Li–Fraumeni Syndrome: Mutation of TP53 Is a Biomarker of Hereditary Predisposition to Tumor: New Insights and Advances in the Treatment

Round 1

Reviewer 1 Report

Li-Fraumeni Syndrome (LFS) is a rare tumor pre-disposition syndrome mainly due to pathogenic germline variants of TP53 gene. However, LFS patients develop a broad spectrum of cancers in their lifetime. This review aimed to report novel molecular mechanisms involved in the oncogenic functions of mutant p53 in LFS in addition, they discuss recent new diagnostic and therapeutic approaches exploiting TP53 mutations as biomarkers and druggable targets.

According to the variability of the disease intra and inter families is the paramount importance the understanding the molecular mechanisms involved in the pathogenesis to improve druggable target to treat personally patients with Li-Fraumeni syndrome.


There are important papers published that the authors should be cited and commented as follow (at least): XAF1 as modifier of p53 function and cancer susceptibility (Science 2020) and about ATRX – Genomic landscape of paediatric adrenocortical tumors (Nature Communication 2015)

Authors concluded the necessity of collaborative studies between different groups to integrate clinical practice, since the results of genomic, metabolomic and biological analyses will be advantageous in developing the understanding of the cancer predisposition.

This information may be an important source for explaining the different manifestations of LFS, such as differences in disease and penetrance and the heterogeneity of the tumors that arise. The dream would be to identify the driving factors and the phenotype of the disease to fine-tune the development of an individualized monitoring protocol.

Figure 3(A) A lolliplot showing six mutant p53 germline variants in Li-Fraumeni syndrome with their frequency of mutation:

Please add the significance of acronyms: TAD, PRD, OD, RD at text

Figure 3B (B) Diagram representing the frequency of occurrence of the tumors in LFS in which six mutant p53 hotspots are present.
 It is not clear for me the significance of orange line

Author Response

Cancers Editorial Office

 

We wish to thank you for giving us the opportunity to revise and improve the manuscript at the final stage. We revised the manuscript accordingly.

Below please find the detailed list of our responses and the changes we made in the revised version of the manuscript.

Changes in the manuscript text have been highlighted in red and by using “track change” function.

Reviewer 1

We thank the referee for the general positive comments.

1. There are important papers published that the authors should be cited and commented as follow (at least): XAF1 as modifier of p53 function and cancer susceptibility (Science 2020) and about ATRX – Genomic landscape of pediatric adrenocortical tumors (Nature Communication 2015).

Response: Following the suggestions, we have added the References in the most appropriate places of the text with a brief description.

2. Figure 3(A) A lolliplot showing six mutant p53 germline variants in Li-Fraumeni syndrome with their frequency of mutation: Please add the significance of acronyms: TAD, PRD, OD, RD at text

Response: Thank you for the observation. In previous manuscript, we have indicated the significance of acronyms only in the figure legends. In the revised version we added the meaning also in the text.

3. Figure 3B (B) Diagram representing the frequency of occurrence of the tumors in LFS in which six mutant p53 hotspots are present.
   It is not clear for me the significance of orange line

Response: We thank the reviewer for the comment. We actually realized that we had not sufficiently commented on this statistical analysis. In the revised manuscript, we added some details to the graph and we think to have provided enough statistical information in the figure legend, leaving the text lighter and more fluent. We hope to meet the reviewer's approval.

We used a Pareto analysis which is a bar graph and it is one of the seven basic tools of quality control. The lengths of the bars represent frequency and are arranged with longest bars on the left and the shortest to the right, so in descending order. In this way the chart visually depicts which situations are more significant. Pareto charts are extremely useful for analyzing what problems need attention first because the taller bars on the chart, which represent frequency, clearly illustrate which variables have the greatest cumulative effect on a given system.

The left vertical axis is the frequency of occurrence. The right vertical axis is the cumulative percentage of the total number of occurrences. Although it is common to refer to Pareto analysis as the "80/20" rule, assuming that, in all situations, 20% of the causes determine 80% of the problems, this ratio is simply a practical and qualitative rule.

In simple terms, 80% is considered a cut-off percentage below which events are not significant within the total group of events considered. In the case of Figure 3A, among all LFS tumors where TP53 mutations are present, those that reach the 80% point in the right Y axis (orange bars in the new figure) are those that statistically weigh the most in the total tumor group. On the left, it is indicated the percentage of mutp53 incidence in LFS.

 

 

Furthermore, an expert in reviewing articles in English made the necessary corrections to the manuscript.

 

 

Author Response File: Author Response.pdf

Reviewer 2 Report

The content of this review is comprehensive and the field may be useful for the management of LFS and TP53 mutated families. I recommend it for publication. In the complex manuscript is well written, however I would suggest a minor revision:

The authors should integrate the paragraph “Tumor Prevention and treatment” including additional information about surveillance protocols and clinical management of patients with TP53 mutations and their relatives, as reported by Frebourg et al European Journal of Human Genetics (2020) 28:1379–1386.

Author Response

Cancers Editorial Office

 

We wish to thank you for giving us the opportunity to revise and improve the manuscript at the final stage. We revised the manuscript accordingly.

Below please find the detailed list of our responses and the changes we made in the revised version of the manuscript.

Changes in the manuscript text have been highlighted in red and by using “track change” function.

Reviewer 2

We thank the reviewer for the positive comments.

The suggested reference is now integrated in the revised paragraph indicated by referee with the number [91].

 

Author Response File: Author Response.pdf