Review for 10.1186/s12876-024-03552-w (2024)

Title: The additive interaction of healthy lifestyles and genetic susceptibility on colorectal
cancer risk in prediabetes: a large population-based prospective cohort study
Version: 3 Date: 14 Oct 2024
Reviewer's report:
The manuscript offers a valuable contribution to the field of colorectal cancer (CRC) research
by focusing on the interaction between genetic risk (via polygenic risk scores or PRS), lifestyle
factors, and colorectal cancer (CRC) risk within a prediabetic population.
Strengths of the Manuscript
1. The most distinctive and novel aspect of the manuscript is its focus on prediabetes as a critical
condition in relation to CRC risk. Previous papers did not specifically address the prediabetic
population, which is increasingly recognized as a high-risk group for chronic diseases, including
cancer. The exploration of CRC risk in individuals with prediabetes, who are often overlooked
in CRC prevention research, is a unique angle that adds valuable insights to the literature.
2. The manuscript narrows its focus to a population with an elevated baseline risk (prediabetic
individuals) and investigates how lifestyle factors may mitigate CRC risk in individuals
with varying degrees of genetic susceptibility. This population-based cohort study provides
actionable insights for clinicians targeting CRC prevention in a high-risk group and offers
evidence for personalized prevention strategies.
3. The manuscript emphasizes practical, modifiable lifestyle interventions (diet, BMI, smoking,
alcohol consumption) as strategies to reduce CRC risk. This preventive approach aligns well
with public health efforts aimed at managing prediabetes and potentially reducing CRC risk.
Critical Comments for Improvement
1. Previous studies evaluated comprehensively many specific foods and nutrients, providing
detailed dietary insights that directly link individual components to CRC risk (see e.g., Jin D,
et al. Diet-Wide Association, Genetic Susceptibility and Colorectal Cancer Risk: A Prospective
Cohort Study. Nutrients 2023;15:4801). The present manuscript, by contrast, only broadly
assessed dietary habits without focusing on specific nutrients like calcium, magnesium, fiber,
or alcohol. The absence of specific nutritional data in the present manuscript limits the depth of
dietary analysis and the ability to provide precise dietary recommendations for CRC prevention.
2. Jin D, et al.'s paper in Nutrients boasts a large sample size of 118,210 participants and a
robust analysis of CRC risk across multiple dietary components, genetic risk levels, and cancer
subtypes. Wu E, et al. (Front Oncol 2022;12:894086) also included a much larger population
(390,365 participants) compared to the 22,408 prediabetic participants in the present manuscript.
The smaller sample size may limit the generalizability of its findings, and the analysis might
benefit from a larger cohort to improve statistical power and broader applicability. The PRS in
the paper by Wu E, et al. was constructed using data from the FinnGen biobank, which includes
a large number of SNPs (16,380,465 SNPs) and underwent thorough quality control to select
the “best-fit” PRS using 59 SNPs. In comparison, the submitted manuscript used PRS data from
previous studies in the UK Biobank, which may not have undergone the same level of detailed
SNP selection or meta-analysis, potentially limiting the accuracy of genetic risk prediction.
3. While the present manuscript focused on lifestyle factors like diet, BMI, smoking, and
alcohol consumption, it did not include emerging lifestyle factors such as sleep, which Wu et
al. incorporated. Given that recent research suggests that sleep disturbances can increase CRC
risk, the exclusion of sleep factors weakens the lifestyle analysis.
4. Previous studies explored different CRC subtypes, distinguishing between colon and rectal
cancers, and provided insights into how different dietary and genetic factors affect each subtype.
The present manuscript did not differentiate between CRC subtypes, missing an opportunity to
provide a more nuanced understanding of how risk factors vary between different forms of CRC.
5. Previously published studies discussed the biological mechanisms linking lifestyle factors
and genetics to CRC development. Wu E, et al. for example, explored how nutrients like
alcohol and white bread may promote CRC through processes like acetaldehyde production
and gut microbiota interactions. The submitted manuscript could benefit from a more thorough
discussion of the biological pathways that explain how prediabetes, genetics, and lifestyle factors
interact to influence CRC risk.
6. Previous studies explored gene-lifestyle and gene-diet interactions in greater depth than the
submitted manuscript. In particular, the interaction between genetic predisposition and specific
dietary factors like fiber, calcium, and alcohol in influencing CRC risk has been investigated.
While the submitted manuscript addresses PRS and lifestyle, it lacks a detailed analysis of how
specific genetic variants may interact with certain dietary factors.