Association of KRAS G12C Status with Age at Onset of Metastatic Colorectal Cancer

Round 1

Reviewer 1 Report

Aruquipa et al. investigated the potential association between KRAS G12C polymorphism and the age at the onset of metastatic CRC. They found that KRAS G12C mutation is more frequent in early-onset metastatic CRC. This is an interesting observation with potential prognostic value. This reviewer has some minor questions.

1, Information on author affiliations is not complete.

2, Introduction, first sentence, a more recent reference should be used: Xie Y, Shi L, He X, Luo Y. Gastrointestinal cancers in China, the USA, and Europe. Gastroenterol Rep (Oxf). 2021 Mar 29;9(2):91-104. doi: 10.1093/gastro/goab010. PMID: 34026216; PMCID: PMC8128023.

3, Add some legends for the figures and footnotes for the tables.

4, The Discussion sections seems to be a simple collection of references without a story line. Suggest to add some transitional sentences to make a better flow.

There are a few typoes

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Summary

The study by Aruquipa et al. investigated KRAS/NRAS and BRAF mutation status in 858 metastatic colorectal cancer patients and found associations between early disease onset and KRAS G12C mutations. The authors managed to collect a large data set to assess the mutation status which is impressive given the described current clinical situation in Brazil. However, I am unsure what the clinical implications of the association between KRAS G12C mutation and early-onset mCRC are. Are there specific treatments that should be given to this patient group? Are there any benefits in identifying this patient subgroup?

Major Comments

Introduction

- Do CRC and EOCRC have different clinical outcomes (e.g. response to treatment, survival times, mortality) or different clinical interventions (e.g. differences in standard-of-care, treatment options)?

- Does the sidedness of tumours have a clinical impact (e.g. treatment type, response, survival, etc.)?

Material and Methods

- Is it possible to include tumour stage in the clinical data?

- Have the p-values been corrected for multiple testing? Given there are 27 different KRAS mutations reported, I assume each was tested and therefore p-values should be adjusted for multiple testing.

Results

- Table 2: In the text the p-value for KRAS G12C mutation is described as 0.046, but in the table it is shown as <0.046. Please provide the exact p-values here (Same for BRAF mutation status).

Discussion

- Given the manuscript is about the association between KRAS G12C mutation and early onset mCRC, it would be beneficial to focus more on the implications of this finding.

Minor style/typo/grammar

- Please avoid abbreviations that only occur once in the abstract (e.g. mCRC)

- Please introduce all used abbreviations even if they are commonly used in the field to avoid confusion for readers outside of the field (e.g. mCRC)

- Table 1: Please add a column on the left hand side to name the variables for easier readability (e.g. ‘Male’/’Female’ should have a ‘Gender’ label, ‘Northeast’/’Midwest’/… should have a ‘Region’ label).

- Figure 1/2: If possible, please remove the ‘3D’ effect from the bar charts. The 3D effect makes it hard to accurately see the percentage values each bar represents (especially in the low percentage cases). I would also suggest combining the 2 figures into 1 figure with parts A (KRAS mutation types) and B (NRAS mutation types). That way the RAS mutations are in one figure and the reader gets a good overview of the mutations across the cohort.

- Table 2: The values in the ‘>80 years’ column don’t line up

- Please use consistent spelling (e.g. MSI-High vs MSI-high)

n/a

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

Thank you for a clinically relevant study.

Introduction

a)      Correct typo in the 8th line (33), 10th line (35), 11th line (36) and 12th line (37) of the first paragraph.

b)      Explain the abbreviation “mCRC” metastatic colorectal cancer in the 3rd paragraph.

c)       Include the definition of metastatic CRC.

d)      Similarly, explain infrequently used/less familiar abbreviations at first use.

e)      Otherwise: Happy.

Materials and Methods

a)      It would help to expand and specify participants that were selected e.g. tumours whose tumours had metastized. Is it either to lymph nodes and systemically.  Systemically to the liver and/or other organs.

b)      Add how the metastases were diagnosed and documented.

c)       Need to include the type of specimens. Were they of the primary tumour - colonoscopic biopsies or some included biopsy of metastasis.

Results

a)      Table 1: The sum of percentages for regional contributions is 99% instead of 100%. Correct Midwest – 32/858 = 3.7%.

b)      Table 2: p-values of <0.046 and p<0.815 are confusing. Are they not p=0.046 and p=0.815.

c)       Otherwise: Happy.

Discussion

a)      Replace “This study” with ‘The study’ in the last line of the 2nd paragraph as “this” would refer to the current study.

b)      Do the same for a similar sentence in paragraph 3.

c)       Check and revise “However, this study did not find a significant association of age at onset with age (p=0.879) or sidedness (p=0.776) as it is confusing.

d)      Correct typo “.and” in the 4th paragraph.

Comments for author File: Comments.pdf

Few minor typos but overall, no concerns.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Thank you to the author(s) to address and incorporate my previous comments and concerns.

I only have one last comment

- If the p values were adjusted for multiple testing, please add this to the methods and include what adjustment was used (e.g. Bonferroni/Benjamin-Hochberg etc.). At the moment it reads as if p values were not corrected for multiple testing.

Author Response

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Author Response File: Author Response.docx