Quantitative, spatial resolution of the epigenetic field effect in prostate cancer.
BACKGROUND
Although a field effect in which transformed cells extend beyond morphologically evident tumor has been proposed in cancer, little direct evidence exists as to its magnitude and spatial resolution. We tested this hypothesis using molecular techniques to detect epigenetic changes in the primary tumor and surrounding tissues.


METHODS
Ex vivo core biopsies, each spaced approximately 1 mm apart, were generated from 37 unique prostatectomy samples. The first core biopsy was confirmed to be histologically positive for cancer, and the subsequent biopsies were confirmed to be histologically negative. The methylation ratio of GSTP1, APC, RARbeta2, and RASSF1A were measured for all of the 159 cores.


RESULTS
No field effect, defined as absence of epigenetically transformed cells, for GSTP1 was observed whereas APC, RARbeta2, and RASSF1A showed a field effect up to 3 mm from the malignant core in three prostatectomy samples. Furthermore, for each case, different patterns of the field effect were observed. The field effect appeared most pronounced with RARbeta2. In 11 prostatectomy samples in which a second focus of cancer was identified, cells harboring RARbeta2 methylation extended a large distance away from the primary tumor in one sample. Bisulfite sequencing of RARbeta2 confirmed the presence of epigenetic aberrations.


CONCLUSIONS
This study quantifies previous observations of methylation in histologically negative samples and provides important assessment of field effects based on epigenetic events in cancer. These molecular approaches set the stage for consideration of such data in prospective trials for assessment of surgical margins and prediction of recurrence.
Mehrotra
Jyoti
J
Veridex LLC, a Johnson and Johnson Company, Warren, New Jersey, USA.
Varde
Shobha
S
Wang
Haiying
H
Chiu
Hsiling
H
Vargo
Janet
J
Gray
Karen
K
Nagle
Raymond B
RB
Neri
Jaclyn R
JR
Mazumder
Abhijit
A
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D001706:Biopsy; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins / Q000235:genetics
D025601:Adenomatous Polyposis Coli Protein; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi