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11.
Evolution of neoplastic cell lineages in Barrett oesophagus. 总被引:20,自引:0,他引:20
M T Barrett C A Sanchez L J Prevo D J Wong P C Galipeau T G Paulson P S Rabinovitch B J Reid 《Nature genetics》1999,22(1):106-109
It has been hypothesized that neoplastic progression develops as a consequence of an acquired genetic instability and the subsequent evolution of clonal populations with accumulated genetic errors. Accordingly, human cancers and some premalignant lesions contain multiple genetic abnormalities not present in the normal tissues from which the neoplasms arose. Barrett oesophagus (BE) is a premalignant condition which predisposes to oesophageal adenocarcinoma (EA) that can be biopsied prospectively over time because endoscopic surveillance is recommended for early detection of cancer. In addition, oesophagectomy specimens frequently contain the premalignant epithelium from which the cancer arose. Neoplastic progression in BE is associated with alterations in TP53 (also known as p53) and CDKN2A (also known as p16) and non-random losses of heterozygosity (LOH). Aneuploid or increased 4N populations occur in more than 90-95% of EAs, arise in premalignant epithelium and predict progression. We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer. Here, we determine the evolutionary relationships of non-random LOH, TP53 and CDKN2A mutations, CDKN2A CpG-island methylation and ploidy during neoplastic progression. Diploid cell progenitors with somatic genetic or epigenetic abnormalities in TP53 and CDKN2A were capable of clonal expansion, spreading to large regions of oesophageal mucosa. The subsequent evolution of neoplastic progeny frequently involved bifurcations and LOH at 5q, 13q and 18q that occurred in no obligate order relative to each other, DNA-content aneuploidy or cancer. Our results indicate that clonal evolution is more complex than predicted by linear models. 相似文献
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M. L. Barrett A. M. Scutt F. J. Evans 《Cellular and molecular life sciences : CMLS》1986,42(4):452-453
Summary Two novel prenylat flavones, termed Cannflavin A and B, were isolated from the cannabinoid free ethanolic extract ofCannabis sativa L. Both compounds inhibited prostaglandin E2 production by human rheumatoid synovial cells in culture.This communication is dedicated to the memory of the late Professor J. W. Fairbairn and the late Dr. J. T. Pickens. We are grateful to the Medical Research Council for a project grant and to Ms J. Elliot of King's College London for NMR spectra. 相似文献
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Two novel prenylated flavones, termed Cannflavin A and B, were isolated from the cannabinoid free ethanolic extract of Cannabis sativa L. Both compounds inhibited prostaglandin E2 production by human rheumatoid synovial cells in culture. 相似文献
17.
He XC Yin T Grindley JC Tian Q Sato T Tao WA Dirisina R Porter-Westpfahl KS Hembree M Johnson T Wiedemann LM Barrett TA Hood L Wu H Li L 《Nature genetics》2007,39(2):189-198
Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts, which contain intestinal stem cells (ISCs). In mice, widespread deletion of the tumor suppressor Phosphatase and tensin homolog (PTEN) generates hamartomatous intestinal polyps with epithelial and stromal involvement. Using this model, we have established the relationship between stem cells and polyp and tumor formation. PTEN helps govern the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In PTEN-deficient mice, excess ISCs initiate de novo crypt formation and crypt fission, recapitulating crypt production in fetal and neonatal intestine. The PTEN-Akt pathway probably governs stem cell activation by helping control nuclear localization of the Wnt pathway effector beta-catenin. Akt phosphorylates beta-catenin at Ser552, resulting in a nuclear-localized form in ISCs. Our observations show that intestinal polyposis is initiated by PTEN-deficient ISCs that undergo excessive proliferation driven by Akt activation and nuclear localization of beta-catenin. 相似文献
18.
Hunt KA Smyth DJ Balschun T Ban M Mistry V Ahmad T Anand V Barrett JC Bhaw-Rosun L Bockett NA Brand OJ Brouwer E Concannon P Cooper JD Dias KR van Diemen CC Dubois PC Edkins S Fölster-Holst R Fransen K Glass DN Heap GA Hofmann S Huizinga TW Hunt S Langford C Lee J Mansfield J Marrosu MG Mathew CG Mein CA Müller-Quernheim J Nutland S Onengut-Gumuscu S Ouwehand W Pearce K Prescott NJ Posthumus MD Potter S Rosati G Sambrook J Satsangi J Schreiber S Shtir C Simmonds MJ Sudman M Thompson SD Toes R 《Nature genetics》2012,44(1):3-5
19.
Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease 总被引:1,自引:0,他引:1
Fisher SA Tremelling M Anderson CA Gwilliam R Bumpstead S Prescott NJ Nimmo ER Massey D Berzuini C Johnson C Barrett JC Cummings FR Drummond H Lees CW Onnie CM Hanson CE Blaszczyk K Inouye M Ewels P Ravindrarajah R Keniry A Hunt S Carter M Watkins N Ouwehand W Lewis CM Cardon L;Wellcome Trust Case Control Consortium Lobo A Forbes A Sanderson J Jewell DP Mansfield JC Deloukas P Mathew CG Parkes M Satsangi J 《Nature genetics》2008,40(6):710-712
We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases. 相似文献
20.
Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease 总被引:2,自引:0,他引:2
Barrett JC Hansoul S Nicolae DL Cho JH Duerr RH Rioux JD Brant SR Silverberg MS Taylor KD Barmada MM Bitton A Dassopoulos T Datta LW Green T Griffiths AM Kistner EO Murtha MT Regueiro MD Rotter JI Schumm LP Steinhart AH Targan SR Xavier RJ;NIDDK IBD Genetics Consortium Libioulle C Sandor C Lathrop M Belaiche J Dewit O Gut I Heath S Laukens D Mni M Rutgeerts P Van Gossum A Zelenika D Franchimont D Hugot JP de Vos M Vermeire S 《Nature genetics》2008,40(8):955-962
Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development. 相似文献