Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Breast Cancer Methylomes Establish an Epigenomic Foundation for Metastasis

ABSTRACT: Cancer-specific changes in DNA methylation can alter genetic stability, genomic structure, and gene expression. Promoter CpG island methylation can result in transcriptional silencing and plays an important role in the oncogenic process. We used genome-wide analysis to characterize the methylomes of breast cancers with diverse metastatic behavior. Here, we describe the identification of novel groups of breast tumors characterized by the presence or absence of coordinate hypermethylation at a large number of genes, demonstrating the existence of a breast-CpG island methylator phenotype (B-CIMP). B-CIMP imparts a distinct epigenomic profile and is a strong determinant of metastatic potential. Gene Expression Samples (GSM647057-GSM647077): Twenty-one breast cancer primary samples were analyzed. There are 10 CIMP positive and 11 CIMP negative samples. Methylation Profiling Samples (GSM651372-GSM651410): Thirty-nine breast cancer primary samples were analyzed. There are 17 CIMP positive and 22 CIMP negative samples.

ORGANISM(S): Homo sapiens

SUBMITTER: FANG FANG

PROVIDER: E-GEOD-26349 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Breast cancer methylomes establish an epigenomic foundation for metastasis.

Fang Fang F Turcan Sevin S Rimner Andreas A Kaufman Andrew A Giri Dilip D Morris Luc G T LG Shen Ronglai R Seshan Venkatraman V Mo Qianxing Q Heguy Adriana A Baylin Stephen B SB Ahuja Nita N Viale Agnes A Massague Joan J Norton Larry L Vahdat Linda T LT Moynahan Mary Ellen ME Chan Timothy A TA

Science translational medicine 20110301 75

Cancer-specific alterations in DNA methylation are hallmarks of human malignancies; however, the nature of the breast cancer epigenome and its effects on metastatic behavior remain obscure. To address this issue, we used genome-wide analysis to characterize the methylomes of breast cancers with diverse metastatic behavior. Groups of breast tumors were characterized by the presence or absence of coordinate hypermethylation at a large number of genes, demonstrating a breast CpG island methylator p ...[more]

PMID: 21430268

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Project description:Purpose: The long-term follow-up results from the EORTC-26951 trial showed that the addition of PCV after radiotherapy increases survival in anaplastic oligodendrogliomas/oligoastrocytomas (AOD/AOA). However, some patients appeared to benefit more from PCV treatment than others. Experimental Design: We performed genome-wide methylation profiling of 115 samples included in the EORTC-26951 trial and extracted the CpG island hypermethylated phenotype (CIMP) and MGMT promoter methylation (MGMT-STP27) status. Results: We first demonstrate that methylation profiling can be performed on archival tissues with a performance that is similar to snap frozen tissue samples. We then performed methylation profiling on EORTC-26951 clinical trial samples. Univariate analysis indicated that CIMP+ or MGMT-STP27 methylated tumors had an improved survival compared to CIMP- and/or MGMT-STP27 unmethylated tumors (median overall survival (OS) 1.05 v. 6.46 years and 1.06 v. 3.8 years, both P<0.0001 for CIMP and MGMT-STP27 status respectively). Multivariable analysis indicates that CIMP and MGMT-STP27 are significant prognostic factors for survival in presence of age, sex performance score and review diagnosis in the model.Multivariate analysis indicates that CIMP and MGMT-STP27 status are prognostic factors for survival independent of age, sex, performance score and review diagnosis. CIMP+ and MGMT-STP27 methylated tumors showed a clear benefit from adjuvant PCV chemotherapy: the median OS of CIMP+ samples in the RT and RT-PCV arms was 3.27 and 9.51 years respectively P=0.0033; for MGMT-STP27 methylated samples it was 1.98 and 8.65 years. There was no such benefit for CIMP- or for MGMT-STP27 unmethylated tumors. MGMT-STP27 status remained significant in an interaction test (P=0.003). Statistical analysis of microarray (SAM) identified 259 novel CpGs associated with treatment response. Conclusions: MGMT-STP27 may be used to guide treatment decisions in this tumor type. Bisulphite converted DNA from the 58 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip The following sample characteristics are provided; OS: overall survival; PFS: progression free survival; CIMP: CpG Island Methylator phenotype; IGS: Intrinsic Glioma subtype; MGMT: O6-methylguanine-DNA-methyltransferase; OR diagn: original diagnosis; Rev diag: review diagnosis; Tum loc: Tumor location; Perf: Performance score; TRT: treatment Performance is based on the ECOG performance status Tum loc: tumor location indicated by 1: Biopsy; 2: Partial Resection; 3: Total Resection. The MGMT promoter methylation status was determined previously (van den Bent et al, J. Clin Oncol 27: 5881-6, 2009) using MS-MLPA and may differ from the MGMT-SPT27 status.

Project description:We analyzed 28 fresh frozen samples from pure SCLC patients and 13 noncancerous lung tissues, using the Illumina Infinium 27k Human DNA methylation Beadchip v1.2 Background: Small cell lung cancer (SCLC) accounts for 13-15% of new lung cancer cases in worldwide and has the poor therapeutic outcomes with a median survival of just over one year. A CpG island methylate phenotype (CIMP) is well known as a methylator phenotype with characteristic promoter DNA methylation alterations, in colorectal cancers, glioblastoma and breast cancers, although there has been no report about any CIMP of SCLC. We investigated whether DNA methylation profiles can provide useful molecular subtyping of SCLC in terms of etiology and prognosis of SCLC. Results: We selected a total of 1741 most differentially methylated CpG sites (s.d. > 0.20) across the 28 SCLC tumor tissues in each DNA methylation platform, after an elimination of the probes related with the X- and Y- chromosome. Unsupervised hierarchical clustering of methylation data from SCLC samples reveals two major subgroups with different prognosis: the 5 years disease-free interval (DFI) rate of patients in cluster 1 (11.1%) was lower than that of patients in cluster 2 (61.57%) (p = 0.001). By multivariate analysis for DFI, both postoperative chemotherapy and cluster 1 were a significant prognostic factor (p = 0.002 and 0.002; respectively). Next, among 1220 genes with methylation and expression data both available, the CpG sites were ranked on the basis of the spearman’s correlation coefficient between cluster 1 and cluster 2 into an ascending order. Finally, we identified that fifty-five CpG sites were nagetively correlated and found that apoptosis pathway was a most differentially expressed. Conclusion: By comprehensive DNA methylation profiling, two distinct subgroups with different molecular and clinical phenotype were identified to evoke a CIMP of SCLC. We found some promoter markers in the apoptosis pathway could make a difference between the two groups, and we hope that our data can contribute to provide a useful resource for the construction of therapeutic strategy and the development of a new chemotherapeutic agent. After genomic DNA was treated with sodium bisulfite, bisulfite-converted genomic DNA was analyzed using Illumina’s Infinium HumanMethylation27 BeadChip.

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Dataset Information

Breast Cancer Methylomes Establish an Epigenomic Foundation for Metastasis

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Breast cancer methylomes establish an epigenomic foundation for metastasis.

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