title: Identification of subgroup-specific miRNA patterns by epigenetic profiling of sporadic and Lynch syndrome-associated colorectal and endometrial carcinoma.
abstract: 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.
authors.affiliation: Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, Helsinki, FIN-00014 Finland.
authors.forename: Sippy
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, Helsinki, FIN-00014 Finland.
authors.forename: Johanna E
authors.initials: JE
authors.lastname: Lotsari
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010 Australia.
authors.forename: Sam
authors.initials: S
authors.lastname: Al-Sohaily
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010 Australia.
authors.forename: Janindra
authors.initials: J
authors.lastname: Warusavitarne
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010 Australia.|St Vincent's Clinical School, UNSW Medicine, Darlinghurst, NSW 2052 Australia.|School of Medicine, University of Western Sydney, Campelltown, Sydney, NSW 2560 Australia.
authors.forename: Maija Rj
authors.initials: MR
authors.lastname: Kohonen-Corish
authors.affiliation: Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, Helsinki, FIN-00014 Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Peltomäki
keywords: Colorectal cancer; Endometrial cancer; Lynch syndrome; Methylation; Microsatellite instability; miRNA