Prognostic Impact of TP53 Mutations and Tumor Mutational Load in Colorectal Cancer

Round 1

Reviewer 1 Report

The manuscript title promises to highlight the contribution of the DDR/DNA repair genes mutation to  both colorectal cancer (CRC) development/prognosis and response to treatment. In fact, the study brings no conclusion pointing out the importance of DDR genes status investigation for predicting CRC prognosis, with exception of widely-accepted p53 mutational status. Substantially, the study offers significant data proving:

i)                    the association of high tumor mutational load with worse overall survival/ disease-free survival  

ii)                   that patients with mutant p53 displayed worse overall survival/ disease-free survival  

Thus, the DDR/DNA repair genes in the title makes no sense to me and I find it to large extent misleading. I would suggest to replace the title and focus it rather on the major findings diplayed by authors (not including DDR/DNA repair).

Non-significance of the results of DDR/DNA repair analysis may be affected by the small size of the sample (N=22). In this case, the correct methodology and the clear goal-oriented research setup could not compensate for the critically small sample size, resulting into limitations in significance. We can only hypothesize, whether the appreciation of the DDR proteins role in CRC would bring more clear, therapy-suitable results, if adressed within large sample of patients.

In table 4, somatic mutations in CRC patients are presented, including ERCC2 mutation in P4, P6, P16, P21. ERCC2 represents the XPD, involved in DNA repair. In the abstract, line 27 to 29, XPD is not included into the group of DDR muations found in analyses CRC patient samples. This should be made clear/explained.  

Altogether, the novelty of the findings, especially with respect to DDR/DNA repair is below the expectations. On the other hand, in-significance should be considered as a consequence of small sample size. From technical point of view, content of the manuscripts includes high-quality texts and correct presentation of obtained data. 

Author Response

Thank you for the time to review and provide feedback. We have addressed the points raised (see attached document) and incorporated changes in the revised manuscript

Author Response File: Author Response.pdf

Reviewer 2 Report

The manuscript is interesting, but the significant results are few.

This probably is a reason the authors bet on an extensive "Introduction" and "Discussion" sections, which does not improve the manuscript.

Part of some small remarks:

Table 1 precedes the explanation of the formation of the two groups - patients with low and high TML. In table 1 comparison regarding the metastatic stage of the patients and between patients receiving neoadjuvant therapy and those non-receiving - are redundant.

The title may be more specific. 

 

Author Response

Thank you for the time taken to review the manuscript and provide feedback. We have addressed the points raised (see attached document) and have incorporated changes in the revised manuscript

Author Response File: Author Response.pdf