Researchers have identified two genetic markers that may illuminate the association between red and/or processed meat consumption and the risk of colorectal cancer, according to a novel study published by Stern et al in Cancer Epidemiology, Biomarkers & Prevention.
Background
Previous studies have demonstrated that the frequent consumption of red and processed meat could increase the risk of developing colorectal cancer; however, the predominant biological mechanism behind the correlation has yet to be established. Understanding the disease process and which genes underlie the mechanism could help advance prevention strategies for colorectal cancer.
Study Methods and Results
In the new study, the researchers analyzed the red and processed meat intake of 29,842 patients with colorectal cancer and 39,635 individuals without cancer who participated in 27 studies of colorectal cancer risk in those of European origin. They compiled data from the Genetics and Epidemiology of Colorectal Cancer Consortium, the Colorectal Cancer Transdisciplinary Study, and the Colon Cancer Family Registry.
The researchers harmonized the data from the various studies to create standard measures for the consumption of red meat (beef, pork, and lamb) and processed meat (bacon, sausages, lunch/deli meats, and hot dogs). For each category, they calculated servings per day, adjusted for body mass index, and divided the participants into four groups based on their levels of red or processed meat intake.
The participants with the highest levels of red and processed meat intake had a 30% and 40% increased risk of colorectal cancer, respectively. However, the increased risk did not account for genetic variability that may put some individuals at higher risk than others.
The researchers next used DNA samples to collect data on over 7 million gene variants spanning the genome for each of the study participants. They then conducted a genome-wide gene-environment interaction analysis of the link between red meat intake and cancer risk. Utilizing single-nucleotide polymorphisms, they examined whether having a certain gene variant altered the risk of developing colorectal cancer among those who consumed more red meat.
“These state-of-the-art statistical methods and software allowed us to maximize efficiency as we tested for gene-meat interactions across 7 million genetic variants,” explained senior study author James Gauderman, PhD, Professor of Population and Public Health Sciences at the Keck School of Medicine at USC.
At almost every single-nucleotide polymorphism on the genome, the researchers determined that regardless of which gene variant the participants had, their cancer risk based on red meat consumption remained the same. However, at two specific single-nucleotide polymorphisms, the association changed.
Using a standard statistical analysis approach, they identified the rs4871179 single-nucleotide polymorphism in chromosome 8 near the HAS2 gene. The gene is part of a pathway that codes for protein modification inside cells and has been linked to colorectal cancer in some previous studies but never to red meat consumption. The analysis showed that the participants with a common variant of the HAS2 gene—present in 66% of the population—had a 38% higher likelihood of developing colorectal cancer if they consumed the highest level of meat. In contrast, those with a rarer variant of the HAS2 gene experienced no increased risk of colorectal cancer when they consumed more red meat.
“We then used our novel, two-step machine learning approach to first identify patterns among [single-nucleotide polymorphisms], red meat consumption, and cancer, then focus on the most promising combinations in our gene-environment interaction tests,” Dr. Gauderman stated.
This method identified the rs35352860 single-nucleotide polymorphism in chromosome 18, part of the SMAD7 gene. This gene is responsible for regulating hepcidin, a protein linked to iron metabolism. Because red and processed meats contain high levels of heme iron, the researchers hypothesized that different variants of SMAD7 may increase the risk of colorectal cancer by altering the way the body processes iron.
“When hepcidin is dysregulated, that can lead to increased iron absorption and even iron overload inside cells,” revealed lead study author Mariana C. Stern, PhD, Professor of Population and Public Health Sciences and Urology, the Ira Goodman Chair in Cancer Research, and Associate Director of Population Science at the Norris Comprehensive Cancer Center at the University of Southern California (USC).
The participants with two copies of the most common variant of the SMAD7 gene—present in about 74% of the population—had an 18% greater risk of developing colorectal cancer if they ate high levels of red meat. Those with only one copy of the most common variant or two copies of a less common variant had a substantially higher risk of colorectal cancer: 35% and 46%, respectively.
Conclusions
“These findings suggest that different genetic variants may confer a differing risk of colorectal cancer in individuals who consume red meat and highlight possible explanations for how the disease develops,” suggested co–study author Joel Sanchez Mendez, MBBS, a doctoral student in the Department of Population and Public Health Sciences at the Keck School of Medicine at USC.
The researchers commented that the new research unveiled promising new details about the link between meat consumption and colorectal cancer. Nonetheless, the research does not yet prove a causal link for these genetic variants.
“These findings suggest that there's a subset of the population that faces an even higher risk of colorectal cancer if they eat red or processed meat. It also allows us to get a peek at the potential mechanism behind that risk, which we can then follow up with experimental studies,” underscored Dr. Stern. “We do these gene-environment interaction studies when we know there’s a clear association between an environmental exposure and a disease, but what happens in between is still a black box,” she stressed.
The researchers plan to conduct further experimental studies to provide stronger evidence for the role of dysregulated iron metabolism in the development of colorectal cancer.
Disclosure: The research in this study was funded by grants from the National Cancer Institute and National Institutes of Health. For full disclosures of the study authors, visit aacrjournals.org.
