Identification of subgroup-specific miRNA patterns by epigenetic profiling of sporadic and Lynch syndrome-associated colorectal and endometrial carcinoma

Clinical Epigenetics

Päivi Peltomäki³  Maija RJ Kohonen-Corish²  Janindra Warusavitarne¹  Sam Al-Sohaily¹  Johanna E Lotsari³  Sippy Kaur³ 

[1] The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, Sydney 2010, NSW, Australia;School of Medicine, University of Western Sydney, Campelltown, Sydney 2560, NSW, Australia;Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, Helsinki FIN-00014, Finland

关键词: Endometrial cancer;    Colorectal cancer;    Lynch syndrome;    Microsatellite instability;    Methylation;    miRNA;   

Others  :  1147829
DOI  :  10.1186/s13148-015-0059-3

 received in 2014-10-10, accepted in 2015-02-13,  发布年份 2015

【 摘 要 】

Background

Altered expression of microRNAs (miRNAs) commonly accompanies colorectal (CRC) and endometrial carcinoma (EC) development, but the underlying mechanisms and clinicopathological correlations remain to be clarified. We focused on epigenetic mechanisms and aimed to explore if DNA methylation patterns in tumors depend on DNA mismatch repair (MMR) status, sporadic vs. Lynch-associated disease, and geographic origin (Finland vs. Australia). Treatment of cancer cell lines with demethylating agents revealed 109 significantly upregulated miRNAs. Seven met our stringent criteria for possible methylation-sensitive miRNAs and were used to screen patient specimens (205 CRCs and 36 ECs) by methylation-specific multiplex ligation-dependent probe amplification.

Results

Three miRNAs (129-2, 345, and 132) with low methylation levels in normal tissue and frequent hypermethylation in tumors were of particular interest. Hypermethylation of miR-345 and miR-132 associated with MMR deficiency in CRC regardless of geographic origin, and hypermethylation of miR-132 distinguished sporadic MMR-deficient CRC from Lynch-CRC. Finally, hypermethylation of miRNAs stratified 49 endometrial hyperplasias into low-methylator (simple hyperplasia) and high-methylator groups (complex hyperplasia with or without atypia) and suggested that miR-129-2 methylation in particular could serve as a marker of progression in early endometrial tumorigenesis.

Conclusions

Our study identifies miR-345 and miR-132 as novel differentially methylated miRNAs in CRC, thereby facilitating sub-classification of CRC and links miR-129-2 methylation to early endometrial tumorigenesis.

【 授权许可】

   
2015 Kaur et al.; licensee BioMed Central.

【 图 表 】

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