Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer
| Autor: | Christopher Darlak, He Shen, Dong Hai Xiong, Annette Hill, Sean T. Glenn, Carl Morrison, Christopher Hoeflich, Donald L. Trump, Jeffrey M. Conroy, Khurshid A. Guru, Wiam Bshara, Dimiter Kunnev, Steven C. Pruitt, Anna Woloszynska-Read, Angela Omilian, Srividya Veeranki, Linda M. Sabatini, Kevin H. Eng, Robert W. Leach, Jianmin Zhang, Maochun Qin, Candace S. Johnson, Yinwei Li, Jianmin Wang, Song Liu, Karen Head, Wei Luo, Pengyuan Liu, Ming You, Peter Vedell |
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| Rok vydání: | 2014 |
| Předmět: |
Population
Biology Polymorphism Single Nucleotide Receptors N-Methyl-D-Aspartate Genetic Heterogeneity Genotype medicine Chromosomes Human Humans education In Situ Hybridization Fluorescence Genetics education.field_of_study Multidisciplinary Chromothripsis Urinary bladder Bladder cancer Genome Human Genetic heterogeneity Oncogenes medicine.disease Minichromosome Maintenance Complex Component 4 medicine.anatomical_structure Transitional cell carcinoma PNAS Plus Urinary Bladder Neoplasms NAV1.6 Voltage-Gated Sodium Channel Mutation Human genome Tumor Suppressor Protein p53 |
| Zdroj: | Proceedings of the National Academy of Sciences. 111 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1313580111 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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