Insulin-like growth factor-2 (IGF2) loss of imprinting marks a field defect within human prostates containing cancer

• Published in: The Prostate Vol. 71; no. 15; pp. 1621 - 1630
• Main Authors: Bhusari, Sachin, Yang, Bing, Kueck, Jessica, Huang, Wei, Jarrard, David F.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.11.2011; Wiley-Liss
• Subjects: Adult; Aged; Biological and medical sciences; field effect; Gene Expression Regulation, Neoplastic; Genomic Imprinting; Genotype; Gynecology. Andrology. Obstetrics; H19; Humans; IGF2; Insulin-Like Growth Factor II - genetics; Male; Male genital diseases; Medical sciences; Middle Aged; Nephrology. Urinary tract diseases; Polymorphism, Single Nucleotide; Prostate; prostate cancer; Prostatic Neoplasms - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm - chemistry; RNA, Neoplasm - genetics; Statistics, Nonparametric; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Human; Andrology; Nephrology; Urinary system disease; Prostate disease; Gynecology; field effect; IGF2; Malignant tumor; Insulin like growth factor 2; Genomic imprinting; H19; Defect; Male genital diseases; Prostate cancer; Cancer
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.21379

BACKGROUND Loss of imprinting (LOI) is an epigenetic alteration involving loss of parental origin‐specific expression at normally imprinted genes. A LOI for IGF2, a paracrine growth factor, has been implicated in the development of prostate and other cancers. In the current study, we define IGF2 LOI in histologically normal prostate tissues in relationship to tumor foci and gene expression. METHODS Microdissected tumor associated (TA) adjacent (2 mm) and distant (10 mm) tissues surrounding tumor foci were generated. IGF2 imprinting in informative prostate tissue sets was quantitated using a fluorescent primer extension assay and expression analyzed utilizing quantitative PCR. DNA methylation analyses were performed using quantitative pyrosequencing. RESULTS A marked IGF2 LOI was found in adjacent TA tissues (39 ± 3.1%) and did not significantly decrease in tissues distant (38 ± 5.3%) from tumor foci (45 ± 2.9%; P = 0.21). IGF2 imprinting correlated with IGF2 expression in TA tissues, but not within the tumor foci. Hypomethylation of the IGF2 DMR0 region correlated with decreased IGF2 expression in tumors (P < 0.01). The expression of IGF2 and its adjacent imprinted gene H19 were increased in adjacent and distant tissues compared to tumors (P < 0.05) indicating the importance of factors other than LOI in driving IGF2 expression. CONCLUSIONS LOI of IGF2 occurs not only adjacent to prostate tumor foci, but is widely prevalent even in distant areas within the peripheral zone. These data provide evidence for a widespread epigenetic field defect in histologically normal tissues that might be employed to identify prostate cancer in patients. Prostate 71:1621–1630, 2011. © 2011 Wiley‐Liss, Inc.