The Role of Diet and Lifestyle in Early-Onset Colorectal Cancer: A Systematic Review

Round 1

Reviewer 1 Report

The authors have adequately addressed all of my comments. They have taken particular care in updating their literature search and also in presenting the extracted information in the manuscript. I do not have any further comments. The authors could run a final spellcheck, as there are still a few typos, e.g. line 422 on page 11.

Author Response

Reviewer #1

 

The authors have adequately addressed all of my comments. They have taken particular care in updating their literature search and also in presenting the extracted information in the manuscript. I do not have any further comments.

We would like to thank reviewer #1 for having strengthened our manuscript with detailed feedback on the previous round of peer-reviewing.

 

The authors could run a final spellcheck, as there are still a few typos, e.g. line 422 on page 11.

We would like to thank reviewer #1 for pointing out that there were minor typos that needed fixing. We carefully inspected the review for grammar and we fixed all the problems.

Author Response File: Author Response.pdf

Reviewer 2 Report

Suggestions of the reviewing process of cancers-1458254.

As to reviewer #1 first report, I find that the authors have answered all the queries and concerns. Nevertheless, the new section 7.1. Epigenetics and eoCRC, included in answer to the reviewer’s question: “Secondly, the manuscript is incomplete as it has missed other risk factors both modifiable and non-modifiable which are critical to the early onset of colorectal cancer. The non-modifiable risk factors include age and predisposing condition which are impacted by diet and lifestyle patterns” is very incomplete. The authors fail to mention histone modifications, which are a relevant epigenetic factor and depend on diet and on other environmental conditions. They also mention small non-coding RNAs as epigenetic factors but they do not discuss their influence on early onset of colorectal cancer. As to the mention of DNA methylation, which occupies almost the whole section, the authors only give a general view and the reference to the article by Wolff et al. (129) is somewhat dated. Finally, the trans-generational transmission of epigenetic alterations must also be mentioned as the parents’ habits of life may result in epigenetic abnormalities in their offspring.

In summary, I will recommend accepting the manuscript with major changes in section 7.1.

Author Response

Reviewer #2

 

As to reviewer #1 first report, I find that the authors have answered all the queries and concerns.

We would like to thank reviewer #2 for the support.

 

Nevertheless, the new section 7.1. Epigenetics and eoCRC, included in answer to the reviewer’s question: “Secondly, the manuscript is incomplete as it has missed other risk factors both modifiable and non-modifiable which are critical to the early onset of colorectal cancer. The non-modifiable risk factors include age and predisposing condition which are impacted by diet and lifestyle patterns” is very incomplete. The authors fail to mention histone modifications, which are a relevant epigenetic factor and depend on diet and on other environmental conditions. They also mention small non-coding RNAs as epigenetic factors but they do not discuss their influence on early onset of colorectal cancer. As to the mention of DNA methylation, which occupies almost the whole section, the authors only give a general view and the reference to the article by Wolff et al. (129) is somewhat dated. Finally, the trans-generational transmission of epigenetic alterations must also be mentioned as the parents’ habits of life may result in epigenetic abnormalities in their offspring.

We would like to thank reviewer #2 for having pointed out that epigenetic changes might include additional biological processes beyond LINE-1 hypomethylation. We have implemented a few more paragraphs on these additional processes. We must acknowledge that these processes have not been investigated in the development of colorectal cancer in individuals younger than 50. The link between the diet, histone modifications, miRNAs, and the development of CRC in young patients is biologically plausible, but there is no definitive proof. Therefore, we highlighted that these biological processes must be thoroughly investigated before drawing meaningful conclusions. For example, it would be worth analyzing the histone status of colonocytes taken from young individuals who follow a Western vs Mediterranean diet. Likewise, the miRNA signature of eoCRC vs loCRC has not been investigated so far. Such studies are necessary to better understand the mechanisms of disease, and this review highlights the need for further data in basic research.

 

In summary, I will recommend accepting the manuscript with major changes in section 7.1.

We would like to thank reviewer #2 for pointing out how this review could be changed and improved. We are delighted to understand that Reviewer #2 finds our work worthy of publication.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Section 7.1 has been thoroughly revised and some of the aspects missing in previous version have been added.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The manuscript is a review article on the role of diet and lifestyle in early onset of colorectal cancer. The authors have provided discussion on certain risk factors including food and dietary patterns, physical activity, obesity, smoking and have analyzed the odd ratio and relative risk. Firstly, there are several review articles on the subject with assessment of various risk factors for colorectal cancer. Secondly, the manuscript is incomplete as it has missed other risk factors both modifiable and non-modifiable which are critical to the early onset of colorectal cancer. The non-modifiable risk factors include age and predisposing condition which are impacted by diet and lifestyle patterns. Thirdly, an important modifiable risk factor the authors have missed is the microbiome. Overall, the review seems to be incomplete and does not provide a comprehensive analysis of the impact of diet and lifestyle factors on early onset of colorectal cancer.

Reviewer 2 Report

Puzzono et al. present a review on the role of diet and lifestyle factors in the pathogenesis of early-onset colorectal cancers. In the recent years, the incidence of early onset (eo) colorectal carcinoma (CRC) has increased, and the etio-pathological basis of eoCRCs has not been well worked out. A review of the existing information on the dietary and lifestyle factors reported to have an association with eoCRCs is therefore useful in the current scenario. The manuscript is well written and the graphics have been well designed and well used in the manuscript.

However, there are certain issues in the study which the authors need to address:

1. My first and foremost concern is that the authors make no attempt to sub-classify their review as a systematic / narrative / scoping review. As the authors have not provided any PRISMA checklist or search strategies with the manuscript, one would assume that this was not a systematic review. Yet, the authors seemed to have performed meta-analysis and have presented forest plots concerning the reported risk-factors for eoCRCs. It is very difficult if not impossible to judge the merit of a literature review if the design of such review is not known. Information pertaining to the search strategies, bibliographic databases that were searched, inclusion criteria for the references, and the number of authors involved in searching and inclusion are absolutely essential for the manuscript.
2. Although I recognize the gaps in current knowledge on the etiopathogenesis of eoCRCs and the importance of reviewing the available evidence, I feel the authors did not sufficiently explain the value of performing a literature review on the exogenous factors. E.g. a potential rationale could be that exogenous factors are modifiable and therefore recognition of exogenous factors could lead to establishment / modification of public health strategies for eoCRC prevention. The authors need to address this in the introduction.
3. In most publications, the cut-off age of 50 years has been sued to stratify CRCs as early-onset or late-onset. However, some recent publications (e.g. PMIDPMID: 33922024) have challenged this cut-off. The authors could discuss the different view-points on the cut-off age for defining eoCRCs.
4. In figures 1 – 4, the authors could consider adding the countries where the studies were based next to the name of the author and year of publication.
5. Page 5, line 135: The authors should mention the country of origin of the EPIC study.
6. The authors could consider adding subheadings in section on dietary factors with each subheading describing the dietary factor (e.g. red meat, alcohol, dairy products etc.) being discussed. While presenting the data in the text on the several dietary factors, the authors could stratify the data based on gender, if such information was available in the included references.
7. Recent publications highlight the association of dietary and lifestyle factors with epigenetic changes that may play a role in eoCRC pathogenesis. The authors need to discuss this.
8. How was physical activity defined and measured in the included references? Were there any details provided on the specific nature of physical activities?
9. In addition to the studies discussed in the review, a more recent prospective multinational cohort study on eoCRC patients observed no correlation between higher BMI and CRC risk (PMID: 34359718). The authors should discuss.
10. The authors need to appraise the data related to the association of smoking and eoCRC risk by stratifying the data as never smokers, former smokers, and current smokers, and also by taking into consideration the number of pack-years if such information is available in the included references.
11. Lines 323 – 327 – the authors need to explain what kind of data would information related to cooking, preserving, and storage provide and how that would be valuable for eoCRC risk prediction.
12. The authors need to discuss the limitations of their review in the Discussion section.
13. The authors highlight the importance of ‘concrete and discrete actions’ for addressing the increasing incidence of eoCRC. It would add value to the manuscript if they could very briefly describe what such actions could be.