Eating less red meat is standard medical advice for preventing colorectal cancer, but the way it causes cells to mutate has remained unclear, and not all experts were convinced there was a strong link.
A new paper in the journal Cancer Discovery has now identified specific patterns of DNA damage triggered by diets rich in red meat – further implicating the food as a carcinogen while heralding the possibility of detecting the cancer early and designing new treatments.
Prior research establishing the connection was mainly epidemiologic, meaning that people who developed the condition were surveyed on their eating habits, and researchers spotted associations with colorectal cancer incidence.
But a lack of clarity around the biology meant that the case wasn’t quite slam dunk, and in 2019, one team of researchers made waves when they declared they only had a “low” degree of certainty that reducing consumption would prevent cancer deaths.
“When we say red meat is carcinogenic, and that it impacts incidence of cancer, there has to be some plausible way by which it does it,” Dana-Farber Cancer Institute oncologist Marios Giannakis, who led the new study, told AFP.
After all, scientists discovered long ago which chemicals in cigarette smoke are to blame for cancer, and how certain bands of UV light penetrate the skin and trigger mutations in genes that control how cells grow and divide.
To address the knowledge gap, Giannakis and his colleagues sequenced DNA data from 900 patients with colorectal cancer, who were drawn from a much larger group of 280,000 health workers participating in a years-long studies that included lifestyle surveys.
The strength of this approach is that the people documenting their diet had no way of knowing of their future cancer diagnosis, rather than asking people to recall their eating habits after they became ill.
The analysis revealed a distinct mutational signature – a pattern that had never before been identified but was indicative of a type of DNA damage called “alkylation.”
Not all cells that contain these mutations will necessarily become cancerous, and the signature was present in some healthy colon samples too.
The mutation signature was significantly associated with intake of red meat, both processed and unprocessed, prior to the patient’s diagnosis of cancer, but not with the intake of poultry, fish or other lifetsyle factors that were examined.
“With red meat, there are chemicals that can cause alkylation,” explained Giannakis.
The mutation patterns were strongly associated with the distal colon – the lower part of the bowels that leads to the anal canal, which is where past research suggested colon cancer linked to red meat mostly occurs.
What’s more, among the genes that were most affected by the alkylation patterns were those that previous research has shown are among the most common drivers of colorectal cancer when they mutate.
Taken as a whole, the multiple lines of evidence build up a compelling argument, said Giannakis, likening the research to careful detective work.
In this case, the suspicious mutation signature has a lot to answer for: patients whose tumors had the highest levels of alkylation damage had a 47 percent greater risk of colorectal cancer-specific death, compared to patients with lower levels of damage.
But Giannakis, also a practicing doctor, said it was important to focus on how the research can be used to help patients.
Future work might help physicians identify which patients are genetically predisposed to accumulating alkylation damage, then counsel them to limit their red meat intake.
Identifying patients who have already started to accrue the mutational signature could help identify who’s at greater risk of developing cancer, or catch the disease at an earlier stage.
And because the amount of alkylation damage appears to be a biomarker of patient survival, it could possibly be used to tell patients about their prognosis.
Finally, understanding the biological pathway through which colorectal cancer occurs paves the way for medicines that interrupt or reverse the process, preventing the disease.
Giannakis stressed the takeaway message is not that people should totally abstain from red meat: “My recommendation would be that moderation and a balanced diet is key.”
High levels of tumor alkylation damage were only seen among patients eating on average more than 150 grams (five ounces) a day, roughly equal to two or more servings.
In October 2015, the International Agency for Research on Cancer concluded that processed meat could be classified as “carcinogenic to humans”, and red meat could be classified as “probably carcinogenic to humans” [1,2]. The conclusions were primarily related to colorectal cancer (CRC). In 2018, the World Cancer Research Fund and American Institute for Cancer Research stated that there is strong evidence that consuming red and processed meat increases the risk of CRC . Poultry is not mentioned as a risk factor for CRC, neither by the International Agency for Research on Cancer nor by the World Cancer Research Fund and American Institute for Cancer Research.
Some, but not all, prospective, population-based studies from different countries have associated high red and processed meat intake with increased risk of mortality, in particular in American cohorts [4,5,6,7,8]. An inverse association between poultry intake and total mortality was observed among low meat consumers in Asia  and among American men . Thus, a high intake of red and processed meat but not poultry seems to be associated with CRC, and in some populations with mortality.
Since composition of diets is complex and persons with different diets may differ on other characteristics, cohort studies on associations between meat intake and health have many confounders. However, it is possible to have a high meat content in a healthy diet . Therefore, we suggest that analyses of associations between meat intake and disease risk should be stratified by dietary quality.
Dietary quality should be expressed as a diet quality index and not as division in, e.g., “Western” and “Mediterranean” diets, where a high meat intake automatically becomes a proxy for an unhealthy diet, and where it is not possible to correct for all the dietary confounders, of which several are inter-correlated.
The aim of the study is to evaluate the associations between the intake of red and processed meat and poultry and CRC and all-cause mortality risk, both in an adult study population in general and in subgroups with different dietary guideline compliance, minimising the influence of diet-related confounding.
We found no significant association between red meat or processed meat intake and CRC risk. For poultry, however, high compared with low intake increased CRC risk significantly by 62%, but we found no increased CRC risk per 100 g poultry per day.
In accordance with our result on red meat, several prospective cohort studies representing more than 10 European countries, including Denmark, found no association between red meat intake and CRC risk [16,17,18,19], but an increased hazard ratio of CRC per 1 serving of red meat per day was seen in two American prospective cohorts . In meta-analyses covering America, Australia, European and Asian countries, a positive association between red meat intake and CRC risk has been observed [19,21,22].
The association was stronger in Asian and Australian cohorts compared with European and North American cohorts . The latest meta-analysis performed by the World Cancer Research Fund Continuous Update Project found that red meat intake was positively associated with CRC risk .
It is difficult to obtain and compare information about actual meat intake (g/day) for different types of meat in different cohorts, which affects the possibility to compare outcomes in studies of effects of high versus low meat intake. For example, high red meat intake in an Asian cohort may be similar in magnitude to low red meat intake in some Western cohorts.
In contrast to our results on processed meat, others found positive associations between processed meat intake and CRC risk in American, Australian, Asian, and European cohorts [16,17,20,21,22,23]. However, no association was found in the Danish Diet, Cancer and Health cohort study .
Studies on the effects of meat intake from different countries and continents can be difficult to compare because the proportions of the different types of red and processed meat differ significantly between regions. The types of meat—both red and processed meat—constitute different hazards due to their structure and composition. Moreover, certain meat subtypes may be more prevailing in unhealthy diets than others, which can affect the risk estimates. Therefore, analyses on effects of meat subtypes can contribute to our understanding of differences observed in different cohorts and are warranted in future studies.
In a meta-analysis comparing the highest versus lowest red meat intake in Asian and European cohorts, Carr et al.  found that beef intake was associated with an increased risk of CRC in European cohorts but no association was found for pork. In a Danish cohort, no associations were seen for beef or pork intake and colon cancer risk but beef intake was associated with decreased risk and pork intake with increased risk of rectal cancer .
We had too few cases to make subgroup analysis on red meat intake, but from analysis of dietary patterns among the participants , we know that pork constitutes a slightly higher part of their red meat intake than beef/veal, which may have affected our findings.
For poultry intake, our results were in contrast with what others have found. No association between poultry intake and CRC risk was reported by the World Cancer Research Fund Continuous Update Project  or seen in European cohorts [16,17,18]. A decreased CRC risk was associated with 50 g poultry increment per day in a meta-analysis including prospective cohort studies from America, Australia, Europe, and Japan . Thus, more studies are needed to confirm our findings.
A pronounced difference in meat content in high-meat diets with different healthy eating indices was found by Kappeler et al. . Thus, comparing groups with low and high meat intake without considering dietary quality and what foods replace the meat will simultaneously be a comparison of healthy and unhealthy diets. Therefore, we analysed our data by looking at the effects of meat intake stratified by DGCS to reduce the confounding from dietary quality. However, when stratified by DGC, we found no statistically significant differences in the associations between meat intake and CRC risk in low-compliers and high-compliers.
Norat et al.  found that the CRC risk associated with high intakes of red and processed meat was more pronounced in participants from a European cohort including Denmark with low and medium fibre intake (≤26–28 g/day) compared with those with high fibre intake (>26–28 g/day). Others have found that in two US cohorts, an increase in total fibre, cereal fibre, or whole-grain intake of 5 g per day reduced CRC risk by 7–25%, while fibres from fruit and vegetables did not have such effect . From dietary pattern analyses of our participants’ diet, we know that those who comply well with dietary guidelines had both a high whole-grain intake and total fibre intake, but it apparently did not influence the CRC risk associated with meat intake.
We found no significant associations between red meat, processed meat, and poultry intake and all-cause mortality.
Similar results were found for red meat in a large American cohort  but not in another American cohort , and not in European cohorts [6,28]. Three meta-analyses showed no associations between red meat intake and all-cause mortality risk [5,6,29], while one meta-analysis showed that each additional intake of 100 g red meat/day was positively associated with all-cause mortality .
In contrast to our results, in a European cohort including Denmark, intake of processed meat was positively associated with all-cause mortality , which was also the result of four meta-analyses [5,6,29,30].
In a recent meta-analysis, Han et al. found a small, positive association between red and processed meat intake and cancer mortality, but the evidence was rated to be of low certainty .
White meat (including chicken, turkey, and rabbit) intake was not associated with all-cause mortality in meta-analyses of prospective cohort studies [5,28]. Likewise, no association was found between poultry intake and CRC mortality in a dose-response meta-analysis of prospective cohort studies , and no association was found between poultry intake and cancer mortality in a meta-analysis of prospective cohort studies .
In our study, a diet composition that did not comply well with the official, quantitative Danish dietary guidelines (independent of meat content) was significantly associated with mortality risk in the least adjusted model (adjusted by sex and age) (HR 1.66; 95%CI 1.32–2.10). However, DGCS was not significantly associated with mortality risk in the multivariate model (adjusted by sex, age, educational attainment, ethnicity, smoking, physical activity, alcohol, BMI, and total energy intake), and p for trend showed no significant effect of DGCS.
Kappeler et al.  found a 27% decreased mortality risk among Americans with the top third Healthy Eating Index score (developed by the US Department of Agriculture) compared with the bottom third Healthy Eating Index score. Unfortunately, these authors did not estimate the all-cause mortality risk in participants with different meat intake stratified by dietary quality.
We showed no significant associations between red and processed meat intake and risk of CRC and all-cause mortality. A significant increase in CRC risk, but not in all-cause mortality, was found for high versus low poultry intake but not for risk change per 100 g increment per day. None of these associations were modified by dietary guideline compliance.
reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823645/
More information: Carino Gurjao et al, Discovery and features of an alkylating signature in colorectal cancer, Cancer Discovery (2021). DOI: 10.1158/2159-8290.CD-20-1656