Validation study of genes with hypermethylated promoter regions associated with prostate cancer recurrence.
BACKGROUND
One challenge in prostate cancer is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in prostate cancer, but few studies of DNA methylation in relation to features of more aggressive tumors or prostate cancer recurrence have been completed.


METHODS
We used the Infinium HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized prostate cancer who underwent radical prostatectomy. Recurrence status was determined by follow-up patient surveys, medical record review, and linkage with the Surveillance, Epidemiology, and End Results (SEER) registry. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Average methylation level for promoter region CpGs in patients who recurred compared with those with no evidence of recurrence was analyzed. For two genes with differential methylation, time to recurrence was examined.


RESULTS
During an average follow-up of 11.7 years, 104 (26%) patients recurred. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared with those without recurrence. Evidence was strongest for HOXD3 (lowest P = 9.46 × 10(-6)), with higher average methylation across promoter region CpGs associated with reduced recurrence-free survival (P = 2 × 10(-4)). DNA methylation profiles did not differ by recurrence status for the other genes.


CONCLUSIONS
These results validate the association between promoter hypermethylation of ADHB9 and HOXD3 and prostate cancer recurrence.


CONCLUSIONS
Tumor DNA methylation profiling may help to distinguish patients with prostate cancer at higher risk for disease recurrence.
Authors' Affiliations: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center;
Marni
M
Stott-Miller
Authors' Affiliations: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center;
Shanshan
S
Zhao
Authors' Affiliations: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center; Department of Urology, University of Washington School of Medicine; Departments of.
Jonathan L
JL
Wright
Authors' Affiliations: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center;
Suzanne
S
Kolb
Illumina, Inc., San Diego, California; and.
Marina
M
Bibikova
Illumina, Inc., San Diego, California; and.
Brandy
B
Klotzle
Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland.
Elaine A
EA
Ostrander
Illumina, Inc., San Diego, California; and.
Jian-Bing
JB
Fan
Authors' Affiliations: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center; Biostatistics and.
Ziding
Z
Feng
Authors' Affiliations: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center; Epidemiology, University of Washington, Seattle, Washington; jstanfor@fhcrc.org.
Janet L
JL
Stanford
D000368:Aged; D019175:DNA Methylation / Q000235:genetics*; D004851:Epoxide Hydrolases / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors
D018398:Homeodomain Proteins; D014157:Transcription Factors; C073547:HOXA4 protein, human; C577760:EPHX3 protein, human; D004851:Epoxide Hydrolases