Macroscopic somatic clonal expansion in morphologically normal human urothelium

Science ◽  
2020 ◽  
Vol 370 (6512) ◽  
pp. 82-89 ◽  
Author(s):  
Ruoyan Li ◽  
Yiqing Du ◽  
Zhanghua Chen ◽  
Deshu Xu ◽  
Tianxin Lin ◽  
...  
Keyword(s):  
Neutral Loss ◽  
Clonal Expansion ◽  
Mutation Accumulation ◽  
Small Scale ◽  
Copy Number Alterations ◽  
Urothelial Cells ◽  
Normal Human ◽  
Natural Herb ◽  
Development And Evolution ◽  
Normal Human Urothelium

Knowledge of somatic mutation accumulation in normal cells, which is essential for understanding cancer development and evolution, remains largely lacking. In this study, we investigated somatic clonal events in morphologically normal human urothelium (MNU; epithelium lining the bladder and ureter) and identified macroscopic clonal expansions. Aristolochic acid (AA), a natural herb-derived compound, was a major mutagenic driving factor in MNU. AA drastically accelerates mutation accumulation and enhances clonal expansion. Mutations in MNU were widely observed in chromatin remodeling genes such as KMT2D and KDM6A but rarely in TP53, PIK3CA, and FGFR3. KMT2D mutations were found to be common in urothelial cells, regardless of whether the cells experience exogenous mutagen exposure. Copy number alterations were rare and largely confined to small-scale regions, along with copy-neutral loss of heterozygosity. Single AA-associated clones in MNU expanded to a scale of several square centimeters in size.

A biomimetic tissue from cultured normal human urothelial cells: analysis of physiological function

2005 ◽  
Vol 289 (2) ◽  
pp. F459-F468 ◽  
Author(s):  
W. R. Cross ◽  
I. Eardley ◽  
H. J. Leese ◽  
J. Southgate
Keyword(s):  
Urothelial Cells ◽  
Functional Relationships ◽  
Basal Expression ◽  
Physiological Investigation ◽  
Cell Culture Systems ◽  
Diffusive Permeability ◽  
Normal Human ◽  
Sodium Ion Channels ◽  
Normal Human Urothelium

The urinary bladder and associated tract is lined by the urothelium. Once considered as just an impermeable epithelium, it is becoming evident that the urothelium not only functions as a volume-accommodating urinary barrier but has additional roles, including sensory signaling. Lack of access to normal human urothelium has hampered physiological investigation, and although cell culture systems have been developed, there has been a failure to demonstrate that normal human urothelial (NHU) cells grown in vitro retain the capacity to form a functional differentiated urothelium. The aim of this study was to develop a biomimetic human urothelium from NHU cell cultures. Urothelial cells isolated from normal human urothelium and serially propagated as monolayers in serum-free culture were homogeneous and adopted a proliferative, nondifferentiated phenotype. In the presence of serum and physiological concentrations of calcium, these cells could be reproducibly induced to form stratified urothelia consisting of basal, intermediate, and superficial cells, with differential expression of cytokeratins and superficial tight junctions. Functionally, the neotissues showed characteristics of native urothelium, including high transepithelial electrical resistance of >3,000 Ω·cm2, apical membrane-restricted amiloride-sensitive sodium ion channels, basal expression of Na+-K+-ATPase, and low diffusive permeability to urea, water, and dextran. This model represents major progress in developing a biomimetic human urothelial culture model to explore molecular and functional relationships in normal and dysfunctional bladder physiology.

scholarly journals ZIP8 expression in human proximal tubule cells, human urothelial cells transformed by Cd+2 and As+3 and in specimens of normal human urothelium and urothelial cancer

2012 ◽  
Vol 12 (1) ◽  
pp. 16 ◽  
Author(s):  
Amornpan Ajjimaporn ◽  
Tom Botsford ◽  
Scott H Garrett ◽  
Mary Sens ◽  
Xu Zhou ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Urothelial Cancer ◽  
Urothelial Cells ◽  
Proximal Tubule Cells ◽  
Normal Human ◽  
Tubule Cells ◽  
Normal Human Urothelium ◽  
Human Proximal Tubule

scholarly journals Distribution of lymphocytes of the α E β 7 phenotype and E-cadherin in normal human urothelium and bladder carcinomas

2001 ◽  
Vol 126 (3) ◽  
pp. 397-402 ◽  
Author(s):  
J. Cresswell ◽  
H. Robertson ◽  
D. E. Neal ◽  
T. R. L. Griffiths ◽  
J. A. Kirby
Keyword(s):  
Normal Human ◽  
Bladder Carcinomas ◽  
Normal Human Urothelium ◽  
E Cadherin

scholarly journals Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

2017 ◽  
Vol 114 (40) ◽  
pp. 10743-10748 ◽  
Author(s):  
Tali Mazor ◽  
Charles Chesnelong ◽  
Aleksandr Pankov ◽  
Llewellyn E. Jalbert ◽  
Chibo Hong ◽  
...  
Keyword(s):  
Copy Number ◽  
Cpg Island ◽  
Clonal Expansion ◽  
Low Grade ◽  
Copy Number Alterations ◽  
Wild Type ◽  
Mutant Idh1

IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite d-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions.

Growth, Differentiation and Senescence of Normal Human Urothelium in an Organ-Like Culture

2004 ◽  
Vol 45 (6) ◽  
pp. 799-805 ◽  
Author(s):  
Ahmad Daher ◽  
Willem I de Boer ◽  
Marie-Aude Le Frère-Belda ◽  
Laurence Kheuang ◽  
Claude C Abbou ◽  
...  
Keyword(s):  
Normal Human ◽  
Normal Human Urothelium

scholarly journals Heterogeneity of uroplakin localization in human normal urothelium, papilloma and papillary carcinoma

2013 ◽  
Vol 47 (4) ◽  
pp. 338-345 ◽  
Author(s):  
Dasa Zupancic ◽  
Rok Romih
Keyword(s):  
Papillary Carcinoma ◽  
Recurrence Rate ◽  
Ultrastructural Localization ◽  
Ultrastructural Level ◽  
Apical Plasma Membrane ◽  
High Recurrence Rate ◽  
Tumour Resection ◽  
Urothelial Cells ◽  
Normal Human ◽  
Normal Urothelium

Abstract Background. Uroplakins are differentiation-related membrane proteins of urothelium. We compared uroplakin expression and ultrastructural localization in human normal urothelium, papilloma and papillary carcinoma. Because of high recurrence rate of these tumours, treated by transurethral resection, we investigated urothelial tumour, resection border and uninvolved urothelium. Patients and methods. Urinary bladder samples were obtained from tumour free control subjects and patients with papilloma and papillary carcinoma. Immunohistochemical and immunoelectron labelling of uroplakins were performed. Results. In normal human urothelium with continuous uroplakin-positive superficial cell layer uroplakins were localized to flattened mature fusiform vesicles and apical plasma membrane of umbrella cells. Diverse uroplakin expression was found in papilloma and papillary carcinoma. Three aberrant differentiation stages of urothelial cells, not found in normal urothelium, were recognized in tumours. Diverse uroplakin expression and aberrant differentiation were occasionally found in resection border and in uninvolved urothelium. Conclusions. We demonstrated here that uroplakin expression and localization in urothelial tumours is altered when compared to normal urothelium. In patients with papilloma and papillary carcinoma immunolabelling of uroplakins at ultrastructural level shows aberrant urothelial differentiation. It is possible that aberrant differentiation stages of urothelial cells in resection border and in uninvolved urothelium contribute to high recurrence rate.

Utility of SNP Microarray in the Diagnosis of MDS

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4806-4806
Author(s):  
Peter Papenhausen ◽  
Stuart Schwartz ◽  
Henry Y. Dong ◽  
Alan F. List ◽  
Ronald Thomason
Keyword(s):  
Copy Number ◽  
Neutral Loss ◽  
Diagnostic Testing ◽  
Uniparental Disomy ◽  
Selective Advantage ◽  
Copy Number Alterations ◽  
Driver Genes ◽  
Jak2 Mutation ◽  
Snp Microarray ◽  
Early Primary

Abstract Abstract 4806 A series of 206 bone marrow aspirates/blood submitted for diagnostic testing for possible MDS/MPN was studied by high resolution SNP microarray to determine the efficacy of this technology for detecting clonal copy number alterations and copy neutral loss of heterozygosity. The latter, acquired uniparental disomy (aUPD), is associated with oncogene mutations that through mitotic recombination have converted to the homozygous state, offering additional selective advantage to daughter cells. Of the 206 patient samples classified as possible MDS, 76 were abnormal by the array. Thirty one of these were either copy neutral or demonstrated copy number alterations below the resolution of cytogenetics. Twenty-three cases demonstrated aUPD and in 14 of these it was the only abnormality detected. Two of these 14 had multiple aUPD (9q/14q and 1p/4q/14q). When the aUPD clones were accompanied by copy number alterations, they could be seen as either the early primary alteration or as a later evolutionary event. The most common segmental UPD regions in MDS were 4q(9), 7q(4),11q(4) and 14q(4) while 9p(4) was the most common a(UPD in the patients with MPN which was likely to be associated with a homozygous JAK2 mutation (confirmed in two cases). The small MPN group (12 cases) demonstrated eight clones with aUPD, only three of which had copy number alterations. All the aUPDs found in this study involved terminal chromosome arm exchange and almost all involved a percentage of the DNA tested, consistent with an acquired change. Whole chromosome aUPD was not seen in these patients. There were three instances of possible interstitial LOH which were not included in this report until normal patient DNA can be obtained to confirm this uncommon observation. Two of these three showed mosaic LOH consistent with an acquired change. The most common deletions below the resolution of cytogenetics involved the RUNX1 and TET2 genes. In summary, the SNP microarray increased the abnormal clone detection from 45 by cytogenetics to 76 in cases of MDS and from 4 to 8 in the small MPN cohort, underscoring the utility of the testing while laying the groundwork for the discovery of new driver genes in the aUPD regions in the pathogenesis of MDS. Disclosures: Papenhausen: LabCorp: Employment. Schwartz:LabCorp: Employment. Thomason:LabCorp: Employment.

scholarly journals The effects of dietary fatty acids on the proliferation of normal human urothelial cells in vitro

1996 ◽  
Vol 74 (5) ◽  
pp. 728-734 ◽  
Author(s):  
J Southgate ◽  
E Pitt ◽  
LK Trejdosiewicz
Keyword(s):  
Fatty Acids ◽  
Dietary Fatty Acids ◽  
Urothelial Cells ◽  
Normal Human
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