Enrichment of CpG island shore region hypermethylation in epigenetic breast field cancerization

Abstract

While changes in DNA methylation are known to occur early in breast carcinogenesis and the landscape of breast tumour DNA methylation is profoundly altered compared with normal tissue, there have been limited efforts to identify DNA methylation field cancerization effects in histologically normal breast tissue adjacent to tumour. Matched tumour, histologically normal tissue of the ipsilateral breast (ipsilateral-normal), and histologically normal tissue of the contralateral breast (contralateral-normal) were obtained from nine women undergoing bilateral mastectomy. Laser capture microdissection was used to select epithelial cells from normal tissue, and neoplastic cells from tumour for genome-scale measures of DNA methylation with the Illumina HumanMethylationEPIC array. We identified substantially more CpG loci that were differentially methylated between contralateral-normal and tumour (63,271 CpG loci q < 0.01), than between ipsilateral-normal and tumour (38,346 CpG loci q < 0.01). We identified differential methylation in ipsilateral-normal relative to contralateral-normal tissue (9,562 CpG loci p < 0.01). In this comparison, hypomethylated loci were significantly enriched for breast cancerrelevant transcription factor binding sites including those for ESR1, FoxA1, and GATA3 and hypermethylated loci were significantly enriched for CpG island shore regions. In addition, progression of shore hypermethylation was observed in tumours compared to matched ipsilateral normal tissue, and these alterations tracked to several well-established tumour suppressor genes. Our results indicate an epigenetic field effect in surrounding histologically normal tissue. This work offers an opportunity to focus investigations of early DNA methylation alterations in breast carcinogenesis and potentially develop epigenetic biomarkers of disease risk.

A phase 1 study of combined guadecitabine and cisplatin in platinum refractory germ cell cancer

“…For Patient 5, genomic DNA was extracted from formalin‐fixed and paraffin‐embedded (FFPE) samples from C1D1 and C1D8 biopsies and purified using the Qiagen DNeasy assay. Infinium MethylationEPIC beadchip array analysis was performed by the genomics core at the University of Southern California 34 . DNA was bisulfite treated using the EZ DNA methylation kit (Zymo) and also processed for FFPE restoration by standard protocols.…”

“…Infinium MethylationEPIC beadchip array analysis was performed by the genomics core at the University of Southern California. 34 DNA was bisulfite treated using the EZ DNA methylation kit (Zymo) and also processed for FFPE restoration by standard protocols. The MethylationEPIC array targets 862,927 CpG sites across the genome.…”

Tissue‐disruption‐induced cellular stochasticity and epigenetic drift: Common origins of aging and cancer?

“…[9] There is abundant evidence that epigenetics is involved in the early steps of oncogenesis. For example, the presence of epigenetic [10,11] and gene expression [12,13] alterations in healthy tissue near tumors,or the epigenetic changes induced by cigarette smoke condensate, which provides an "epigenetic substrate" allowing subsequent "addiction" to mutated driver genes [14] -can be considered important arguments for revising cancer theory, where epigenetic modifications could be the initiator events. The massive presence of oncogenic events in healthy tissues such as skin, [15] esophagus, [16] lung, [17] and many others [18] is another source of data leading us to consider alternatives to genetic-based theories.…”

Upregulation of LINC00511 expression by DNA hypomethylation promotes the progression of breast cancer

“…Teschendorff (26) analyzed the changes of DNA methylation levels in breast tissues of 50 cancer-free women and 84 paired cancers and normal tissues through a cohort study, and found that there were DNA methylation changes associated with tumorigenesis in the adjacent normal tissues of breast cancer, and 30% of the changes were increased in paired cancer tissue samples. Moreover, compared with the normal tissue on the opposite side of the tumor, the hypomethylation locus in the normal tissue on the ipsilateral side of the tumor was rich in transcription factor binding sites related to breast cancer (P<0.01), and the hypermethylation locus in the normal tissue on the ipsilateral side of the tumor relative to the normal tissue on the contralateral side of the tumor was depleted for CpG island, but enriched for adjacent shore regions (P<0.01) (27). Studies have found that detection of DNA methylation in peripheral blood is helpful for breast cancer risk assessment.…”