Aberrant epigenetic and transcriptional events associated with breast cancer risk

Natascia Marino,Anna Maria V Storniolo,Ram Podicheti,Sandra Althouse,Jie Huang,Ashley Vode,Constance J Temm,Harikrishna Nakshatri,Jun Liu,Kenneth P Nephew,Pam Rockey,Douglas B Rusch,George E Sandusky,Rana German,Sha Cao

doi:10.1186/s13148-022-01239-1

Abstract

BackgroundGenome-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 high and those at average risk of breast cancer (Tyrer-Cuzick model) at FDR < 0.05 and fold change ≥ 2. 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 changes 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.

Highlights

Genome-wide association studies have identified several breast cancer susceptibility loci
Genome-wide association studies (GWAS) have detected more than 170 genomic loci harboring common variants associated with breast cancer (BC) risk including modifier alleles with high (e.g., BRCA1, BRCA2, TP53, PTEN) to moderate penetrance (e.g., BRIP1, CHEK2, ATM, and PALB2) [1,2,3,4]
Study cohort used to investigate molecular aberrations in association with breast cancer (BC) risk To identify transcriptomic and epigenetic differences linked with BC risk, we analyzed cancer-free breast tissue cores donated by 146 healthy women, including 112 Caucasian, 24 African American, and 10 Asian subjects (Additional file 1: Table S1)

Summary

Introduction

Genome-wide association studies have identified several breast cancer susceptibility loci. We investigated cancer-related molecular changes detected in tissues from women at high risk for breast cancer prior to disease manifestation. Marino et al Clinical Epigenetics (2022) 14:21 studies were used to integrate GWAS and gene expression datasets and identified 154 genes whose predicted expression associated with the risk for BC [5,6,7,8,9]. These studies drew data from the Genotype-Tissue Expression (GTEx) project, and, because of the use of autopsy-derived normal breast tissues, the breast-specific transcriptome profilings may be questionable. The relative lack of molecular profiling of normal breast tissue from subjects who are disease-free makes the field challenging

Objectives

Methods

Results

Discussion

Conclusion