Identification of methylated genes associated with aggressive bladder cancer.
Approximately 500,000 individuals diagnosed with bladder cancer in the U.S. require routine cystoscopic follow-up to monitor for disease recurrences or progression, resulting in over $2 billion in annual expenditures. Identification of new diagnostic and monitoring strategies are clearly needed, and markers related to DNA methylation alterations hold great promise due to their stability, objective measurement, and known associations with the disease and with its clinical features. To identify novel epigenetic markers of aggressive bladder cancer, we utilized a high-throughput DNA methylation bead-array in two distinct population-based series of incident bladder cancer (n = 73 and n = 264, respectively). We then validated the association between methylation of these candidate loci with tumor grade in a third population (n = 245) through bisulfite pyrosequencing of candidate loci. Array based analyses identified 5 loci for further confirmation with bisulfite pyrosequencing. We identified and confirmed that increased promoter methylation of HOXB2 is significantly and independently associated with invasive bladder cancer and methylation of HOXB2, KRT13 and FRZB together significantly predict high-grade non-invasive disease. Methylation of these genes may be useful as clinical markers of the disease and may point to genes and pathways worthy of additional examination as novel targets for therapeutic treatment.
Marsit
Carmen J
CJ
Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America.
Houseman
E Andres
EA
Christensen
Brock C
BC
Gagne
Luc
L
Wrensch
Margaret R
MR
Nelson
Heather H
HH
Wiemels
Joseph
J
Zheng
Shichun
S
Wiencke
John K
JK
Andrew
Angeline S
AS
Schned
Alan R
AR
Karagas
Margaret R
MR
Kelsey
Karl T
KT
D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053535:Keratin-13 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D014157:Transcription Factors / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D000099274:Frizzled-Related Proteins
D004247:DNA; D006023:Glycoproteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053535:Keratin-13; D014157:Transcription Factors; D000099274:Frizzled-Related Proteins; C086061:HOXB2 protein, human; C507426:KRT13 protein, human
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