Loss of imprinting and marked gene elevation are 2 forms of aberrant IGF2 expression in colorectal cancer.
Loss of imprinting (LOI) of insulin-like growth factor 2 (IGF2) is a common event in many cancers and typically activates the maternally silenced allele. The resulting biallelic IGF2 expression correlates strongly with the hypomethylation of a differentially methylated region (DMR) near its promoter. It has also been shown that IGF2 undergoes overexpression in human malignancies; nevertheless, this phenomenon and its link to aberrant DMR methylation have not been reported in colorectal cancer (CRC). The aim of this study was to determine the relationship between IGF2 LOI, overexpression and DMR hypomethylation in CRC. By analyzing IGF2 and H19 methylation in 97 primary CRC and 64 matched normal colorectal tissues, we have shown a significant correlation between IGF2 LOI and DMR hypomethylation of IGF2 and H19. Additionally, when analyzing Affymetrix expression data of 167 primary CRC tumors and 32 normal tissues, 15% of tumors showed marked IGF2 elevation. We further investigated if substantially elevated IGF2 levels were linked to IGF2 or H19 hypomethylation, but found no significant correlation. However, we demonstrated that noticeable IGF2 overexpression, rather than LOI, negatively correlated with CRC microsatellite instability. These observations indicate that IGF2 expression, particularly when transcribed at significantly high levels, is a result of mechanisms unrelated to LOI. Our results suggest that IGF2 participates in CRC tumorigenesis through 2 different forms of aberrant gene expression.
Cheng
Yu-Wei
YW
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA. yuc2002@med.cornell.edu
Idrees
Kamran
K
Shattock
Richard
R
Khan
Sajid A
SA
Zeng
Zhaoshi
Z
Brennan
Cameron W
CW
Paty
Philip
P
Barany
Francis
F
D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic
C035170:IGF2 protein, human; D007335:Insulin-Like Growth Factor II