Grant Details
Grant Number: |
3R01CA247987-02S1 Interpret this number |
Primary Investigator: |
Long, Jirong |
Organization: |
Vanderbilt University Medical Center |
Project Title: |
DNA Methylation Markers, Genes and Breast Cancer Risk |
Fiscal Year: |
2022 |
Abstract
Summary
This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-
22-036. There is no change for the parent grant. Genome-wide association studies (GWAS) have identified
common variants in ~200 genetic loci associated with breast cancer risk. However, it is difficult to translate
these findings to disease prevention and treatment because causal genes and underlying mechanisms in
these loci are largely unknown. Increasing evidence suggests that epigenetic regulation may be on the causal
pathway between genetic variants and diseases. DNA methylation, one of the most frequent and important
epigenetic modifications, plays a crucial role in cancer development. However, it is almost impossible to collect
pre-diagnostic breast tissues to profile the methylome from a large number of participants. Herein, we propose
a novel -omics approach: a methylation-wide association study (MeWAS) using genetic instruments. In Aim 1,
we will build race-specific prediction models using genome wide methylation and genetic data in fresh-frozen
breast samples from 600 cancer-free women of African-, Asian- and European- ancestry (200 per race). These
models will then be applied to the GWAS data from three large consortia, including ~123,000 cases and
~106,000 controls of European, ~25,000 cases and ~25,000 controls of Asian-, ~20,000 cases and ~20,000
controls of African- ancestry to impute methylation levels. The genetically predicted methylation levels will be
tested in association with breast cancer overall and by estrogen receptor and HER2 status. In Aim 2, we will
perform a series of integrative functional analyses to evaluate the functions of promising methylation sites and
the potential target genes regulated by these methylation sites. In Aim 3, we will select the top 20 methylation
sites and their target genes for in vitro functional assays to assess their influence on major cell functions
related to cancer biology. Given the strong pilot data, unique resources from three large genetic consortia, and
our team's extensive expertise and experience, we are uniquely positioned to conduct this project. The findings
will greatly improve our understanding of the genetic and biological basis of breast cancer pathogenesis and
facilitate the translation of genetic findings to prevention and treatment.
Publications
None. See parent grant details.