Mutational context and diverse clonal development in early and late bladder cancer.
Bladder cancer (or urothelial cell carcinoma [UCC]) is characterized by field disease (malignant alterations in surrounding mucosa) and frequent recurrences. Whole-genome, exome, and transcriptome sequencing of 38 tumors, including four metachronous tumor pairs and 20 superficial tumors, identified an APOBEC mutational signature in one-third. This was biased toward the sense strand, correlated with mean expression level, and clustered near breakpoints. A>G mutations were up to eight times more frequent on the sense strand (p<0.002) in [ACG]AT contexts. The patient-specific APOBEC signature was negatively correlated to repair-gene expression and was not related to clinicopathological parameters. Mutations in gene families and single genes were related to tumor stage, and expression of chromatin modifiers correlated with survival. Evolutionary and subclonal analyses of early/late tumor pairs showed a unitary origin, and discrete tumor clones contained mutated cancer genes. The ancestral clones contained Pik3ca/Kdm6a mutations and may reflect the field-disease mutations shared among later tumors.
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark.
Iver
I
Nordentoft
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark.
Philippe
P
Lamy
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark.
Karin
K
Birkenkamp-Demtröder
BC Cancer Research Centre, 675 West 10(th) Avenue, Vancouver, BC V5T4E6, Canada.
Karey
K
Shumansky
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark.
Søren
S
Vang
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark.
Henrik
H
Hornshøj
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark.
Malene
M
Juul
Department of Bioinformatic Research, Aarhus University, Universitetsparken, 8000 Aarhus, Denmark.
Palle
P
Villesen
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark.
Jakob
J
Hedegaard
BC Cancer Research Centre, 675 West 10(th) Avenue, Vancouver, BC V5T4E6, Canada.
Andrew
A
Roth
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark.
Kasper
K
Thorsen
Department of Pathology, Aarhus University Hospital, North Road Ringgade 8000 Aarhus, Denmark.
Søren
S
Høyer
Department of Urology, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark.
Michael
M
Borre
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark.
Thomas
T
Reinert
Department of Urology, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark.
Niels
N
Fristrup
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark.
Lars
L
Dyrskjøt
BC Cancer Research Centre, 675 West 10(th) Avenue, Vancouver, BC V5T4E6, Canada.
Sohrab
S
Shah
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark.
Jakob Skou
JS
Pedersen
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus, Denmark. Electronic address: orntoft@ki.au.dk.
Torben F
TF
Ørntoft
D000071479:APOBEC-1 Deaminase; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D060965:Clonal Evolution; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D016373:DNA, Antisense / Q000235:genetics; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017354:Point Mutation; D059467:Transcriptome; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
D016373:DNA, Antisense; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; D003564:Cytidine Deaminase