Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer.
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.
Center for Personalized Medicine and Departments of Pharmacology and Therapeutics, Cancer Genetics, Biostatistics and Bioinformatics, Pathology, Urology, Molecular and Cellular Biology, and Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263.
Carl D
CD
Morrison
Pengyuan
P
Liu
Anna
A
Woloszynska-Read
Jianmin
J
Zhang
Wei
W
Luo
Maochun
M
Qin
Wiam
W
Bshara
Jeffrey M
JM
Conroy
Linda
L
Sabatini
Peter
P
Vedell
Donghai
D
Xiong
Song
S
Liu
Jianmin
J
Wang
He
H
Shen
Yinwei
Y
Li
Angela R
AR
Omilian
Annette
A
Hill
Karen
K
Head
Khurshid
K
Guru
Dimiter
D
Kunnev
Robert
R
Leach
Kevin H
KH
Eng
Christopher
C
Darlak
Christopher
C
Hoeflich
Srividya
S
Veeranki
Sean
S
Glenn
Ming
M
You
Steven C
SC
Pruitt
Candace S
CS
Johnson
Donald L
DL
Trump
D002877:Chromosomes, Human; D018740:Genetic Heterogeneity; D015894:Genome, Human; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D064148:Minichromosome Maintenance Complex Component 4 / Q000235:genetics; D009154:Mutation; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics; D009857:Oncogenes; D020641:Polymorphism, Single Nucleotide; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
D064148:Minichromosome Maintenance Complex Component 4; D062557:NAV1.6 Voltage-Gated Sodium Channel; D016194:Receptors, N-Methyl-D-Aspartate; D016159:Tumor Suppressor Protein p53; C100681:SCN8A protein, human; C495901:TP53 protein, human; C099243:MCM4 protein, human
GRIN2A; next-generation sequencing; replication; tumor heterogeneity