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Alkylating Signature in Colorectal Cancer May Be Linked to High Red Meat Intake


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The association between the consumption of red and processed meats and the development of colorectal cancer, as well as pancreatic and prostate cancers, has been known since 2015, when the International Agency for Research on Cancer (IARC) classified the consumption of red meat as probably carcinogenic to humans.

Now, findings from a new study provide a mechanistic link between a diet high in red meat and colorectal cancer. According to the study’s results, high red meat consumption may cause alkylating damage in colon cells that lead to cancer-causing mutations in KRAS and PIK3CA genes, promoting the development of colorectal cancer. The study, published by Gurjao et al in Cancer Discovery, also found that patients whose tumors had the highest levels of alkylating damage had a 47% greater risk of death compared to patients with tumors with lower levels of damage. These results provide opportunities for colorectal cancer prevention through lifestyle modifications, including dietary interventions, concluded the study authors.

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Study Methodology

To identify genetic changes associated with red meat intake, the researchers sequenced DNA from matched normal and colorectal tumors from 900 patients with colorectal cancer who had participated in one of three nationwide prospective cohort studies, namely the Nurses’ Health Studies I and II and the Health Professionals Follow-up Study. The study participants repeatedly provided data on diet, lifestyle, and other factors, without knowing their future colorectal cancer diagnosis, if any.

Results

The researchers’ analysis of DNA sequencing found the presence of several mutational signatures in normal and cancerous colon tissue, including a signature indicative of alkylation. The alkylating signature was significantly associated with the prediagnosis intake of processed or unprocessed red meat, but not with the prediagnosis 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 the study. As in previous studies linking a diet of red meat and cancer incidence in the distal colon, the study found that normal and cancerous tissue from the distal colon had significantly higher alkylating damage than tissue from the proximal colon.

The researchers devised a simple model that predicts the relative likelihood of mutational processes to target colorectal cancer recurrent drivers in non–microsatellite instability–high, non–POLE-mutated tumors, and identified the KRAS and PIK3CA genes as potential targets of alkylation-induced mutation. Consistent with this prediction, they found that colorectal tumors harboring KRAS G12D, KRAS G13D, or PIK3CA E545K driver mutations had greater enrichment of the alkylating signature compared to tumors without these mutations.

The alkylating signature was also associated with patient survival. The patients whose tumors had the highest levels of alkylating damage had a 47% greater risk of death from colorectal cancer than patients with tumors with lower levels of damage.

Clinical Significance

“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,” said senior study author Marios Giannakis, MD, PhD, Assistant Professor of Medicine at Harvard Medical School and a physician at Dana-Farber Cancer Institute. “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.”

Disclosure: Funding for this study was provided by the National Institutes of Health, Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant, the Project P Fund, the Cancer Research UK Grand Challenge Award, the Nodal Award from the Dana-Farber Harvard Cancer Center, the Friends of the Dana-Farber Cancer Institute, the Bennett Family Fund, and the Entertainment Industry Foundation. For full disclosures of the study authors, visit cancerdiscovery.aacrjournals.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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