Coordinate hypermethylation at specific genes in prostate carcinoma precedes LINE-1 hypomethylation.
In prostate carcinoma (PCa) increased DNA methylation ('hypermethylation') occurs at specific genes such as GSTP1. Nevertheless, overall methylation can be decreased ('hypomethylation') because methylation of repetitive sequences like LINE-1 retrotransposons is diminished. We analysed DNA from 113 PCa and 36 noncancerous prostate tissues for LINE-1 hypomethylation by a sensitive Southern technique and for hypermethylation at eight loci by methylation-specific PCR. Hypermethylation frequencies for GSTP1, RARB2, RASSF1A, and APC in carcinoma tissues were each >70%, strongly correlating with each other (P<10(-6)). Hypermethylation at each locus was significantly different between tumour and normal tissues (10(-11)<P<10(3)), although hypermethylation, particularly of RASSF1A, was also observed in noncarcinoma tissues. ASC1 hypermethylation was observed in a subgroup of PCa with concurrent hypermethylation. Hypermethylation of CDH1, CDKN2A, and SFRP1 was rare. LINE-1 hypomethylation was detected in 49% PCa, all with hypermethylation at several loci. It correlated significantly with tumour stage, while hypermethylation was neither related to tumour stage nor Gleason score. Coordinate hypermethylation of several genes may occur early in PCa, with additional hypermethylation events and LINE-1 hypomethylation associated with progression. Hypermethylation allows detection of >82% of PCas. PCa may fall into three classes, that is, with few DNA methylation changes, with frequent hypermethylation, or with additional LINE-1 hypomethylation.
Florl
A R
AR
Department of Urology, Heinrich-Heine-University Duesseldorf, Moorenstr 5, 40225 Duesseldorf, Germany.
Steinhoff
C
C
Müller
M
M
Seifert
H-H
HH
Hader
C
C
Engers
R
R
Ackermann
R
R
Schulz
W A
WA
D000217:Acyltransferases / Q000378:metabolism; D015139:Blotting, Southern; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000032:analysis*; D017491:Genes, APC / Q000502:physiology; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D004273:DNA, Neoplasm; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; D000217:Acyltransferases; C043403:fatty acyl ethyl ester synthase