Mapping Geographic Zones of Cancer Risk with Epigenetic Biomarkers in Normal Breast Tissue

Yan, Pearlly S.; Venkataramu, Chinnambally; Ibrahim, Ashraf E.K.; Liu, Joseph C.; Shen, Rulong; Diaz, Nils M.; Centeno, Barbara A.; Weber, Frank; Leu, Yu Wei; Shapiro, Charles L.; Eng, Charis; Yeatman, Timothy J.; Huang, Tim H.M.

doi:10.1158/1078-0432.ccr-06-0467

Cited by 188 publications

(161 citation statements)

References 40 publications

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“…In the present study no significant differences were found for BRCA1, ATM and BARD1 immunoreactivity between normal breast from cancer-containing breasts and non-cancerous breasts. Genomic instability has been reported to be present at a higher frequency in cancer-containing breasts [19,20] and hypermethylation, which can modify gene expression, of genes involved in growth regulation has been found [18,43]. A higher frequency of hypermethylation is found in benign lesions [reviewed in 44].…”

Section: Discussionmentioning

confidence: 99%

Altered expression of anti-apoptotic proteins in non-involved tissue from cancer-containing breasts

Batchelder

Gordon-Weeks

Walker

2008

Breast Cancer Res Treat

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In a previous investigation reduced apoptosis was identified in normal breast tissue from cancer-containing breasts away from the cancer in comparison to age-matched normal breast from women without cancer. The hypothesis for this study was that defects in expression of apoptotic regulatory and DNA repair proteins would facilitate persistence of genetic alterations and predispose to breast cancer development.Using immunohistochemistry normal breast from 120 age-matched women (58 with breast cancer, 62 without) was analysed for proliferation, apoptosis, bcl2, BAX, caspase 3, Hsp27, Hsp70, BRCA1, ATM and BARD1. All assessments were performed without knowledge as to whether it was a cancer case or control. A significant difference was found for apoptotic index which was higher in controls p<0.02). There was no change in apoptotic and proliferation index with age for cancer cases unlike controls. Higher expression of bcl2 (p=0.001) and Hsp27 (p=0.001) in was found in normal breast from cancer-containing breast in comparison to controls. There were no differences in the other proteins.Apoptosis has been found to be reduced in normal breast in a separate cohort of women with breast cancer, along with increased expression of the anti-apoptotic proteins bcl2 and Hsp27.These alterations in apoptotic regulation would enhance tumour development. Further studies are needed to examine the value of these proteins as risk markers.

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Section: Discussionmentioning

confidence: 99%

Altered expression of anti-apoptotic proteins in non-involved tissue from cancer-containing breasts

Batchelder

Gordon-Weeks

Walker

2008

Breast Cancer Res Treat

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“…The semiquantitative methylation-specific PCR (qMSP) experiment was conducted and products were quantified according to the protocol described in Yan and colleagues (22). Briefly, bisulfite-converted genomic DNAs (0.5 mg) were subject to real-time PCR (RT-PCR) with methylation-specific primers (Supplementary Table S2).…”

Section: Semiquantitative Real-time Methylation-specific Pcrmentioning

confidence: 99%

Targeted Methylation of Two Tumor Suppressor Genes Is Sufficient to Transform Mesenchymal Stem Cells into Cancer Stem/Initiating Cells

et al. 2011

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Although DNA hypermethylation within promoter CpG islands is highly correlated with tumorigenesis, it has not been established whether DNA hypermethylation within a specific tumor suppressor gene (TSG) is sufficient to fully transform a somatic stem cell. In this study, we addressed this question using a novel targeted DNA methylation technique to methylate the promoters of HIC1 and RassF1A, two well-established TSGs, along with a two-component reporter system to visualize successful targeting of human bone marrow-derived mesenchymal stem cells (MSC) as a model cell system. MSCs harboring targeted promoter methylations of HIC1/RassF1A displayed several features of cancer stem/initiating cells including loss of anchorage dependence, increased colony formation capability, drug resistance, and pluripotency. Notably, inoculation of immunodeficient mice with low numbers of targeted MSC resulted in tumor formation, and subsequent serial xenotransplantation and immunohistochemistry confirmed the presence of stem cell markers and MSC lineage in tumor xenografts. Consistent with the expected mechanism of TSG hypermethylation, treatment of the targeted MSC with a DNA methyltransferase inhibitor reversed their tumorigenic phenotype. To our knowledge, this is the first direct demonstration that aberrant TSG hypermethylation is sufficient to transform a somatic stem cell into a fully malignant cell with cancer stem/initiating properties. Cancer Res; 71(13); 4653-63. Ó2011 AACR.

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“…11,12 Importantly, Helicobacter pylori infection, a major carcinogenic factor in the stomach, was shown to potently induce aberrant DNA methylation in gastric epithelial cells. 11 In addition to gastric cancers, the presence of aberrant DNA methylation in noncancerous tissues and possible association with cancer risks have been reported for liver, 13 colon, 14 esophageal, 15 breast 16 and renal cancers. 17 Genes so far analyzed in noncancerous gastric mucosae are those methylated in gastric cancers, including tumor-suppressor genes, such as CDKN2A, MLH1, CDH1, LOX and APC, 2,11,18,19 and genes with little or no expression in normal gastric mucosae, such as FLNc, HAND1 and THBD.…”

mentioning

confidence: 99%

DNA methylation of microRNA genes in gastric mucosae of gastric cancer patients: Its possible involvement in the formation of epigenetic field defect

Ando

Yoshida

Enomoto

et al. 2009

Intl Journal of Cancer

258

207

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Accumulation of aberrant DNA methylation in normal-appearing gastric mucosae, mostly induced by H. pylori infection, is now known to be deeply involved in predisposition to gastric cancers (epigenetic field defect), and silencing of protein-coding genes has been analyzed so far. In this study, we aimed to clarify the involvement of microRNA (miRNA) gene silencing in the field defect. First, we selected three miRNA genes as methylation-silenced after analysis of six candidate ''methylation-silenced'' tumor-suppressor miRNA genes. Methylation levels of the three genes (miR124a-1, miR-124a-2 and miR-124a-3) were quantified in 56 normal gastric mucosae of healthy volunteers (28 volunteers with H. pylori and 28 without), 45 noncancerous gastric mucosae of gastric cancer patients (29 patients with H. pylori and 16 without), and 28 gastric cancer tissues (13 intestinal and 15 diffuse types). Among the healthy volunteers, individuals with H. pylori had 7.8-13.1-fold higher methylation levels than those without (p < 0.001). Among individuals without H. pylori, noncancerous gastric mucosae of gastric cancer patients had 7.2-15.5-fold higher methylation levels than gastric mucosae of healthy volunteers (p < 0.005). Different from protein-coding genes, individuals with past H. pylori infection retained similar methylation levels to those with current infection. In cancer tissues, methylation levels were highly variable, and no difference was observed between intestinal and diffuse histological types. This strongly indicated that methylationsilencing of miRNA genes, in addition to that of protein-coding genes, contributed to the formation of a field defect for gastric cancers. ' 2008 Wiley-Liss, Inc.Key words: field for cancerization; microRNA; methylation; gastric cancer; Helicobacter pylori Metachronous occurrence of gastric cancers is becoming an important issue as localized resection of early gastric cancers by endoscopic submucosal dissection (ESD) has become common. 1 The incidence of secondary primary gastric cancers after ESD reaches as high as 2.0% per year 2 whereas the incidence of gastric cancer in the general Japanese population is 0.14% per year. 3 This indicates that noncancerous gastric mucosae are already predisposed to developing gastric cancers, forming a field defect (field for cancerization). High incidences of metachronous cancers have been known not only for gastric cancers but also for bladder, liver, and esophageal cancers 4-6 and are becoming recognized for lung, breast and colorectal cancers. [7][8][9] A molecular basis for the field defect has been considered as an accumulation of genetic and epigenetic alterations in normalappearing tissues. Traditionally, cells with a genetic alteration were considered to form a physically continuous patch, producing a genetically altered field. 10 Recently, we found that aberrant DNA methylation of specific genes can be induced in as high as several percentage of cells in noncancerous gastric mucosae (thus in multiple independent gastric glands), and the degre...

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Mapping Geographic Zones of Cancer Risk with Epigenetic Biomarkers in Normal Breast Tissue

Cited by 188 publications

References 40 publications

Altered expression of anti-apoptotic proteins in non-involved tissue from cancer-containing breasts

Altered expression of anti-apoptotic proteins in non-involved tissue from cancer-containing breasts

Targeted Methylation of Two Tumor Suppressor Genes Is Sufficient to Transform Mesenchymal Stem Cells into Cancer Stem/Initiating Cells

DNA methylation of microRNA genes in gastric mucosae of gastric cancer patients: Its possible involvement in the formation of epigenetic field defect

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