Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer

Using complete genome analysis, we sequenced five bladder tumors accrued from patients with muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) and identified a spectrum of genomic aberrations. In three tumors, complex genotype changes were noted. All three had tumor protein...

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Vydáno v:	Proceedings of the National Academy of Sciences - PNAS Ročník 111; číslo 6; s. E672
Hlavní autoři:	Morrison, Carl D, Liu, Pengyuan, Woloszynska-Read, Anna, Zhang, Jianmin, Luo, Wei, Qin, Maochun, Bshara, Wiam, Conroy, Jeffrey M, Sabatini, Linda, Vedell, Peter, Xiong, Donghai, Liu, Song, Wang, Jianmin, Shen, He, Li, Yinwei, Omilian, Angela R, Hill, Annette, Head, Karen, Guru, Khurshid, Kunnev, Dimiter, Leach, Robert, Eng, Kevin H, Darlak, Christopher, Hoeflich, Christopher, Veeranki, Srividya, Glenn, Sean, You, Ming, Pruitt, Steven C, Johnson, Candace S, Trump, Donald L
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 11.02.2014
Témata:	Chromosomes, Human Genetic Heterogeneity Genome, Human Humans In Situ Hybridization, Fluorescence Minichromosome Maintenance Complex Component 4 - genetics Mutation NAV1.6 Voltage-Gated Sodium Channel - genetics Oncogenes Polymorphism, Single Nucleotide Receptors, N-Methyl-D-Aspartate - genetics Tumor Suppressor Protein p53 - genetics Urinary Bladder Neoplasms - genetics replication GRIN2A next-generation sequencing tumor heterogeneity
ISSN:	1091-6490, 1091-6490
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Shrnutí:	Using complete genome analysis, we sequenced five bladder tumors accrued from patients with muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) and identified a spectrum of genomic aberrations. In three tumors, complex genotype changes were noted. All three had tumor protein p53 mutations and a relatively large number of single-nucleotide variants (SNVs; average of 11.2 per megabase), structural variants (SVs; average of 46), or both. This group was best characterized by chromothripsis and the presence of subclonal populations of neoplastic cells or intratumoral mutational heterogeneity. Here, we provide evidence that the process of chromothripsis in TCC-UB is mediated by nonhomologous end-joining using kilobase, rather than megabase, fragments of DNA, which we refer to as "stitchers," to repair this process. We postulate that a potential unifying theme among tumors with the more complex genotype group is a defective replication-licensing complex. A second group (two bladder tumors) had no chromothripsis, and a simpler genotype, WT tumor protein p53, had relatively few SNVs (average of 5.9 per megabase) and only a single SV. There was no evidence of a subclonal population of neoplastic cells. In this group, we used a preclinical model of bladder carcinoma cell lines to study a unique SV (translocation and amplification) of the gene glutamate receptor ionotropic N-methyl D-aspertate as a potential new therapeutic target in bladder cancer.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1091-6490 1091-6490
DOI:	10.1073/pnas.1313580111