Genomic Insults and their Redressal in the Eutopic Endometrium of Women with Endometriosis

Round 1

Reviewer 1 Report

Dear Authors,

Congrats on the lovely review. Minor suggestions/corrections are needed.

Introduction

Line 85-86. “There also exist data to suggest that the factors involved in various repair machineries i.e. 85 MMR [14], [15], HR [16], NHEJ [17] and BER [13], [18] are expressed in human endometrium.”

These abbreviation where not explain before.

4. DNA repair in women with endometriosis

                The mutations presented are not correct. Please, correct it. I have no idea what means “161CC”.

                Ex. 1394T/G is c.1394T<G

                      Prol2ALA is p.Pro2ALA

Best.

Author Response

We thank the reviewer for the constructive critiques and valuable suggestions. The suggestions/ remarks have helped us improvise the manuscript.

Q1. Introduction line 85-86. “There also exist data to suggest that the factors involved in various repair machineries i.e. 85 MMR [14], [15], HR [16], NHEJ [17] and BER [13], [18] are expressed in human endometrium.” These abbreviation where not explain before.

A1. MMR, HR, NHEJ and BER terms have been expanded in the revised version. Please see lines 90-91.

Q2. DNA repair in women with endometriosis. The mutations presented are not correct. Please, correct it. I have no idea what means “161CC”.

                Ex. 1394T/G is c.1394T<G

                      Prol2ALA is p.Pro2ALA

A2. We thank the reviewer for describing the correct nomenclature. Corrections have been made accordingly in the revised version. Please see lines 440-460.

Reviewer 2 Report

Thank you very much for the invitation to review of the manuscript. It a great pleasure for me.

The purpose of Munshi and Sachdeva was to compile inferences from studies conducted to assess DNA damage and DDR in endometriosis. This is very interesting paper, However, I have a few suggestions and advice:

1.     The introduction part is too long, it would be worth to divide it for 2 parts.

2.     It would be worth to add some tables or figures to summarize chapters or even conclusions.

3.     How this is related to infertility?

4.     Are there any studies on its use in therapy?

5.     The abbreviation should be explained only once.

6.     The methodology of the paper is unclear and the Authors should include more precise information about inclusion/exclusion criteria as well as basic key words used in literature research.

Author Response

We thank the reviewer for a very constructive critique.

Q1. The introduction part is too long, it would be worth to divide it for 2 parts.

A1. As suggested by the reviewer, the introduction is now divided into two parts.

Q2. It would be worth to add some tables or figures to summarize chapters or even conclusions. 

A2. As suggested, we have included a figure in the revised version to summarize the review.

Q3. How this is related to infertility?

A3. The review presents available information on DNA damage and its repair in the eutopic and ectopic endometrium from women with endometriosis. Data exist to suggest the presence of oxidative factors/ inflammatory cytokines in the peritoneal microenvironment of women with endometriosis. Altogether these can contribute to damage in the oocyte and/or endometrium. Poor quality oocytes or dysfunctional eutopic endometrium with higher damage can contribute to infertility. However, a direct link between DNA damage in the eutopic endometrium from women with endometriosis and infertility remains to be studied.

Q3. Are there any studies on its use in therapy?

A3. To the best of our knowledge DDR has not been investigated for its potential therapeutic targets in endometriosis.

Q4. The abbreviation should be explained only once. 

A4. As suggested repetitions have been deleted.

Q5. The methodology of the paper is unclear and the Authors should include more precise information about inclusion/exclusion criteria as well as basic key words used in literature research.

A5. Key words used in the literature search on PubMed were ‘(DNA damage) AND (endometriosis)’, ‘(DNA repair) AND (endometriosis)’, ‘(Oxidative stress) AND (endometriosis)’, ‘(Inflammation) AND (endometriosis)’. This has been included in the revised  version.

Reviewer 3 Report

With great interest, I read the manuscript on an important clinical issue that impacts the life of many patients. Authors show interesting perspective underlying important but often omitted aspects of disease. Nevertheless, authors did not shy away from minor shortcomings and deficiencies, which I will present in points:

-Determiners are missing in many places in text. English native speaker assistance should be warranted.

-v 14 - There is no evidence that endometriosis causes irregular cycles - by the way, I don't know what the point of such a statement is in the abstract - if even irregular cycles are more common in endometriosis (which is doubtful) it is not known whether they cause endometriosis or endometriosis causes irregularity.

-v 137- The authors discuss NGS studies on ovarian cancer, and discuss studies on genomic sequencing of cancer driver mutations in endometriosis itself such as 33805315.

-v 255 - “endometriosis women” is an obsolete term

-v 276-277,299 - Please use the current name of TNF. TNF-alpha is a no longer valid name - see https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/11892

Author Response

Q1. Determiners are missing in many places in text. English native speaker assistance should be warranted.

A1. The manuscript has been revised for its language.

Q2. -v 14 - There is no evidence that endometriosis causes irregular cycles - by the way, I don't know what the point of such a statement is in the abstract - if even irregular cycles are more common in endometriosis (which is doubtful) it is not known whether they cause endometriosis or endometriosis causes irregularity.

A2.  We agree that  there is no proven link between endometriosis and irregular cycles, this has been omitted from revised version.

Q3. -v 137- The authors discuss NGS studies on ovarian cancer, and discuss studies on genomic sequencing of cancer driver mutations in endometriosis itself such as 33805315.

A3. As suggested, additional reference such as Koppolu et al. 2021 have been added to the review. Koppolu et al. have reported presence of somatic KRAS mutation (p.Gly12AspKRAS) in the eutopic and ectopic endometrium from women with endometriosis. 

Q4. -v 255 - “endometriosis women” is an obsolete term

A4:  ‘endometriosis women’ is replaced by ‘women with endometriosis’ in the revised version.

Q5. -v 276-277,299 - Please use the current name of TNF. TNF-alpha is a no longer valid name - see https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/11892

A5 : We thank the reviewer for pointing out this. Appropriate symbols (TNF) have been used in the revised version.

Round 2

Reviewer 1 Report

Dear authors,

congrats on the excellent work.

I suggested the acceptance of the paper.

Reviewer 2 Report

Thank you for adding all new information and clarification.

Reviewer 3 Report

Publication in its current form can be considered.