TY - JOUR
T1 - Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer
AU - Morrison, Carl D.
AU - Liu, Pengyuan
AU - Woloszynska-Read, Anna
AU - Zhang, Jianmin
AU - Luo, Wei
AU - Qin, Maochun
AU - Bshara, Wiam
AU - Conroy, Jeffrey M.
AU - Sabatini, Linda
AU - Vedell, Peter
AU - Xiong, Donghai
AU - Liu, Song
AU - Wang, Jianmin
AU - Shen, He
AU - Li, Yinwei
AU - Omilian, Angela R.
AU - Hill, Annette
AU - Head, Karen
AU - Guru, Khurshid
AU - Kunnev, Dimiter
AU - Leach, Robert
AU - Eng, Kevin H.
AU - Darlak, Christopher
AU - Hoeflich, Christopher
AU - Veeranki, Srividya
AU - Glenn, Sean
AU - You, Ming
AU - Pruitt, Steven C.
AU - Johnson, Candace S.
AU - Trump, Donald L.
PY - 2014/2/11
Y1 - 2014/2/11
N2 - 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.
AB - 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.
KW - GRIN2A
KW - Next-generation sequencing
KW - Replication
KW - Tumor heterogeneity
UR - http://www.scopus.com/inward/record.url?scp=84893848638&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84893848638&partnerID=8YFLogxK
U2 - 10.1073/pnas.1313580111
DO - 10.1073/pnas.1313580111
M3 - Article
C2 - 24469795
AN - SCOPUS:84893848638
SN - 0027-8424
VL - 111
SP - E672-E681
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 6
ER -