scholarly journals Aberrant epigenetic and transcriptional events associated with breast cancer risk

2021 ◽  
Author(s):  
Natascia Marino ◽  
Rana German ◽  
Ram Podicheti ◽  
Douglas B. Rush ◽  
Pam Rockey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Breast Cancer Risk ◽  
Epithelial Cells ◽  
Cancer Risk ◽  
Breast Tissue ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Normal Breast ◽  
Breast Tissues

ABSTRACTBackgroundGenome-wide association studies have identified several breast cancer susceptibility loci. However, biomarkers for risk assessment are still missing. Here, we investigated cancer-related molecular changes detected in tissues from women at high risk for breast cancer prior to disease manifestation. Disease-free breast tissue cores donated by healthy women (N=146, median age=39 years) were processed for both methylome (MethylCap) and transcriptome (Illumina’s HiSeq4000) sequencing. Analysis of tissue microarray and primary breast epithelial cells was used to confirm gene expression dysregulation.ResultsTranscriptomic analysis identified 69 differentially expressed genes between women at either high and those at average risk of breast cancer (Tyrer-Cuzick model) at FDR<0.05 and fold change≥2. The majority of the identified genes were involved in DNA damage checkpoint, cell cycle, and cell adhesion. Two genes, FAM83A and NEK2, were overexpressed in tissue sections (FDR<0.01) and primary epithelial cells (p<0.05) from high-risk breasts. Moreover, 1698 DNA methylation aberrations were identified in high-risk breast tissues (FDR<0.05), partially overlapped with cancer-related signatures and correlated with transcriptional changes (p<0.05, r≤0.5). Finally, among the participants, 35 women donated breast biopsies at two time points, and age-related molecular alterations enhanced in high-risk subjects were identified.ConclusionsNormal breast tissue from women at high risk of breast cancer bears molecular aberrations that may contribute to breast cancer susceptibility. This study is the first molecular characterization of the true normal breast tissues and provides an opportunity to investigate molecular markers of breast cancer risk, which may lead to new preventive approaches.

Epigenetic control of breast cancer susceptibility.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1560-1560
Author(s):  
Natascia Marino ◽  
Rana German ◽  
Nakshatri Harikrishna ◽  
Ram Podicheti ◽  
Ashley Vode ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Methylation ◽  
High Risk ◽  
Breast Cancer Risk ◽  
Breast Tissue ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Average Risk ◽  
Coding Regions

1560 Background: Epigenetic mechanisms such as DNA methylation are important regulators of gene expression and are frequently dysregulated early in breast carcinogenesis. The relationship between DNA methylation aberrations in normal breast tissue and breast cancer risk remains unclear. Methods: Disease-free breast tissue cores donated by 71 high-risk (Tyrer-Cuzick lifetime risk ≥20%) and 79 average-risk women were obtained from the Komen Tissue Bank and processed for whole methylome (Diagenode's MethylCap Library and single-end 75-bp sequencing on Illumina Nextseq) and whole transcriptome (Illumina Nextseq) profiling. Reads from RNA-seq data were aligned to the human genome reference, GRCh38.p12 using STAR v.2.5.2b and tested for differential gene expression using DESeq2 ver. 1.24.0. For DNA methylation data, difference of variation in deduplicated read coverage among 250-bp fixed sized bins spanning CpG islands between high- and average-risk libraries was computed as z-ratios to identify differentially methylated regions. Pathway analysis was performed using IPA v06_01. Results: We identified 1355 CpGs that were differentially methylated between high- and average-risk breast tissues (ΔZ > 0.5, FDR < 0.05). Hypomethylated CpGs were overrepresented in high-risk tissue and were found predominantly (68%) in non-coding regions. Hypermethylated CpG sites were found equally in the gene body and non-coding regions. Transcriptomic analysis identified 112 differentially expressed genes (fold change≥2, FDR < 0.05), involved in chemokines signaling, metabolism and estrogen biosynthesis. Among those, FAM83A (logfc = 2.3, FDR = 0.004) was previously described as epigenetically dysregulated in multiple cancers and transforms breast epithelial cell in vitro. Methylation-expression correlations revealed 11 epigenetically regulated genes including cellular transformation-associated BMPR1B. Two hypomethylated/upregulated long non-coding RNAs were also identified in high-risk breasts. Conclusions: This is the first gene expression/DNA methylation analysis of normal breasts from women at either high or average risk of breast cancer. Our discovery of epigenetically regulated genes associated with breast cancer risk provides an opportunity to mechanistically dissect breast cancer susceptibility and risk-associated molecular alterations. Unlike the current focus of identifying germline mutations or single nucleotide polymorphisms responsible for higher risk, our studies reveal an epigenetic mechanism, which is not discernable through simple genomic sequencing.

scholarly journals DNA Methylation and Breast Cancer Risk: An Epigenome-Wide Study of Normal Breast Tissue and Blood

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3088 ◽  
Author(s):  
Kaoutar Ennour-Idrissi ◽  
Dzevka Dragic ◽  
Elissar Issa ◽  
Annick Michaud ◽  
Sue-Ling Chang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Breast Tissue ◽  
Normal Breast Tissue ◽  
Normal Breast ◽  
Breast Epithelium ◽  
Normal Breast Epithelium ◽  
Differentially Methylated Genes

Differential DNA methylation is a potential marker of breast cancer risk. Few studies have investigated DNA methylation changes in normal breast tissue and were largely confounded by cancer field effects. To detect methylation changes in normal breast epithelium that are causally associated with breast cancer occurrence, we used a nested case–control study design based on a prospective cohort of patients diagnosed with a primary invasive hormone receptor-positive breast cancer. Twenty patients diagnosed with a contralateral breast cancer (CBC) were matched (1:1) with 20 patients who did not develop a CBC on relevant risk factors. Differentially methylated Cytosine-phosphate-Guanines (CpGs) and regions in normal breast epithelium were identified using an epigenome-wide DNA methylation assay and robust linear regressions. Analyses were replicated in two independent sets of normal breast tissue and blood. We identified 7315 CpGs (FDR < 0.05), 52 passing strict Bonferroni correction (p < 1.22 × 10−7) and 43 mapping to known genes involved in metabolic diseases with significant enrichment (p < 0.01) of pathways involving fatty acids metabolic processes. Four differentially methylated genes were detected in both site-specific and regions analyses (LHX2, TFAP2B, JAKMIP1, SEPT9), and three genes overlapped all three datasets (POM121L2, KCNQ1, CLEC4C). Once validated, the seven differentially methylated genes distinguishing women who developed and who did not develop a sporadic breast cancer could be used to enhance breast cancer risk-stratification, and allow implementation of targeted screening and preventive strategies that would ultimately improve breast cancer prognosis.

scholarly journals Single Nucleotide Polymorphism in hsa-mir-196a-2 and Breast Cancer Risk: A Case Control Study

2011 ◽  
Vol 14 (5) ◽  
pp. 417-421 ◽  
Author(s):  
Dominik J. Jedlinski ◽  
Plamena N. Gabrovska ◽  
Stephen R. Weinstein ◽  
Robert A. Smith ◽  
Lyn R. Griffiths
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Case Control ◽  
Cancer Tissue ◽  
Transcriptional Level ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

microRNAs are small, non-coding RNAs that influence gene expression on a post-transcriptional level. They participate in diverse biological pathways and may act as either tumor suppressor genes or oncogenes. As they may have an effect on thousands of target mRNAs, single-nucleotide polymorphisms in microRNA genes might have major functional consequences, because the microRNA's properties and/or maturation may change. miR-196a has been reported to be aberrantly expressed in breast cancer tissue. Additionally, the SNP rs11614913 in hsa-mir-196a-2 has been found to be associated with breast cancer risk in some studies although not in others. This study evaluated the association between rs11614913 and breast cancer risk in a Caucasian case-control cohort in Queensland, Australia. Results do not support an association of the tested hsa-mir-196a-2 polymorphism with breast cancer susceptibility in this cohort. As there is a discrepancy between our results and previous findings, it is important to assess the role of rs11614913 in breast cancer by further larger studies investigating different ethnic groups.

Birth weight, breast cancer susceptibility loci, and breast cancer risk

2010 ◽  
Vol 21 (5) ◽  
pp. 689-696 ◽  
Author(s):  
Rulla M. Tamimi ◽  
Pagona Lagiou ◽  
Kamila Czene ◽  
Jianjun Liu ◽  
Anders Ekbom ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Birth Weight ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Susceptibility Loci

Cell-based breast cancer risk stratification based on DNA methylation in fine needle aspiration samples

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1508-1508
Author(s):  
D. Euhus ◽  
D. Bu ◽  
S. Milchgrub ◽  
A. M. Leitch ◽  
C. M. Lewis
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Lower Risk ◽  
Breast Tissue ◽  
Needle Aspiration ◽  
Gail Model ◽  
Rassf1a Methylation ◽  
Risk Patients

1508 Background: Tumor suppressor gene (TSG) methylation is identified in nearly all breast cancers, but rarely in histologically normal breast tissue from wonen unaffected with breast cancer. Its occurrence in high risk preneoplasia and in benign breast tissue adjacent to breast cancer suggests that it may represent a high risk field change that could be exploited for cell-based breast cancer risk stratification. Methods: TSG methylation was measured by quantitative methylation-specific real time PCR in 53 breast tumor fine needle aspiration (FNA) biopsies, 84 cellular random periareolar FNAs (RP-FNA) ipsilateral or contralateral to these cancers, 36 cellular RP- FNAs from unaffected women at high risk for breast cancer by the Gail model, and 95 cellular RP-FNAs from unaffected women at lower risk by the Gail model. Results: The breast tumors showed a high frequency of TSG methylation: RASSF1A 80%, HIN-1 65%, Cyclin D2 60%, RAR-β2 53%, and APC 47%. In general, RP-FNA samples from cancer patients and Gail high risk patients showed a greater frequency of methylation than samples from Gail lower risk patients: RASSF1A 43% vs. 21%, P = 0.001, HIN-1 32% vs. 20%, P = 0.05; Cyclin D2 18% vs. 9%, P = 0.10; RAR-β2 21% vs. 18%, P = 0.68; and APC 25% vs. 16%, P = 0.17. Twelve of 215 RP-FNA samples (5%) showed very high levels of methylation (>10% methylation for two or more genes). Only two of these samples were from women classified as lower risk by the Gail model. Methylation frequencies were entirely independent of cell yields but the frequency of RASSF1A methylation increased with increasing Masood scores (P = 0.05). Methylation of RASSF1A in one breast was highly predictive of RASSF1A methylation in the opposite breast (P < 0.0001). Conclusions: TSG methylation appears to be a breast cancer risk-associated field change that can be quantified in RP-FNA samples. RASSF1A methylation occurs frequently in benign breast epithelium, provides reasonable discrimination between high and lower risk breasts (O.R. = 2.0), is related to cytological atypia, and may be an early marker of a methylator phenotype. Quantification of TSG methylation in RP-FNA samples may provide a valuable surrogate endpoint biomarker for Phase II prevention trials. No significant financial relationships to disclose.

Normal Breast Physiology: The Reasons Hormonal Contraceptives and Induced Abortion Increase Breast-Cancer Risk

2009 ◽  
Vol 76 (3) ◽  
pp. 236-249 ◽  
Author(s):  
Angela Lanfranchi
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Breast Tissue ◽  
Induced Abortion ◽  
Normal Breast ◽  
Increase Breast Cancer Risk ◽  
Hormonal Contraceptives ◽  
Proliferative Effect ◽  
Breast Physiology

A woman gains protection from breast cancer by completing a full-term pregnancy. In utero, her offspring produce hormones that mature 85 percent of the mother's breast tissue into cancer-resistant breast tissue. If the pregnancy ends through an induced abortion or a premature birth before thirty-two weeks, the mother's breasts will have only partially matured, retaining even more cancer-susceptible breast tissue than when the pregnancy began. This increased amount of immature breast tissue will leave the mother with more sites for cancer initiation, thereby increasing her risk of breast cancer. Hormonal contraceptives increase breast-cancer risk by their proliferative effect on breast tissue and their direct carcinogenic effects on DNA. Hormonal contraceptives include estrogen-progestin combination drugs prescribed in any manner of delivery: orally, transdermally, vaginally, or intrauterine. This article provides the detailed physiology and data that elucidate the mechanisms through which induced abortion and hormonal contraceptives increase breast-cancer risk.

scholarly journals Genomic Changes in Normal Breast Tissue in Women at Normal Risk or at High Risk for Breast Cancer

2016 ◽  
Vol 10 ◽  
pp. BCBCR.S39384 ◽  
Author(s):  
David N. Danforth
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
High Risk ◽  
Breast Tissue ◽  
Sporadic Breast Cancer ◽  
Normal Breast Tissue ◽  
Normal Breast ◽  
Breast Carcinogenesis ◽  
Molecular Changes ◽  
Breast Tissues

Sporadic breast cancer develops through the accumulation of molecular abnormalities in normal breast tissue, resulting from exposure to estrogens and other carcinogens beginning at adolescence and continuing throughout life. These molecular changes may take a variety of forms, including numerical and structural chromosomal abnormalities, epigenetic changes, and gene expression alterations. To characterize these abnormalities, a review of the literature has been conducted to define the molecular changes in each of the above major genomic categories in normal breast tissue considered to be either at normal risk or at high risk for sporadic breast cancer. This review indicates that normal risk breast tissues (such as reduction mammoplasty) contain evidence of early breast carcinogenesis including loss of heterozygosity, DNA methylation of tumor suppressor and other genes, and telomere shortening. In normal tissues at high risk for breast cancer (such as normal breast tissue adjacent to breast cancer or the contralateral breast), these changes persist, and are increased and accompanied by aneuploidy, increased genomic instability, a wide range of gene expression differences, development of large cancerized fields, and increased proliferation. These changes are consistent with early and long-standing exposure to carcinogens, especially estrogens. A model for the breast carcinogenic pathway in normal risk and high-risk breast tissues is proposed. These findings should clarify our understanding of breast carcinogenesis in normal breast tissue and promote development of improved methods for risk assessment and breast cancer prevention in women.

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