Epigenetic change in DNA associated with cancer risk in multi-omics research

A research team led by researchers from Vanderbilt University Medical Center and the University of Virginia has identified associations between DNA methylation and cancer risk. DNA methylation is an epigenetic change – the addition of ‘methyl groups’ to DNA – that can affect gene expression without changing the DNA sequence. Most DNA methylation occurs at CpG sites in the genome.

The new study, published in the news Nature communicationidentifies 4,248 CpG sites associated with the risk of seven different types of cancer: breast, colorectal, renal cell, lung, ovarian, prostate, and testicular germ cell cancer.

“The findings significantly advance our understanding of the interplay between genetics, epigenetics and gene expression in the etiology of cancer,” said Qiuyin Cai, MD, Ph.D., co-corresponding author of the new study with Jirong Long, Ph.D. , and Yaohua Yang, Ph.D. Cai and Long are both professors of medicine at the Department of Epidemiology at VUMC; Yang is an assistant professor of public health sciences at the University of Virginia.

Although genome-wide association studies (GWAS) have identified more than 1,000 common genetic variants (changes in the DNA sequence) associated with cancer risk, many of these variants are located in regions of the genome that do not code for proteins. This poses a challenge to identifying the target genes of these genetic variants and investigating how they influence cell function and contribute to cancer development.

Cai, Long and their colleagues previously identified DNA methylation levels in blood samples that are associated with cancer risk. They are now expanding their research to cancer-relevant tissues.

Using DNA methylation data in normal tissues and paired genetic data from cancer-free donors from the Genotype-Tissue Expression consortium, they developed genetic models to predict DNA methylation levels at CpG sites in the genome for seven tissues.

The researchers then applied their prediction models to the corresponding GWAS data for cancers of the seven tissue types to determine associations between genetically predicted DNA methylation levels and cancer risk.

Of the 4,248 CpG sites associated with cancer risk, 95% were specific to a certain type of cancer.

For the cancer-associated CpG sites, the researchers performed integrative “multi-omics” analyzes of DNA methylomic, transcriptomic, genomic, and cancer GWAS data to investigate whether DNA methylation levels influence cancer risk through the expression of nearby modulate genes.

These studies revealed that DNA methylation levels at 309 different CpG sites could influence cancer risk by regulating the expression of 205 unique genes.

“Our findings highlight the effectiveness of multi-omics integration and advance our understanding of the critical role of genetics and epigenetics in cancer development,” Long said.