Red meat consumption and colorectal cancer
Researchers used a new statistical method to identify the genetic basis of the link between red and processed meat intake and colorectal cancer risk.
Does red meat cause cancer?
A recent study published in the journal Cancer Epidemiology, Biomarkers & Prevention explored the impact of red meat consumption on a person's cancer risk based on their genotype, allowing researchers to identify two genetic markers that may help explain the association between the two factors and explain why some people run a higher risk of cancer.
Past studies showed that frequent consumption of red and processed meat increases the risk of developing colorectal cancer, but the predominant biological mechanism has never been precisely established. Understanding the disease process and which genes underlie it can help doctors develop better prevention strategies.
The new study, supported by the National Institutes of Health and led by the USC Norris Comprehensive Cancer Center, part of the Keck School of Medicine at USC, analysed data on the intake of red and processed meat by 29,842 people with colorectal cancer and 39,635 people without cancer. It was found that those who consumed more red or processed meat had a 30 or 40 per cent higher risk of colorectal cancer, respectively. Using genome-wide data, the researchers also identified two genes, HAS2 and SMAD7, that altered cancer risk levels depending on levels of red or processed meat consumption.
The authors point out that the results suggest the existence of a subset of the population that faces an even higher risk of colorectal cancer if they eat red or processed meat. This is the starting point for investigating the potential mechanism underlying this risk.
The researchers used a combination of standard methods to identify interactions between genes and environment, as well as a new statistical approach developed in the biostatistics division of the Keck School of Medicine. State-of-the-art statistical methods and software maximised the efficiency of testing gene-meat interactions on seven million genetic variants.
The risks posed by red and processed meat
The analysis included data from 27 studies on the risk of colorectal cancer in people of European origin. The research team harmonised the data from the various studies to create standard measures for consumption of red meat (beef, pork and lamb) and processed meat (bacon, sausages, hot dogs). For each category, daily servings were calculated, adjusted for body mass index, and participants were divided into four groups according to their levels of red or processed meat intake.
Those with the highest level of red meat intake had a 30% increased risk of colorectal cancer. Those with the highest level of processed meat intake had a 40% increased risk. These results do not take into account genetic variability that may make some people in the population more at risk than others.
Genetic markers of colorectal cancer risk
Next, based on DNA samples, the researchers collected data on more than seven million genetic variants covering the genome of each study participant. They then conducted a genome-environment interaction analysis on the link between red meat intake and cancer risk. Looking at each position in the genome - known as a Single Nucleotide Polymorphism (SNP) - they asked whether the presence of a particular gene variant altered the risk of getting colorectal cancer in people who ate more red meat.
The answer was negative for almost all SNPs in the genome. Regardless of the gene variant, the cancer risk according to red meat consumption remained unchanged. However, at two specific SNPs, the association changed.
Using a standard statistical analysis approach, the researchers identified the SNP rs4871179 in chromosome 8, close to the HAS2 gene. The gene has already been linked to colorectal cancer in some previous studies, but never to red meat consumption.
The analysis showed that people with a common variant of the HAS2 gene, present in 66% of the population, had a 38% higher risk of colorectal cancer if they consumed the highest level of meat. In contrast, people with another, rarer variant of the same gene did not have a higher risk of cancer if they ate more red meat.
This method identified the SNP rs352860 in chromosome 18, part of the SMAD7 gene. SMAD7 regulates hepcidin, a protein linked to iron metabolism. Since red and processed meats contain high levels of iron-eme, the researchers speculate that different SMAD7 variants may increase cancer risk by altering the way the body processes iron. According to the authors, when hepcidin is dysregulated, this can lead to increased iron absorption and even iron overload within cells.
People with two copies of the most common variant of the SMAD7 gene, found in about 74% of the population, had an 18% higher risk of colorectal cancer if they ate high levels of red meat. Individuals with only one copy of the most common variant or with two copies of a less common variant had a substantially higher cancer risk of 35% and 46%, respectively.
Further evidence is needed
According to the researchers, these results suggest that different genetic variants may confer a different risk of colorectal cancer in individuals who consume red meat and highlight possible explanations for disease development.
The study results highlight new details on the link between meat consumption and colorectal cancer, but do not yet demonstrate a causal link for these genetic variants. The authors hope to continue with experimental studies that could provide stronger evidence for the role of iron metabolism dysregulation in colorectal cancer development.
- Stern MC, Sanchez Mendez J, Kim AE, Obón-Santacana M, Moratalla-Navarro F, Martín V, Moreno V, Lin Y, Bien SA, Qu C, Su YR, White E, Harrison TA, Huyghe JR, Tangen CM, Newcomb PA, Phipps AI, Thomas CE, Kawaguchi ES, Lewinger JP, Morrison JL, Conti DV, Wang J, Thomas DC, Platz EA, Visvanathan K, Keku TO, Newton CC, Um CY, Kundaje A, Shcherbina A, Murphy N, Gunter MJ, Dimou N, Papadimitriou N, Bézieau S, van Duijnhoven FJB, Männistö S, Rennert G, Wolk A, Hoffmeister M, Brenner H, Chang-Claude J, Tian Y, Le Marchand L, Cotterchio M, Tsilidis KK, Bishop DT, Melaku YA, Lynch BM, Buchanan DD, Ulrich CM, Ose J, Peoples AR, Pellatt AJ, Li L, Devall MAM, Campbell PT, Albanes D, Weinstein SJ, Berndt SI, Gruber SB, Ruiz-Narvaez E, Song M, Joshi AD, Drew DA, Petrick JL, Chan AT, Giannakis M, Peters U, Hsu L, Gauderman WJ. Genome-Wide Gene-Environment Interaction Analyses to Understand the Relationship between Red Meat and Processed Meat Intake and Colorectal Cancer Risk. Cancer Epidemiol Biomarkers Prev. 2024 Mar 1;33(3):400-410. doi: 10.1158/1055-9965.EPI-23-0717. PMID: 38112776.