Breast tumor DNA methylation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Brock Christensen
PROVIDER: E-GEOD-22290 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Breast cancer DNA methylation profiles are associated with tumor size and alcohol and folate intake.
Christensen Brock C BC Kelsey Karl T KT Zheng Shichun S Houseman E Andres EA Marsit Carmen J CJ Wrensch Margaret R MR Wiemels Joseph L JL Nelson Heather H HH Karagas Margaret R MR Kushi Lawrence H LH Kwan Marilyn L ML Wiencke John K JK
PLoS genetics 20100729 7
Although tumor size and lymph node involvement are the current cornerstones of breast cancer prognosis, they have not been extensively explored in relation to tumor methylation attributes in conjunction with other tumor and patient dietary and hormonal characteristics. Using primary breast tumors from 162 (AJCC stage I-IV) women from the Kaiser Division of Research Pathways Study and the Illumina GoldenGate methylation bead-array platform, we measured 1,413 autosomal CpG loci associated with 773 ...[more]
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Project description:Epigenetic control of gene transcription is critical for normal human development and cellular differentiation. While alterations of epigenetic marks such as DNA methylation have been linked to cancers and many other human diseases, interindividual epigenetic variation in normal tissues due to aging, environmental factors, or innate susceptibility are poorly characterized. The plasticity, tissue-specific nature, and variability of gene expression are related to epigenomic states that vary across individuals. Thus, population-based investigations are needed to further our understanding of the fundamental dynamics of normal individual epigenomes. We analyzed 217 non-pathologic human tissues from 10 anatomic sites at 1413 autosomal CpG loci associated with 773 genes to investigate tissue-specific differences in DNA methylation, and to discern how aging and exposures contribute to normal variation in methylation. Methylation profile classes derived from unsupervised modeling were significantly associated with age (P < 0.0001), and were significant predictors of tissue origin (P < 0.0001). In solid tissues (n=119) we found striking, highly significant CpG island dependent correlations between age and methylation; loci in CpG islands gained methylation with age, loci not in CpG islands lost methylation with age (P < 0.001), and this pattern was consistent across tissues and in an analysis of blood-derived DNA. Our data clearly demonstrate age and exposure related differences in tissue-specific methylation, and significant age associated methylation patterns which are CpG island context dependent. This work provides novel insight into the role of aging and the environment in susceptibility to diseases such as cancer, and critically informs the field of epigenomics by providing evidence of epigenetic dysregulation by age-related methylation alterations. Collectively we reveal key issues to consider both in the construction of reference. The causes and extent of tissue-specific interindividual variation in human epigenomes are underappreciated and hence, poorly characterized. We surveyed over 200 carefully annotated human tissue samples from ten anatomic sites at 1413 CpGs for methylation alterations to appraise the nature of phenotypically, and hence potentially clinically important epigenomic alterations. Within tissue types, across individuals, we found variation in methylation that was significantly related to aging and environmental exposures such as tobacco smoking. Individual variation in age and exposure-related methylation may significantly contribute to increased susceptibility to several diseases. As the NIH-funded HapMap project is critically contributing to annotating the human reference genome defining normal genetic variability, our work raises key issues to consider in the construction of reference epigenomes. It is well recognized that understanding genetic variation is essential to understanding disease. Our work, and the known interplay of epigenetics and genetics, makes it equally clear that a more complete characterization of epigenetic variation and its sources must be accomplished to reach the goal of a complete understanding of disease. Additional research is absolutely necessary to define the mechanisms controlling epigenomic variation. We have begun to lay the foundations for essential normal tissue controls for comparison to diseased tissue, which will allow the identification of the most crucial disease-related alterations and provide more robust targets for novel treatments. Normal human tissues were assembled by a collaborative, multi-institutional network of investigators conducting molecular epidemiologic studies of human cancer. Tissues were obtained through Institutional Review Board approved studies already underway at these institutions, or were obtained from the National Disease Research Interchange (NDRI, Philadelphia, PA). Briefly, normal brain tissues (n=12) were contributed by the Wiencke lab at UCSF through the San Francisco Adult Glioma Study (Wiemels JL, Int J Ca 2002). Normal lung tissues (n=49) were obtained from adjacent non-tumor portions of lung in patients treated for NSCLC (Wiencke JK, Ca Res, 1995) or from the NDRI from non-diseased individuals at autopsy (n=4). Peripheral blood DNA was obtained from controls enrolled in a study of bladder cancer (n=15) (Karagas MR, Env Health Persp 1998), controls enrolled in a study of head and neck cancer (n=15) (Peters ES, CEBP 2005, 14:476-82), and newborn infants (n=55) (Urayama KY, CEBP, 2007, 16:1172). Non-tumorigenic pleural samples (n=18) were obtained from grossly disease-uninvolved regions of incident mesothelioma (Christensen BC, Carcinogenesis 2008). Head and neck anatomic sites (n=11), bladder (n=5), kidney (n=6), and small intestine (n=5) were obtained from the NDRI, all from individuals with no gross diseases or tumors of the obtained tissues. Non-pathologic placenta samples (n=19) were obtained as residual tissues from control infant term births as part of an ongoing hospital-based case-control study of intrauterine growth restriction at Women and Infants Hospital in Providence RI. All tissues obtained from patients with disease (lung, pleura) were histologically confirmed as normal by independent study pathologist review of tissue samples prior to DNA extraction.
2010-06-25 | E-GEOD-19434 | biostudies-arrayexpress
Project description:Using paired tumor and non-tumor lung tissues from 47 individuals we identified common changes in DNA methylation associated with the development of non-small cell lung cancer. Pathologically normal lung tissue taken at the time of cancer resection was matched to tumorous lung tissue and together were probed for methylation status using Illumina GoldenGate arrays. For each matched pair the change in methylation at each CpG was calculated (the odds ratio), and these ratios were averaged across individuals and ranked by magnitude to identify the CpGM-bM-^@M-^Ys with the greatest change in methylation associated with tumor development. Using paired tumor and non-tumor lung tissues from 47 individuals we identified common changes in DNA methylation associated with the development of non-small cell lung cancer. Pathologically normal lung tissue taken at the time of cancer resection was matched to tumorous lung tissue and together were probed for methylation status using Illumina GoldenGate arrays. For each matched pair the change in methylation at each CpG was calculated (the odds ratio), and these ratios were averaged across individuals and ranked by magnitude to identify the CpGM-bM-^@M-^Ys with the greatest change in methylation associated with tumor development.
2012-07-02 | E-GEOD-27902 | biostudies-arrayexpress
Project description:Integrated profiling of somatic molecular alterations present in tumors is necessary to further our understanding of the tumorigenic process. We investigated the potential relationships between gene copy number alterations and DNA methylation profiles in a case series of pleural mesotheliomas (n=23). Gene copy number (CN) alterations profiled with 500K SNP arrays and DNA methylation measured at over 750 cancer-related genes with methylation bead-arrays were examined concomitantly. Considering each probed locus, there were no instances of significantly correlated CN alteration and methylation (no loci with Q < 0.05) and averaging loci over their associated genes revealed only two genes with significantly correlated CN and methylation alterations (Q < 0.04). In contrast to the lack of discrete correlations, the overall extent of tumor CN alteration was significantly associated with DNA methylation profile when comparing CN alteration extent among methylation profile classes (P < 0.02), and there was evidence that this association was partially attributable to prevalent allele loss observed at the maintenance DNA methyltransferase DNMT1. Taken together, this work indicates a strong association between global genetic and global epigenetic dysregulation in mesothelioma rather than a discrete, local coordination of gene inactivation, and further highlights the utility and necessity of integrative genomics approaches in cancer biology. Mesotheliomas were obtained following surgical resection at Brigham and Women’s Hospital through the International Mesothelioma Program from a pilot study conducted in 2002 and an incident case series beginning in 2005 as previously described (PMIDs: 19118007 and 19638575). All patients provided informed consent under the approval of the appropriate Institutional Review Boards. Clinical information, including histologic diagnosis was obtained from pathology reports. The study pathologist confirmed the histologic diagnoses and further assessed the percent tumor from resected specimens (mean >60%). DNA extraction and methylation analysis: DNA from fresh frozen tissue and matched whole blood was isolated with QIAamp DNA mini kit (Qiagen, Valencia, CA) following the manufacturer’s protocol. Tumor DNA was modified with sodium bisulfite using the EZ DNA Methylation Kit (Zymo Research, Orange, CA). Illumina GoldenGate® methylation bead arrays interrogated 1505 CpG loci associated with 803 cancer-related genes processed at the UCSF Institute for Human Genetics, Genomics Core Facility using methods described in (28). The GoldenGate methylation data used in the analysis has been previously described (PMIDs: 19118007 and 19638575).
2010-07-01 | E-GEOD-20989 | biostudies-arrayexpress
Project description:Solid tumors, including head and neck squamous cell carcinomas (HNSCC), arise as a result of genetic and epigenetic alterations in a sustained stress environment. Since it has been hypothesized that epigenetic alterations may act by providing the second carcinogenic hit in gene silencing, we sought to identify genome-wide DNA copy number alterations and CpG dinucleotide methylation events and examine the global/local relationships between these types of alterations in HNSCC. Importantly, we found that the global pattern of copy number alterations in these tumors was significantly associated with tumor methylation profiles. However at the local level, gene promoter regions did not exhibit a correlation between copy number and methylation , and the spectrum of genes affected by each type of alteration was unique. A case-series of 19 tumors and matched blood referents were hybrizided to Affymetrix Human Mapping 500k arrays and copy number was determined via HMM with Copy Number Analysis Tool v4.0.1. This study was designed to investigate the relationship between copy number and DNA methylation alterations in head and neck squamous cell carcinoma. Data in this submission relates to the methylation portion only. Each patient tumor has been de-identified and assigned a number (1-19). We included 11 normal head and neck samples, procured through the National Research Disease Interchange, that were used for reference when comparing tumor to normal. One ug of tissue DNA extracted using the Qiagen Blood and Tissue Kit was bisulfite-modified using a Zymo Research EZ DNA Methylation Kit. Samples were processed and arrayed on the Illumina GoldenGate Methylation Cancer Panel 1 at the University of California-San Francisco Institute for Genetics, Genomic Core Facility.
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2010-06-25 | E-GEOD-16559 | biostudies-arrayexpress
Project description:DNA methylation in colorectal cancer diagnosis. The Illumina GoldenGate Methylation Cancer Panel I was used to select a set of candidates markers informative of colorectal cancer diagnosis from 807 cancer-related genes. In the discovery phase, tumor tissue and paired adjacent normal mucosa from 92 colorectal patients were analyzed. Bisulphite converted DNA from 92 colorectal tumor samples and paired adjacent normal mucosa were hybridised to the Illumina GoldenGate Methylation Cancer Panel I. Additionally, replicates were hybridised for five tumor tissue and their corresponding normal mucosa for reproducibility purposes, totalling 194 samples. Three samples (SAMPLEs 49, 51, and 162) and 50 loci did not reach the quality criteria required regarding the signal-to-noise ratio and were therefore excluded from further analysis. One additional non-tumoral sample (SAMPLE 15) was removed because it exhibited a methylation pattern quiet different from that shown by the rest of normal specimens, which could be indicative of hybridization errors. These Samples and loci are included in the raw data matrix to allow other investigators to use them if different criteria are applied. They have been also included in the Sample tables with missing values in order to preserve the structure of the data across records/files (See 'data processing' section for more details).
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Project description:Analysis of genomic methylation differences between day workers and shift workers. We hypothesized that there would be differences in methylation patterns between day workers and shift workers, and that some of these differences may explain the association between long-term shift work and breast cancer. The array provides methylation data on more than 27,000 CpG sites spread across the genome. Bisulfite-converted DNA from 10 day workers and 10 shift workers were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2.
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2013-01-01 | E-GEOD-41384 | biostudies-arrayexpress
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