Hypermethylation of CpG island loci and hypomethylation of LINE‐1 and Alu repeats in prostate adenocarcinoma and their relationship to clinicopathological features

Abstract

Promoter CpG island hypermethylation is an important carcinogenic event in prostate adenocarcinoma. Regardless of tissue type, human cancers have in common both focal CpG island hypermethylation and global genomic hypomethylation. The present study evaluated CpG island loci hypermethylation and LINE-1 and Alu repeat hypomethylation in prostate adenocarcinoma, analysed the relationship between them, and correlated these findings with clinicopathological features. We examined 179 cases of prostate adenocarcinoma and 30 cases of benign prostate hypertrophy for the methylation status of 22 CpG island loci and the methylation levels of LINE-1 and Alu repeats using methylation-specific polymerase chain reaction and combined bisulphite restriction analysis, respectively. The following 16 CpG island loci were found to display cancer-related hypermethylation: RASSF1A, GSTP1, RARB, TNFRSF10C, APC, BCL2, MDR1, ASC, TIG1, RBP1, COX2, THBS1, TNFRSF10D, CD44, p16, and RUNX3. Except for the last four CpG island loci, hypermethylation of each of the remaining 12 CpG island loci displayed a close association with one or more of the prognostic parameters (ie preoperative serum prostate specific antigen level, Gleason score sum, and clinical stage). Prostate adenocarcinoma with hypermethylation of each of ASC, COX2, RARB, TNFRSF10C, MDR1, TIG1, RBP1, NEUROG1, RASSF1A, and GSTP1 showed a significantly lower methylation level of Alu or LINE-1 than prostate adenocarcinoma without hypermethylation. In addition, hypomethylation of Alu or LINE-1 was closely associated with one or more of the above prognostic parameters. These data suggest that in tumour progression a close relationship exists between CpG island hypermethylation and the hypomethylation of repetitive elements, and that CpG island hypermethylation and DNA hypomethylation contribute to cancer progression.

LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality

“…On the other hand, there was no association between LINE-1 methylation and Gleason score. Although this latter finding is not completely inconsistent with previous studies (a clear association between LINE-1 hypomethylation and Gleason score has been found only in one out of 3 previous studies 22,23,26 ), if global methylation was a late event in prostate cancerogenesis, we would have expected higher hypomethylation among patients with a Gleason score of at least 8. It could be speculated that global methylation is more related to the metastatic potential of aggressive prostate cancers than to the Gleason score, and it is of interest that previous studies strongly indicate a decreased global methylation in the prostate cancer tissue among prostate cancer patients with systemic metastases.…”

“…We have recently conducted a systematic review of studies on prostatic tumor global hypomethylation and prostate cancer progression: 19 although studies were heterogeneous and mostly based on a limited sample size, global hypomethylation was reported to be associated with high Gleason score, advanced tumor stage, high pre-operative PSA, and presence of metastasis. [20][21][22][23][24][25][26] The genome-wide methylation level of the long interspersed nuclear element-1 (LINE-1) is considered as a good surrogate marker for global methylation, [27][28][29] as LINE-1 is widely interspersed and represents about 15% of human genome. 30,31 Thus, in the present study we have analyzed prostate tissue LINE-1 methylation status in a cohort of prostate cancer patients in association with Gleason score, gene-specific hypermethylation, and mortality from prostate cancer.…”

LINE-1 and Alu Methylation Patterns in Lymph Node Metastases of Head and Neck Cancers

“…Nakarin Kitkumthorn 1 , Somboon Keelawat 2 *, Prakasit Rattanatanyong 3 , Apiwat Mutirangura 3 tumor metastasis (Cho, 2007;Shuangshoti, 2007;Tangkijvanich, 2007;Pattamadilok, 2008;Iramaneerat, 2011;Kitkumthorn, 2011;Nopavichai, 2012).…”

Prospects for Epigenetic Epidemiology

“…The increase in tumor suppressor gene CpG island methylation between cancerous and noncancerous tissue is often close to 100% (77) and is usually reversed at CpG sites associated with tandemly repetitive and interspersed repeat DNA in the same tumor cells (78)(79)(80)(81). Specific profiles of methylation have also been associated with factors that predict prognosis (82).…”