Hypermethylation of the polycomb group target gene PCDH7 in bladder tumors from patients of all ages.
OBJECTIVE
Bladder tumors in patients younger than 20 years show a low incidence of the genetic and epigenetic aberrations typically found in older patients. One of the most common epigenetic aberrations in human malignancies is DNA hypermethylation. Polycomb group complexes have an important role during lineage choices in embryogenesis and their target genes are 12 times more likely to be methylated than nonpolycomb group target genes. We hypothesized that methylation of polycomb group target genes is an early event in urothelial carcinogenesis and thus might be observed in young patients.


METHODS
We stratified 167 patients by age into 4 groups, including age less than 20 years in 14, 20 to 40 in 48, 40 to 60 in 47 and greater than 60 in 58. Five previously identified polycomb group target genes (MEIS1, ONECUT2, OTX1, PCDH7 and SOX21) were selected for methylation analysis. Methylation ratios were calculated by using the unmethylated and methylated signal. The outcome represented the fraction of methylated cells within one tumor. Genes with similar methylation ratios in all age groups were considered as potential bladder cancer initiating candidates.


RESULTS
Three genes showed higher methylation ratios in tumors from older patients, including ONECUT2, SOX21 and OTX1 (each p <0.001). MEIS1 showed a similar methylation ratio in all groups but the median methylation ratio was low. PCDH7 showed a similar median methylation percent in all age categories, ie 54% at less than 20, 59% at 20 to 40, 59% at 40 to 60 and 67% at greater than 60 years (p = 0.1).


CONCLUSIONS
Tumors from young patients showed less methylation for most markers. PCDH7 showed high methylation ratios in all age categories. Therefore, it could have an important role in early urothelial carcinogenesis.
Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
Willemien
W
Beukers
Aleksander
A
Hercegovac
Marcel
M
Vermeij
Raju
R
Kandimalla
Arina C
AC
Blok
Madelon M N
MM
van der Aa
Ellen C
EC
Zwarthoff
Tahlita C M
TC
Zuiverloon
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D015820:Cadherins / Q000235:genetics*; D002295:Carcinoma, Transitional Cell / Q000175:diagnosis / Q000235:genetics*; D015331:Cohort Studies; D019175:DNA Methylation / Q000235:genetics* / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D063146:Polycomb-Group Proteins / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D000091363:Protocadherins; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult
D015820:Cadherins; D005819:Genetic Markers; C113391:PCDH7 protein, human; D063146:Polycomb-Group Proteins; D000091363:Protocadherins