Loss of imprinting and marked gene elevation are 2 forms of aberrant IGF2 expression in colorectal cancer

被引:53
作者
Cheng, Yu-Wei [1 ]
Idrees, Kamran [2 ]
Shattock, Richard [1 ]
Khan, Sajid A. [3 ]
Zeng, Zhaoshi [4 ]
Brennan, Cameron W. [5 ]
Paty, Philip [4 ]
Barany, Francis [1 ]
机构
[1] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA
[2] Univ Alabama, Dept Gastrointestinal Surg, Birmingham, AL USA
[3] Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97201 USA
[4] Mem Sloan Kettering Canc Ctr, Dept Surg, Colorectal Surg Serv, New York, NY 10021 USA
[5] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10021 USA
关键词
CpG methylation; LDR; colorectal cancer; IGF2; imprinting; MICROSATELLITE INSTABILITY; WILMS-TUMOR; H19; GENE; CHROMOSOMAL-ABNORMALITIES; FREQUENT LOSS; METHYLATION; TRANSCRIPTION; RELAXATION; CHROMATIN; SITES;
D O I
10.1002/ijc.25086
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
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.
引用
收藏
页码:568 / 577
页数:10
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