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aacrjournals.org

Abstract

Several risk factors have been established for colorectal cancer, yet their direct mutagenic effects in patients’ tumors remain to be elucidated. Here, we leveraged whole-exome sequencing data from 900 colorectal cancer cases that had occurred in three U.S.-wide prospective studies with extensive dietary and lifestyle information. We found an alkylating signature that was previously undescribed in colorectal cancer and then showed the existence of a similar mutational process in normal colonic crypts. This alkylating signature is associated with high intakes of processed and unprocessed red meat prior to diagnosis. In addition, this signature was more abundant in the distal colorectum, predicted to target cancer driver mutations KRAS p.G12D, KRAS p.G13D, and PIK3CA p.E545K, and associated with poor survival. Together, these results link for the first time a colorectal mutational signature to a component of diet and further implicate the role of red meat in colorectal cancer initiation and progression.

Significance:

Colorectal cancer has several lifestyle risk factors, but the underlying mutations for most have not been observed directly in tumors. Analysis of 900 colorectal cancers with whole-exome sequencing and epidemiologic annotations revealed an alkylating mutational signature that was associated with red meat consumption and distal tumor location, as well as predicted to target KRAS p.G12D/p.G13D.

  • jetMAEnglish
    2·
    3 days ago

    Interesting paper, thanks for sharing it. I did a very brief overlook, and they are using FFQs to qualify food intake, they tried to control for healthy patient confounders, but that is very difficult in observational settings.

    Not to mention Carnivore is in a ketogenic metabolism, a very different context then sugar and meat eaters.

    I’ll read the paper in depth tomorrow.

    However, in the mean time, I’d like to draw your attention to this meta analysis of RCTs (very strong evidence) https://www.acpjournals.org/doi/10.7326/M19-0622

    Low- to very-low-certainty evidence suggests that diets restricted in red meat may have little or no effect on major cardiometabolic outcomes and cancer mortality and incidence.

    evidence pyramid

    We have a observational study citing a relationship, and a meta-analysis of RCTs not seeing the relationship. The data currently favors Red Meat.

    • VeganPizza69 Ⓥ@lemmy.worldOPEnglish
      22·
      3 days ago

      You have RCTs for long-term effects like cancer formation? Cool, let’s see:

      Randomized trials (published in any language) comparing diets lower in red meat with diets higher in red meat that differed by a gradient of at least 1 serving per week for 6 months or more.

      6 months you say?

      There were few trials, most addressing only surrogate outcomes, with heterogeneous comparators and small gradients in red meat consumption between lower versus higher intake groups.

      The longest study was 12 years long and their “meat gradient” was 20%. The study itself is weak as the participants didn’t really stick to it (aside from the study being about postmenopausal women):

      In conclusion, this long-term dietary intervention in postmenopausal women, intended to reduce fat intake and increase intake of vegetables, fruits, and grains, achieved an 8.2% of energy decrease in total fat intake but only a 2.9% of energy decrease in saturated fat intake and only modest increases in intakes of vegetables, fruits, and grains. The intervention did not reduce risk of CHD or stroke. To achieve a significant public health impact on CVD events, a greater magnitude of change in multiple macronutrients and micronutrients and other behaviors that influence CVD risk factors may be necessary. https://jamanetwork.com/journals/jama/fullarticle/202339

      this was also an interesting exclusion:

      Eligibility criteria included being postmenopausal and consuming at baseline a diet with fat intake of 32% or more of total calories, as assessed by a food frequency questionnaire (FFQ). Major exclusions for WHI included prior breast or colorectal cancer, other cancers except nonmelanoma skin cancer in the last 10 years, medical conditions with predicted survival less than 3 years, and adherence concerns such as alcoholism. Additional trial-specific exclusions included type 1 diabetes and frequent consumption of meals prepared away from home.

      And, yes, they used FFQ.