Genome-wide DNA methylation profiling of CpG islands in breast cancer identifies novel genes associated with tumorigenicity.

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Genome-wide DNA methylation profiling of CpG islands in breast cancer identifies novel genes associated with tumorigenicity. / Hill, Victoria; Ricketts, Christopher; Bieche, I; Vacher, S; Gentle, Dean; Lewis, C; Maher, Eamonn; Latif, Farida.

In: Cancer Research, Vol. 71, No. 8, 15.04.2011, p. 2988-99.

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@article{41e5de7322e24872bcde77385603958f,
title = "Genome-wide DNA methylation profiling of CpG islands in breast cancer identifies novel genes associated with tumorigenicity.",
abstract = "Epigenetic profiling of tumor DNAs may reveal important new theranostic targets to improve prognosis and treatment of advanced cancer patients. In this study, we performed a genome-wide profile of DNA methylation patterns in sporadic breast tumors by using the HumanMethylation27 BeadChips to assess relationships between DNA methylation changes and patient tumor characteristics. The arrays identified 264 hypermethylated loci/genes present in genomic CpG islands. Hierarchical clustering based on methylation levels divided the specimens into three distinct groups, within which certain clinical features also clustered. Statistically significant differences were determined between overall methylation levels of these clusters and estrogen receptor and progesterone receptor (ER/PR) status (P = 0.001), tumor relapse (P = 0.035), and lymph node metastasis (P = 0.042). We identified several individual methylated genes associated with clinical features, including six genes (RECK, SFRP2, UAP1L1, ACADL, ITR, and UGT3A1) that showed statistical significance between methylation and relapse-free survival. Notably, the RECK gene in this group has been associated in other cancers with poorest prognosis. Among the leading relapse-associated genes and the genes associated with ER/PR status, we sequenced an independent set of paired normal/tumor breast DNA samples to confirm tumor specificity of methylation. Further, we carried out quantitative real-time reverse transcriptase PCR to confirm reduced expression in methylated tumors. Our findings suggest the utility for the DNA methylation patterns in these genes as clinically useful surrogate markers in breast cancer, as well as new molecular pathways for further investigation as therapeutic targets. Cancer Res; 71(8); 2988-99. {\textcopyright}2011 AACR.",
author = "Victoria Hill and Christopher Ricketts and I Bieche and S Vacher and Dean Gentle and C Lewis and Eamonn Maher and Farida Latif",
year = "2011",
month = apr,
day = "15",
doi = "10.1158/0008-5472.CAN-10-4026",
language = "English",
volume = "71",
pages = "2988--99",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research",
number = "8",

}

RIS

TY - JOUR

T1 - Genome-wide DNA methylation profiling of CpG islands in breast cancer identifies novel genes associated with tumorigenicity.

AU - Hill, Victoria

AU - Ricketts, Christopher

AU - Bieche, I

AU - Vacher, S

AU - Gentle, Dean

AU - Lewis, C

AU - Maher, Eamonn

AU - Latif, Farida

PY - 2011/4/15

Y1 - 2011/4/15

N2 - Epigenetic profiling of tumor DNAs may reveal important new theranostic targets to improve prognosis and treatment of advanced cancer patients. In this study, we performed a genome-wide profile of DNA methylation patterns in sporadic breast tumors by using the HumanMethylation27 BeadChips to assess relationships between DNA methylation changes and patient tumor characteristics. The arrays identified 264 hypermethylated loci/genes present in genomic CpG islands. Hierarchical clustering based on methylation levels divided the specimens into three distinct groups, within which certain clinical features also clustered. Statistically significant differences were determined between overall methylation levels of these clusters and estrogen receptor and progesterone receptor (ER/PR) status (P = 0.001), tumor relapse (P = 0.035), and lymph node metastasis (P = 0.042). We identified several individual methylated genes associated with clinical features, including six genes (RECK, SFRP2, UAP1L1, ACADL, ITR, and UGT3A1) that showed statistical significance between methylation and relapse-free survival. Notably, the RECK gene in this group has been associated in other cancers with poorest prognosis. Among the leading relapse-associated genes and the genes associated with ER/PR status, we sequenced an independent set of paired normal/tumor breast DNA samples to confirm tumor specificity of methylation. Further, we carried out quantitative real-time reverse transcriptase PCR to confirm reduced expression in methylated tumors. Our findings suggest the utility for the DNA methylation patterns in these genes as clinically useful surrogate markers in breast cancer, as well as new molecular pathways for further investigation as therapeutic targets. Cancer Res; 71(8); 2988-99. ©2011 AACR.

AB - Epigenetic profiling of tumor DNAs may reveal important new theranostic targets to improve prognosis and treatment of advanced cancer patients. In this study, we performed a genome-wide profile of DNA methylation patterns in sporadic breast tumors by using the HumanMethylation27 BeadChips to assess relationships between DNA methylation changes and patient tumor characteristics. The arrays identified 264 hypermethylated loci/genes present in genomic CpG islands. Hierarchical clustering based on methylation levels divided the specimens into three distinct groups, within which certain clinical features also clustered. Statistically significant differences were determined between overall methylation levels of these clusters and estrogen receptor and progesterone receptor (ER/PR) status (P = 0.001), tumor relapse (P = 0.035), and lymph node metastasis (P = 0.042). We identified several individual methylated genes associated with clinical features, including six genes (RECK, SFRP2, UAP1L1, ACADL, ITR, and UGT3A1) that showed statistical significance between methylation and relapse-free survival. Notably, the RECK gene in this group has been associated in other cancers with poorest prognosis. Among the leading relapse-associated genes and the genes associated with ER/PR status, we sequenced an independent set of paired normal/tumor breast DNA samples to confirm tumor specificity of methylation. Further, we carried out quantitative real-time reverse transcriptase PCR to confirm reduced expression in methylated tumors. Our findings suggest the utility for the DNA methylation patterns in these genes as clinically useful surrogate markers in breast cancer, as well as new molecular pathways for further investigation as therapeutic targets. Cancer Res; 71(8); 2988-99. ©2011 AACR.

U2 - 10.1158/0008-5472.CAN-10-4026

DO - 10.1158/0008-5472.CAN-10-4026

M3 - Article

C2 - 21363912

VL - 71

SP - 2988

EP - 2999

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 8

ER -