PONE-D-21-13839

Glioblastoma Signature in the DNA of Healthy Cells

PLOS ONE

Dear Dr. Bruck,

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Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In this paper the authors describe a potentially useful method and innovative approach to study individual cancer risk.

They describe a computational method to measure the mutational load derived during lifetime of each individuals and the propose to use this methodology as cancer risk predictor.

They declare that is applicable specially or exclusively for Glioblastoma patients.

For this purpose they examine whole exomes data registered in the TCGA for 3874 patients with different type of cancers for mutation histories of tandem repeat regions in “blood-derived healthy DNA”. What does “healthy DNAs” mean?

if it is DNAs coming from lymphocytes of cancer patients, it might be not healthy  at all.

This might invalidate the findings.

So I suggest to send the paper to a journal more related to computational models.

Reviewer #2: The manuscript of Dr. Jain and colleagues is focused on the analysis of the germinal mutational signature in different cancer type patients with the aim of identifying a molecular signature on the DNA can could be informative of which kind of cancer a patient would develop in a tentative predictive approach. Authors, by means of machine learning and computational methods, analyzed the mutational pattern of non-tumor DNA of TGCA-derived genomic data of several cancer types patients. Authors postulated that the historical mutation analysis of that patients could be predictive of kind of cancer. The idea behind the work is very interesting and well inferred in the manuscript. Nevertheless, there are some concerns that need to be fixed by the authors to consider their work for publication in PLOS ONE journal.

Major issues

1. The rationale of limiting mutational analyses of blood-derived DNA to exome is not very clear and should be better explained and discussed, also considering the potential under-represented mutations in non coding regions.

2. How the signature of tandem repeat regions can be different from that of healthy individuals (not affected by cancer of any kind)? Authors did not include in their analysis, nor discussed nothing about. Even if they aligned the genomic information of cancer patients against reference genome hg38, no information is provided, nor discussed, about the possibility that the molecular profiling reported by the authors could discriminate between healthy people from those that will develop cancer (of specific type or of any type).

Minor points

Materials and methods section. “Tandem Repeat Detection and Mutation History Estimation” paragraph. The highlights in bold are not visible in the provided text.

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Reviewer #1: No

Reviewer #2: No

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Glioblastoma Signature in the DNA of Blood-Derived Cells

PONE-D-21-13839R1

Dear Dr. Bruck,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Alvaro Galli

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Roberto Giovannoni