Pattern of DNA Damage Links Colorectal Cancer and Diet High in Red Meat

July 22, 2021, by Sharon Reynolds

Numerous studies have linked a diet high in red and processed meats with colorectal cancer, but it’s been unclear how eating cheeseburgers, hot dogs, and lamb chops could fuel the development of this disease. 

New insights may soon be at hand. Kana Wu, M.D., Ph.D., of the Department of Nutrition at the Harvard T.H. Chan School of Public Health, initiated a study to see if frequent consumption of red and processed meat, a known risk factor for colorectal cancer, may leave a specific pattern of DNA damage, known as a mutational signature, in colorectal tumors.

In collaboration with Dr. Wu, a team of researchers did identify such a pattern in the colorectal tumors of people who had reported having diets that were high in red and processed meat. This "alkylating" damage was caused by specific compounds that are produced in the body after the consumption of red meat.

Such mutational signatures are akin to crime scene fingerprints left behind by a criminal. Researchers can study these patterns to trace the origins of the mutations that led to a tumor’s formation.

The discovery of alkylating mutational signature associated with the consumption of red and processed meats “further implicates” diet in the development of colorectal cancer, said Marios Giannakis, M.D., Ph.D., also of the Dana-Farber Cancer Institute and Harvard Medical School, who co-led the study, published June 17 in Cancer Discovery.

To arrive at their findings, the research team analyzed tumor DNA from hundreds of people with colorectal cancer who had provided in-depth information about what they ate in the years before they were diagnosed with the disease. 

Understanding how red and processed meat may cause genetic damage that can lead to colorectal cancer may make it possible to prevent colorectal cancer, detect it early, and treat it with targeted therapies, Dr. Giannakis noted. One possible approach to prevention, for example, might be to identify people predisposed to accumulating alkylating damage and to encourage them to limit their intake of red meat, he said. 

“This is a really smart study,” said Kurt Straif, M.D., Ph.D., who led the monographs program at the International Agency for Research on Cancer (IARC) that evaluated the carcinogenicity of meat consumption in 2015.

The findings “shed further light” on the link between red and processed meat and colorectal cancer, continued Dr. Straif, who was not involved in the study. “It’s making the evidence even stronger.” 

Evidence Mounts

Evidence implicating red and processed meat in the development of colorectal cancer has been building for years. In 2015, based on data from 800 studies, IARC classified processed meat as a human carcinogen (Group 1), meaning that there is enough evidence to conclude that it can cause cancer in humans. The evidence for red meat was less definitive, so IARC classified it as a probable carcinogen (Group 2A).

Researchers are still trying to tease out exactly how red and processed meat might cause cancer. Some studies have suggested that preservatives such as nitrates and nitrites that are added to processed meats can produce compounds that damage DNA. Other studies have looked into how chemicals that are formed when red meat is cooked at high temperatures, such as in grilling, cause the accumulation of mutations that lead to cancer. 

Using DNA analysis to identify mutational signatures can help scientists identify the origin of the DNA damage that initiated the growth of a given tumor. Mutational signatures are distinct patterns of DNA damage that reflect different mutational processes. Some mutational signatures arise from processes that happen within the body, such as DNA repair or oxidative stress, whereas others are indicative of environmental exposures, such as UV light or tobacco smoke. 

Alkylating signatures are a type of mutational signature that arise when genetic material is damaged by chemicals that form lesions in DNA, a process known as alkylation. When lesions formed by alkylation are not repaired properly, a specific pattern of mutational damage can result. 

Analysis of mutational signatures is increasingly being used to understand associations from epidemiologic studies. For example, scientists have identified specific mutational signatures associated with tobacco smoke exposure. 

“For lung cancer, we developed that mechanistic understanding maybe 10 or 20 years ago,” said Paul Spellman, Ph.D., professor of molecular and medical genetics at Oregon Health & Science University, who studies the genomic origins of cancer but was not involved in the new study. “We now are getting there for red meat and processed meat and colorectal cancer.” 

Looking for Genomic Clues

In this new study, Dr. Giannakis and his colleagues conducted whole-exome sequencing on samples of normal and tumor tissue from 900 people who were diagnosed with colorectal cancer while participating in one of three large, long-running epidemiologic studies: the Nurses’ Health Studies I and II and the Health Professionals Follow-up Study. As part of the studies, participants provided in-depth information on their diet and general lifestyle.

The researchers identified several mutational signatures in the tumor tissue, including an alkylating signature that was associated with red meat consumption. People in the top 10% of red meat consumption—that is, those who consumed on average more than 150 grams, or roughly two servings, of processed or unprocessed red meat per day—had the highest levels of the alkylating signature. 

This alkylating signature wasn’t associated with diets high in chicken or fish. It also wasn’t associated with other lifestyle factors such as smoking, high body mass index, or high alcohol consumption.

What’s more, normal and cancerous tissue in the final length of the colon, known as the distal colon, had much more alkylating DNA damage than tissue in other parts of the colon. Most colorectal cancers develop in the distal colon.

The researchers also found that people whose tumors had the highest levels of the alkylating signature—those in the top quarter of the group—were more likely to die from colorectal cancer than people whose tumors had lower levels of the signature.

The alkylating signatures were often seen alongside mutations in two genes strongly linked with cancer: KRAS and PIK3CA. Colorectal tumors with mutations in either of these genes had higher levels of the alkylating signature than tumors without these mutations, the researchers reported.

“A possible link could be that if you have high red meat consumption, you get this alkylating damage, and this alkylating damage [causes mutations in] the KRAS genes. And we know that KRAS mutations promote cancer growth,” Dr. Giannakis said. “It doesn’t mean that if you have this damage you will certainly get colorectal cancer. But it does raise the question: When does this damage get introduced? There could be opportunities to intervene early on.”

Toward Treatment and Prevention

Normal colorectal tissue also contained alkylating signatures, the researchers found. That could suggest that DNA damage begins long before the cancer starts to form, they wrote. One clue into the timing of when the DNA damage accumulates to a point of no return may lie in the MGMT gene, which is involved in repair of DNA damage.

Dr. Spellman explained that the alkylating signature was seen more frequently after the MGMT gene was inactivated.

“There may be environmental exposures or genetic predispositions that create an increased rate of such inactivation,” he said. “What it implies is that you're probably fine until you get that MGMT defect, and once you do, then red meat is really dangerous."
  
Dr. Giannakis said more studies need to be done to better characterize these tumors. “We still need to do future studies to drill down the mechanism of action even more,” he said. “For example, can we prevent this alkylating damage from accumulating? Can we get a better sense of who’s predisposed to getting this damage?”

The researchers are currently studying whether consumption of red meat is linked to the increasing incidence of colorectal cancer among young adults.

Nuri Faruk Aykan, M.D., of Istinye University in İstanbul, said it would be important to expand these studies to different populations around the world, which may have different thresholds for when alkylating signatures arise. Dr. Aykan also wondered about the role of other factors, such as the colon’s bacterial composition, or microbiome, and specific types of red meat on the emergence of this alkylating signature.

Dr. Giannakis agreed. “I think we’re just scratching the surface of figuring out the exact characteristics and epidemiology of this, but now that we know how to find this alkylating signature, those future studies are certainly worth pursuing.”

Robert Turesky, Ph.D., of the University of Minnesota Masonic Cancer Center, who studies cancer causation, said it’s also important to identify the specific chemical or chemicals in red and processed meat that are causing the mutations that lead to colorectal cancer.

“Ultimately, if we can identify what some of these precursors are, there may be ways to mitigate their formation during cooking or processing of meats,” Dr. Turesky said.

Additional research could lead to changes in how groups like IARC classify red meat, Dr. Straif said. In fact, there have been examples in the past where IARC changed its classification on a particular cancer-causing risk factor based on new mechanistic evidence, he noted.

In the meantime, Dr. Giannakis said, having a balanced diet is key to a healthy lifestyle.