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

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

Research output: Contribution to journalArticlepeer-review

66 Scopus 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 thanmegabase, fragments of DNA,which we refer to as stitchers, to repair this process. We postulate that a potential unifying theme among tumors with themore complex genotype group is adefective replication-licensingcomplex.Asecondgroup (twobladder 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 preclinicalmodel 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.

Original languageEnglish (US)
Pages (from-to)E672-E681
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number6
DOIs
StatePublished - Feb 11 2014

Keywords

  • GRIN2A
  • Next-generation sequencing
  • Replication
  • Tumor heterogeneity

ASJC Scopus subject areas

  • General

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