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Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer. Proc Natl Acad Sci U S A 2014 Feb 11;111(6):E672-81

Date

01/29/2014

Pubmed ID

24469795

Pubmed Central ID

PMC3926024

DOI

10.1073/pnas.1313580111

Scopus ID

2-s2.0-84893848638   62 Citations

Abstract

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.

Author List

Morrison CD, Liu P, Woloszynska-Read A, Zhang J, Luo W, Qin M, Bshara W, Conroy JM, Sabatini L, Vedell P, Xiong D, Liu S, Wang J, Shen H, Li Y, Omilian AR, Hill A, Head K, Guru K, Kunnev D, Leach R, Eng KH, Darlak C, Hoeflich C, Veeranki S, Glenn S, You M, Pruitt SC, Johnson CS, Trump DL

Authors

Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin
Donghai Xiong PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Chromosomes, Human
Genetic Heterogeneity
Genome, Human
Humans
In Situ Hybridization, Fluorescence
Minichromosome Maintenance Complex Component 4
Mutation
NAV1.6 Voltage-Gated Sodium Channel
Oncogenes
Polymorphism, Single Nucleotide
Receptors, N-Methyl-D-Aspartate
Tumor Suppressor Protein p53
Urinary Bladder Neoplasms
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d