers express the histocompatibility alleles HLA-B*57 or HLA-B*27 (ref. 3). These alleles remain by far the most robust associations with low concentrations of plasma virus, yet the mechanism of control in these individuals is not entirely clear. Here we vaccinate Indian rhesus macaques that express Mamu-B*08, an animal model for HLA-B*27-mediated elite control, with three Mamu-B*08-restricted CD8(+) T-cell epitopes, and demonstrate that these vaccinated animals control replication of the highly pathogenic clonal simian immunodeficiency virus (SIV) mac239 virus. High frequencies of CD8(+) T cells against these Vif and Nef epitopes in the blood, lymph nodes and colon were associated with viral control. Moreover, the frequency of the CD8(+) T-cell response against the Nef RL10 epitope (Nef amino acids 137-146) correlated significantly with reduced acute phase viraemia. Finally, two of the eight vaccinees lost control of viral replication in the chronic phase, concomitant with escape in all three targeted epitopes, further implicating these three CD8(+) T-cell responses in the control of viral replication. Our findings indicate that narrowly targeted vaccine-induced virus-specific CD8(+) T-cell responses can control replication of the AIDS virus.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883109/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883109/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mudd, Philip A -- Martins, Mauricio A -- Ericsen, Adam J -- Tully, Damien C -- Power, Karen A -- Bean, Alex T -- Piaskowski, Shari M -- Duan, Lijie -- Seese, Aaron -- Gladden, Adrianne D -- Weisgrau, Kim L -- Furlott, Jessica R -- Kim, Young-il -- Veloso de Santana, Marlon G -- Rakasz, Eva -- Capuano, Saverio 3rd -- Wilson, Nancy A -- Bonaldo, Myrna C -- Galler, Ricardo -- Allison, David B -- Piatak, Michael Jr -- Haase, Ashley T -- Lifson, Jeffrey D -- Allen, Todd M -- Watkins, David I -- HHSN261200800001E/PHS HHS/ -- P51 OD011106/OD/NIH HHS/ -- R01 AI076114/AI/NIAID NIH HHS/ -- R24 RR015371/RR/NCRR NIH HHS/ -- R37 AI052056/AI/NIAID NIH HHS/ -- RR015371/RR/NCRR NIH HHS/ -- T32 GM008692/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 1;491(7422):129-33. doi: 10.1038/nature11443. Epub 2012 Sep 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23023123" target="_blank"〉PubMed〈/a〉

Description: Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412905/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412905/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Robinson, Giles -- Parker, Matthew -- Kranenburg, Tanya A -- Lu, Charles -- Chen, Xiang -- Ding, Li -- Phoenix, Timothy N -- Hedlund, Erin -- Wei, Lei -- Zhu, Xiaoyan -- Chalhoub, Nader -- Baker, Suzanne J -- Huether, Robert -- Kriwacki, Richard -- Curley, Natasha -- Thiruvenkatam, Radhika -- Wang, Jianmin -- Wu, Gang -- Rusch, Michael -- Hong, Xin -- Becksfort, Jared -- Gupta, Pankaj -- Ma, Jing -- Easton, John -- Vadodaria, Bhavin -- Onar-Thomas, Arzu -- Lin, Tong -- Li, Shaoyi -- Pounds, Stanley -- Paugh, Steven -- Zhao, David -- Kawauchi, Daisuke -- Roussel, Martine F -- Finkelstein, David -- Ellison, David W -- Lau, Ching C -- Bouffet, Eric -- Hassall, Tim -- Gururangan, Sridharan -- Cohn, Richard -- Fulton, Robert S -- Fulton, Lucinda L -- Dooling, David J -- Ochoa, Kerri -- Gajjar, Amar -- Mardis, Elaine R -- Wilson, Richard K -- Downing, James R -- Zhang, Jinghui -- Gilbertson, Richard J -- P01 CA096832/CA/NCI NIH HHS/ -- P01CA96832/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30CA021765/CA/NCI NIH HHS/ -- R01 CA129541/CA/NCI NIH HHS/ -- R01CA129541/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):43-8. doi: 10.1038/nature11213.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉St Jude Children's Research Hospital, Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722829" target="_blank"〉PubMed〈/a〉

Description: Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1(+) precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059767/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059767/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gibson, Paul -- Tong, Yiai -- Robinson, Giles -- Thompson, Margaret C -- Currle, D Spencer -- Eden, Christopher -- Kranenburg, Tanya A -- Hogg, Twala -- Poppleton, Helen -- Martin, Julie -- Finkelstein, David -- Pounds, Stanley -- Weiss, Aaron -- Patay, Zoltan -- Scoggins, Matthew -- Ogg, Robert -- Pei, Yanxin -- Yang, Zeng-Jie -- Brun, Sonja -- Lee, Youngsoo -- Zindy, Frederique -- Lindsey, Janet C -- Taketo, Makoto M -- Boop, Frederick A -- Sanford, Robert A -- Gajjar, Amar -- Clifford, Steven C -- Roussel, Martine F -- McKinnon, Peter J -- Gutmann, David H -- Ellison, David W -- Wechsler-Reya, Robert -- Gilbertson, Richard J -- 01CA96832/CA/NCI NIH HHS/ -- P01 CA096832/CA/NCI NIH HHS/ -- P01 CA096832-06A18120/CA/NCI NIH HHS/ -- P01 CA096832-078120/CA/NCI NIH HHS/ -- P30CA021765/CA/NCI NIH HHS/ -- R01 CA129541/CA/NCI NIH HHS/ -- R01 CA129541-01/CA/NCI NIH HHS/ -- R01 CA129541-02/CA/NCI NIH HHS/ -- R01 CA129541-03/CA/NCI NIH HHS/ -- R01 CA129541-04/CA/NCI NIH HHS/ -- R01 CA129541-05/CA/NCI NIH HHS/ -- R01 NS037956/NS/NINDS NIH HHS/ -- R01 NS037956-13/NS/NINDS NIH HHS/ -- R01CA129541/CA/NCI NIH HHS/ -- England -- Nature. 2010 Dec 23;468(7327):1095-9. doi: 10.1038/nature09587. Epub 2010 Dec 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21150899" target="_blank"〉PubMed〈/a〉