Journal Article

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

Carl D. Morrison, He Shen, Song Liu, Annette Hill, Wiam Bshara, Kevin H. Eng, Christopher Hoeflich, Ming You, Pengyuan Liu, Angela R. Omilian, Donghai Xiong, Peter Vedell, Dimiter Kunnev, Christopher Darlak, Jeffrey M. Conroy, Srividya Veeranki, Khurshid Guru, Yinwei Li, Maochun Qin, Candace S. Johnson, Linda Sabatini, Steven C. Pruitt, Jianmin Zhang, Wei Luo, Jianmin Wang, Robert Leach, Anna Woloszynska-Read, Donald L. Trump, Sean Glenn, Karen Head

2014

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Biological Sciences / bladder / Bladder cancer / Cells / Chromosomes, Human / Deoxyribonucleic acid / DNA / DNA fragmentation / genes / Genetic Heterogeneity / Genome, Human / genotype / Genotype & phenotype / glutamic acid / Heterogeneity / Humans / In Situ Hybridization, Fluorescence / Minichromosome Maintenance Complex Component 4 - genetics / Mutation / NAV1.6 Voltage-Gated Sodium Channel - genetics / neoplasm cells / Oncogenes / patients / PNAS Plus / Polymorphism, Single Nucleotide / Proteins / Receptors, N-Methyl-D-Aspartate - genetics / sequence analysis / Translocation / Tumor Suppressor Protein p53 - genetics / Tumors / Urinary bladder / urinary bladder neoplasms / Urinary Bladder Neoplasms - genetics