For the first time, researchers have identified a colorectal cancer mutational signature that they have been able to link to a diet high in consumption of red meat. The consumption of high levels of processed and red meat has long been known to be a risk factor in the development of colorectal cancer. In 2015, the International Agency for Research on Cancer stated processed meat was carcinogenic, and said red meat was most likely carcinogenic to humans. Previous research has suggested diets high in red meat can promote the formation of carcinogenic compounds in the gut, but a molecular link between colorectal cancer and red meat consumption had not been identified.
Now, a team of researchers at the Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and Harvard Medical School have identified a gene mutation signature indicative of alkylating DNA damage that is linked to high red meat consumption. The mutational signature is also associated with an increased risk of cancer-related mortality.
The researchers performed whole-exome sequencing (WES) of DNA from matched normal and colorectal tissue samples taken from 900 patients diagnosed with colorectal cancer that were part of three prospective cohort studies in the United States. The studies included extensive dietary and lifestyle information from the patients.
The researchers identified a previously undescribed alkylating mutational signature in colon cells which they were able to associate with red meat consumption and cancer driving mutations. The mutational signature was only associated with high pre-diagnosis intakes of processed or unprocessed red meat, and not with poultry, fish, or other lifestyle factors. “All available red meat variables showed significant positive associations between prediagnosis intakes and alkylating damage in CRCs,” explained the researchers.
The mutational signature was more prevalent in the distal colorectum and has been predicted to be a driver of the mutations KRAS p.G12D, KRAS p.G13D and PIK3CA p.E5454K which are associated with poor survival. Patients with tumors with the highest levels of alkylating damage had a 47% higher risk of colorectal cancer-specific death.
“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,” said Marios Giannakis, MD, PhD, assistant professor of medicine at HMS, physician at Dana-Farber Cancer Institute, and lead researcher of the study. “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.”
The alkylating mutational signature could also potentially be used as a biomarker for identifying patients at a high risk of developing colorectal cancer to allow medical interventions to take place, or could even potentially be used in diagnostic tests to detect colorectal cancer in the early stages when treatment is likely to be most effective.
You can read more about the study in the paper – Discovery and features of an alkylating signature in colorectal cancer – which was recently published in the Cancer Discovery. DOI: 10.1158/2159-8290.CD-20-1656