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

Sippy Kaur; Johanna E. Lotsari; Sam Al-Sohaily; Janindra Warusavitarne; Maija R. Kohonen-Corish; Paivi Peltomäki

doi:10.1186/s13148-015-0059-3

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

Sippy Kaur, Johanna E. Lotsari, Sam Al-Sohaily, Janindra Warusavitarne, Maija R. Kohonen-Corish, Paivi Peltomäki

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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.

Original language	English
Article number	20
Pages (from-to)	1-13
Number of pages	13
Journal	Clinical Epigenetics
Volume	7
DOIs	https://doi.org/10.1186/s13148-015-0059-3
Publication status	Published - 2015
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

miRNA
Methylation
Microsatellite instability
Lynch syndrome
Colorectal cancer
Endometrial cancer

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10.1186/s13148-015-0059-3Licence: CC BY

Publisher version (open access)Final published version, 1.04 MBLicence: CC BY

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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.",

keywords = "miRNA, Methylation, Microsatellite instability, Lynch syndrome, Colorectal cancer, Endometrial cancer",

author = "Sippy Kaur and Lotsari, {Johanna E.} and Sam Al-Sohaily and Janindra Warusavitarne and Kohonen-Corish, {Maija R.} and Paivi Peltom{\"a}ki",

note = "Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2015",

doi = "10.1186/s13148-015-0059-3",

language = "English",

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AU - Kaur, Sippy

AU - Lotsari, Johanna E.

AU - Al-Sohaily, Sam

AU - Warusavitarne, Janindra

AU - Kohonen-Corish, Maija R.

AU - Peltomäki, Paivi

N1 - Copyright the Author(s) 2015. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - miRNA

KW - Methylation

KW - Microsatellite instability

KW - Lynch syndrome

KW - Colorectal cancer

KW - Endometrial cancer

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U2 - 10.1186/s13148-015-0059-3

DO - 10.1186/s13148-015-0059-3

M3 - Article

C2 - 25767621

SN - 1868-7075

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EP - 13

JO - Clinical Epigenetics

JF - Clinical Epigenetics

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ER -

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

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