Consumption of red meat is associated with a significant increase in the risk of colorectal, colon, and rectal cancers. The overall evidence of prospective studies supports limiting red meat consumption as one of the dietary recommendations for the prevention of colorectal cancer.

The International Agency for Research on Cancer declared that red and processed meat were carcinogenic and that red meat was probably carcinogenic to humans in 2015.[1]

Incidence of colorectal cancer
According to federal estimates, among the most common forms of cancer diagnosed in the United States, an estimated 149,500 people in the United States are expected to be diagnosed with these cancers and 52,980 are expected to die of these diseases in 2021.

Marios Giannakis, MD, Ph.D., an assistant professor of medicine at Harvard Medical School and a physician at Dana-Farber Cancer Institute.

A new study, supported by the National Institutes of Health, the Stand Up To Cancer, the Project P Fund, the Cancer Research UK, the Dana-Farber Harvard Cancer Center, and others, provides a mechanistic link between red meat consumption and colorectal cancer development. The results were published in Cancer Discovery, a journal of the American Association for Cancer Research (AACR)

DNA damage
Genetic mutations indicative of DNA damage were associated with high red meat consumption and increased cancer-related mortality in patients with colorectal cancer.

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“We have known for some time that consumption of processed meat and red meat is a risk factor for colorectal cancer,” said Marios Giannakis, MD, Ph.D., an assistant professor of medicine at Harvard Medical School and a physician at Dana-Farber Cancer Institute.

The missing link
Experiments in preclinical models have suggested that red meat consumption may promote the formation of carcinogenic compounds in the colon, but a direct molecular link to colorectal cancer development in patients has not been shown, Giannakis explained.

To find the missing link, over the last few decades, researchers have conducted many studies designed to establish the molecular link between the consumption of red meat and colorectal cancers.

For example, in 2017 Nancy D Turner from the Nutrition & Food Science Department, Texas A&M University, and her colleague Shannon K Lloyd, from the Department of Veterinary Pathobiology, Texas A&M University, conducted a systematic review of forty studies using animal models or cell cultures that met specified inclusion criteria.  They observed that most of these studies were designed to examine the role of heme iron or heterocyclic amines in relation to colon carcinogenesis. In addition, they noted that most studies used levels of meat or meat components well in excess of those found in human diets.  And while many of the experiments used semi-purified diets designed to mimic the nutrient loads in current westernized diets, most did not include potential biologically active protective compounds present in whole foods. [2]

Turner and Lloyd concluded that because of these limitations in the existing literature, there is currently insufficient evidence to confirm a mechanistic link between the intake of red meat as part of a healthy dietary pattern and colorectal cancer risk.

“What is missing is a demonstration that colorectal cancers from patients have a specific pattern of mutations that can be attributed to red meat,” Giannakis said.

“Identifying these molecular changes in colon cells that can cause cancer would not only support the role of red meat in colorectal cancer development but would also provide novel avenues for cancer prevention and treatment.”

Study design
To identify genetic changes associated with red meat intake, Giannakis and colleagues sequenced DNA from matched normal and colorectal tumor tissues from 900 patients with colorectal cancer who had participated in one of three nationwide prospective cohort studies, namely the Nurses’ Health Studies and the Health Professionals Follow-Up Study. All patients had previously provided information on their diets, lifestyles, and other factors over the course of several years prior to their colorectal cancer diagnoses.

Study results
Analysis of DNA sequencing data revealed the presence of several mutational signatures in normal and cancerous colon tissue, including a signature indicative of alkylation, a form of DNA damage.

The alkylating signature was significantly associated with pre-diagnosis intake of processed or unprocessed red meat, but not with pre-diagnosis intake of poultry or fish or with other lifestyle factors. Red meat consumption was not associated with any of the other mutational signatures identified in this study. In line with prior studies linking red meat consumption with cancer incidence in the distal colon, Giannakis and colleagues found that normal and cancerous tissue from the distal colon had significantly higher alkylating damage than tissue from the proximal colon.

Using a predictive model, the researchers identified the KRAS and PIK3CA genes as potential targets of alkylation-induced mutation. Consistent with this prediction, they found that colorectal tumors harboring KRASG12D, KRASG13D, or PIK3CA E545K driver mutations, which are commonly observed in colorectal cancer, had greater enrichment of the alkylating signature compared to tumors without these mutations. The alkylating signature was also associated with patient survival: Patients whose tumors had the highest levels of alkylating damage had a 47 percent greater risk of colorectal cancer-specific death compared to patients with lower levels of damage. [3]

Alkylating mutational signature
“Our study identified for the first time an alkylating mutational signature in colon cells and linked it to red meat consumption and cancer driver mutations,” Giannakis said

“These findings suggest that red meat consumption may cause alkylating damage that leads to cancer-causing mutations in KRAS and PIK3CA, thereby promoting colorectal cancer development. Our data further support red meat intake as a risk factor for colorectal cancer and also provide opportunities to prevent, detect, and treat this disease,” he added.

Giannakis explained that if physicians could identify individuals who are genetically predisposed to accumulating alkylating damage, these individuals could be counseled to limit red meat intake as a form of precision prevention. In addition, the alkylating mutational signature could be used as a biomarker to identify patients at greater risk of developing colorectal cancer or to detect cancer at an early stage. Because of its association with patient survival, the alkylating signature may also have potential as a prognostic biomarker. However, future studies are needed to explore these possibilities, Giannakis noted.

Limitations of the study
A limitation of the study is the potential selection bias of study participants, as tissue specimens could not be retrieved from all incident colorectal cancer cases in the cohort studies. Current studies from Giannakis and his colleagues are exploring the potential role of red meat intake and alkylating damage in diverse groups of patients.

Reference
[1] Bouvard V, Loomis D, Guyton KZ, Grosse Y, Ghissassi FE, Benbrahim-Tallaa L, Guha N, Mattock H, Straif K; International Agency for Research on Cancer Monograph Working Group. Carcinogenicity of consumption of red and processed meat. Lancet Oncol. 2015 Dec;16(16):1599-600. doi: 10.1016/S1470-2045(15)00444-1. Epub 2015 Oct 29. PMID: 26514947.
[2] Turner ND, Lloyd SK. Association between red meat consumption and colon cancer: A systematic review of experimental results. Exp Biol Med (Maywood). 2017 Apr;242(8):813-839. doi: 10.1177/1535370217693117. Epub 2017 Jan 1. PMID: 28205448; PMCID: PMC5407540.
[3] Luo Q, Chen D, Fan X, Fu X, Ma T, Chen D. KRAS and PIK3CA bi-mutations predict a poor prognosis in colorectal cancer patients: A single-site report. Transl Oncol. 2020 Dec;13(12):100874. doi: 10.1016/j.tranon.2020.100874. Epub 2020 Sep 16. PMID: 32947236; PMCID: PMC7502368.

Featured image: Red Meat. Photo courtesy: © 2021 Rene Lehmkuhl on Unsplash. Used with permission.

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