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Sloane M.A.,Lowy Cancer Research Center and Prince of Wales Clinical School | Wong J.W.H.,Lowy Cancer Research Center and Prince of Wales Clinical School | Perera D.,Lowy Cancer Research Center and Prince of Wales Clinical School | Nunez A.C.,Lowy Cancer Research Center and Prince of Wales Clinical School | And 7 more authors.
Epigenetics | Year: 2014

In mouse models, loss of the candidate tumor suppressor gene Ubiquitin Specific protease 44 (USP44) is associated with aneuploidy and cancer. USP44 is also transcriptionally silenced in human cancers. here we investigated the molecular mechanism of USP44 silencing and whether this correlated with aneuploidy in colorectal adenomas. DNA methylation at the USP44 cpG island (CGI) promoter was measured using combined bisulfite restriction analysis (COBRA) in colorectal cancer (CRC) cell lines (n = 18), and with COBRA and bisulfite sequencing in colorectal adenomas (n = 89) and matched normal colonic mucosa (n = 51). the USP44 CGI was hypermethylated in all CRC cell lines, in most colorectal adenomas (79 of 89, 89%) but rarely in normal mucosa samples (3 of 51, 6%). USP44 expression was also compared between normal mucosa and paired hypermethylated adenomas in six patients using qRT-pCR. hypermethylation of the USP44 CGI in adenomas was associated with a 1.8 to 5.5-fold reduction in expression compared with paired normal mucosa. treatment of CRC cell lines with the DNA hypomethylating agent decitabine resulted in a 14 to 270-fold increase in USP44 expression. Whole genome SNP array data showed that gain or loss of individual chromosomes occurred in adenomas, but hypermethylation did not correlate with more aneuploidy. in summary, our data shows that USP44 is epigenetically inactivated in colorectal adenomas, but this alone is not sufficient to cause aneuploidy in colorectal neoplasia. © 2014 Landes Bioscience.


PubMed | Lowy Cancer Research Center and Prince of Wales Clinical School
Type: Comparative Study | Journal: Cancer prevention research (Philadelphia, Pa.) | Year: 2012

Folate exists as functionally diverse species within cells. Although folate deficiency may contribute to DNA hypomethylation in colorectal cancer, findings on the association between total folate concentration and global DNA methylation have been inconsistent. This study determined global, LINE-1, and Alu DNA methylation in blood and colon of healthy and colorectal cancer patients and their relationship to folate distribution. Blood and normal mucosa from 112 colorectal cancer patients and 114 healthy people were analyzed for global DNA methylation and folate species distribution using liquid chromatography tandem mass spectrometry. Repeat element methylation was determined using end-specific PCR. Colorectal mucosa had lower global and repeat element DNA methylation compared with peripheral blood (P < 0.0001). After adjusting for age, sex and smoking history, global but not repeat element methylation was marginally higher in normal mucosa from colorectal cancer patients compared with healthy individuals. Colorectal mucosa from colorectal cancer subjects had lower 5-methyltetrahydrofolate and higher tetrahydrofolate and formyltetrahydrofolate levels than blood from the same individual. Blood folate levels should not be used as a surrogate for the levels in colorectal mucosa because there are marked differences in folate species distribution between the two tissues. Similarly, repeat element methylation is not a good surrogate measure of global DNA methylation in both blood and colonic mucosa. There was no evidence that mucosal global DNA methylation or folate distribution was related to the presence of cancer per se, suggesting that if abnormalities exist, they are confined to individual cells rather than the entire colon.

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