On the gene expression landscape of cancer

Augusto Gonzalez; Dario A. Leon; Yasser Perera; Rolando Perez

doi:10.1371/journal.pone.0277786

Peer Review History

Original SubmissionJuly 27, 2022
20 Sep 2022 Decision Letter - Elingarami Sauli, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-22-21174On the gene expression landscape of cancerPLOS ONE Dear Dr. Dario Alejandro Leon Valido, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised (by Reviewers 1 and 2) during the review process. Please submit your revised manuscript by Nov 04 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. 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Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 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: Review of “On the Gene Expression Landscape of Cancer” by Gonzales et al. This manuscript is interesting and thought-provoking in that it addresses “grand” questions of cancer from a higher-order viewpoint, rather than ever narrower questions in ever more detail as most papers seem to do nowadays. However, the writing could be clearly improved and be more concise, precise and use a more scientific language. There are many “filling” words and sentences that can be omitted without losing information. The following major and minor points should be addressed: Major points 1. The first two paragraphs of the Results section could be considerably shortened. Parts of it should be transferred to the Methods section, and/or covered by references. It is not necessary to explain in this paper how RNA-seq works, and it is not part of this manuscript`s results. The authors state “In the Methods section, the used PCA methodology is briefly explained”. This statement is sufficient for the Results section, further details on their PCA methodology should be in the Methods. 2. Figure 2 and the corresponding Text shows “a few thousand of genes” differentially expressed between tumors and normal tissue, and the magnitude of this differential expression is at least two-fold, and up to >100-fold. This is unusual, since similar previous analyses show fewer differentially expressed genes, and a lower magnitude of the differences. Are all these differences statistically significant (by t-test or similar test statistics)? Have the authors properly normalized the gene expression data (per-gene and per-sample normalization)? 3. Legends to Figures and Tables should explain what is shown in corresponding Figures and Tables in more detail and with more precision, e.g. all abbreviations should be defined (or at least refer to an item where those are defined), and x- and y-axes should be well defined (e.g. x-axis in Figure 3 is labelled “Differential Expression” – are these fold-changes? Probably yes, but this should be defined!). 4. In statement 4, second part (page 6), the effect of tumor stage (I, II, II, IV) on gene expression of tumors is discussed, and it is assumed that higher-stage tumors should be progressed further on the normal-tumor gene expression axis. However, whereas expression is analysed in the primary tumor, the tumor stage is not a property of the primary tumor alone, e.g. stage IV commonly means that distant metastasis are present, and lymph node metastasis also play a key role in determining the tumor stage (which may or may not affect the gene expression state of the primary tumor analysed here). Probably the tumor size or tumor grade (both a property of the primary tumor) would be a better parameter than tumor stage to address this question. In any case, it should be defined (or a reference provided), how tumor stage I-IV are defined in KIRC, and this potential limitation should be discussed. Minor points 1. “Statement 1-5” in Results: Are these results, conclusions or hypothesis? More precision in wording is needed. 2. Statement 1 (page 4): the authors refer to “the left panel” and “the right panel” of Figure 1. They probably mean the upper panel and the lower panel. 3. This reviewer recommends to omit the scale lines within the panels in Figure 2, they are distracting and may cause problems during printing and photo-copying. 4. Page 4 bottom: “the rest of the 60000 genes”. The authors should explain how they arrive at this number. There are about 25000 human protein-coding human genes, were additional genes (miRNAs, long nc RNAs etc.) included in this number? The authors should provide their (or the TCGA’s) definition of “gene”. 5. Page 6: “Well defined regions in expression space is a fact in favor of the attractor paradigm of cancer” could be replaced by “Well defined regions in expression space support the attractor paradigm of cancer”. 6. “sub-expression” should rather be termed “under-expression”, as opposed to over-expression, or “up-regulation” and “down-regulation” should be used (throughout the manuscript). 7. The Formatting of the References apparently does not adhere to PLOS One style, in particular, the full first names of authors are provided. Reviewer #2: PCA has been used to analyze GE data from TCGA dataset. In detail, the results of the PCA of 15 different tumors seem to support 5 different facts or statements. Overall, the manuscript is well written and PCA well performed. I have some minor comments: - As authors stated: "results are simple, general and unbiased, in the sense that no modeling or elaborated mathematical treatments are used". It would be better to describe the possible limits of this approach. - For example, could we use the pan-cancer genes (i.e, the genes common to all 15 tumors) in therapies designed to act in this group of tumors? Are these druggable targets? ****** 6. 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. 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Revision 1
24 Oct 2022 Author Response Reviewer 1: This manuscript is interesting and thought-provoking in that it addresses “grand” questions of cancer from a higher-order viewpoint, rather than ever narrower questions in ever more detail as most papers seem to do nowadays. However, the writing could be clearly improved and be more concise, precise and use a more scientific language. There are many “filling” words and sentences that can be omitted without losing information. Authors Reply: We thank the reviewer for his/her careful reading of the manuscript and his/her positive comments and suggestions. We have rephrased some sentences along the hole manuscript and added more phrases to make the text clearer and more compressible. All the changes are highlighted in the new version. Reviewer 1: The following major and minor points should be addressed: Major points 1. The first two paragraphs of the Results section could be considerably shortened. Parts of it should be transferred to the Methods section, and/or covered by references. It is not necessary to explain in this paper how RNA-seq works, and it is not part of this manuscript‘s results. The authors state “In the Methods section, the used PCA methodology is briefly explained”. This statement is sufficient for the Results section, further details on their PCA methodology should be in the Methods. Authors Reply: We thanks the referee for his/her suggestions. We have shortened the two paragraphs and moved not relevant information to the Method section. Reviewer 1: 2. Figure 2 and the corresponding Text shows “a few thousand of genes” differentially expressed between tumors and normal tissue, and the magnitude of this differential expression is at least two-fold, and up to ¿100-fold. This is unusual, since similar previous analyses show fewer differentially expressed genes, and a lower magnitude of the differences. 2 Are all these differences statistically significant (by t-test or similar test statistics)? Have the authors properly normalized the gene expression data (per-gene and per-sample normalization)? Authors Reply: We thank the referee for this comment. In the new version of the manuscript we explain in more detail the normalization and the used methodology. Our simple procedure discards statistically irrelevant genes (its differential expression becomes 1 and the log fold variation, which enters the principal component analysis, becomes 0). Genes with high differential expression, highlighted by the methodology, have always a biological meaning. Here, we would like to show data for PRAD as an example. The 1st figure is similar to Fig. 3 of our manuscript. There are only two genes (dlx1 and pca3) with differential expression higher than 20. There are also around 1000 genes with edif f > 2, and around 5000 genes with edif f > 1.5. Note that a study of statistically significant differentially expressed genes in PRAD identifies around 11,000 genes (doi: 10.1371/journal.pone.0145322). In paper doi: 10.1038/s41598-021-87764-0, we relate this relative high GE rearrangement (that is, thousands of diff expressed genes) to a discontinuous transition between the normal and the tumor state. The 2nd figure plots sample data for pca3 (a known PRAD marker) in age groups. Mean geometric averages are represented in red. The NY group is taken as reference for normalization. This 2nd fig contributes with 3 point to the 1st figure: that is, one for each of the NO, TY and TO curves. Reviewer 1: 3. Legends to Figures and Tables should explain what is shown in corresponding Figures and Tables in more detail and with more precision, e.g. all abbreviations should be defined (or at least refer to an item where those are defined), and x- and y-axes should be well defined (e.g. x-axis in Figure 3 is labelled “Differential Expression” – are these fold-changes? Probably yes, but this should be defined!). Authors Reply: We thanks the referee for his/her comments. We have added more details to the caption 3 FIG. 1: PRAD FIG. 2: PRAD 4 of the figures and tables. In particular, the x axis in Fig. 3 is properly the differential expression. The log-log plot is simply to show the Paretto law in the tail distribution function. Reviewer 1: 4. In statement 4, second part (page 6), the effect of tumor stage (I, II, II, IV) on gene expression of tumors is discussed, and it is assumed that higher-stage tumors should be progressed further on the normal-tumor gene expression axis. However, whereas expression is analysed in the primary tumor, the tumor stage is not a property of the primary tumor alone, e.g. stage IV commonly means that distant metastasis are present, and lymph node metastasis also play a key role in determining the tumor stage (which may or may not affect the gene expression state of the primary tumor analysed here). Probably the tumor size or tumor grade (both a property of the primary tumor) would be a better parameter than tumor stage to address this question. In any case, it should be defined (or a reference provided), how tumor stage I-IV are defined in KIRC, and this potential limitation should be discussed. Authors Reply: We recognize the limitations to draw “attractor basins” even in the context of advanced tumors stages (III-IV) by only surveying the primary tumor. However, our assumption here is that in primary tumors some information remains in their gene expression profiles, concerning the original seeding of the distant metastasis, and/or that the process of cell invasion and dissemination from this primary site is continuous. In the same line, other groups have also extracted and proposed prognostic signatures for advanced KIRC stages by studying primary tumor samples. See, for example: https://doi.org/10.3389/fbioe.2019.00270 https://doi.org/10.1111/cbdd.14141 https://doi.org/10.3389/fonc.2022.912155 Reviewer 1: Minor points 1. “Statement 1-5” in Results: Are these results, conclusions or hypothesis? More precision in wording is needed. 5 Authors Reply: We have clarified at the beginning of the Results section, that the statements refer to results/conclusions, following straightforwardly from the analysis of the GE data. Reviewer 1: 2. Statement 1 (page 4): the authors refer to “the left panel” and “the right panel” of Figure 1. They probably mean the upper panel and the lower panel. Authors Reply: We thanks the referee for pointing this out, we have corrected it. Reviewer 1: 3. This reviewer recommends to omit the scale lines within the panels in Figure 2, they are distracting and may cause problems during printing and photo-copying. Authors Reply: Thanks the reviever for this comment, we have removed the grids. Reviewer 1: 4. Page 4 bottom: “the rest of the 60000 genes”. The authors should explain how they arrive at this number. There are about 25000 human protein-coding human genes, were additional genes (miRNAs, long nc RNAs etc.) included in this number? The authors should provide their (or the TCGA’s) definition of “gene”. Authors Reply: The referee is right, TCGA data involves measurement of the expression for 60487 RNA- and protein-coding genes in the Ensembl notation. We have made explicit this point in the text. Reviewer 1: 5. Page 6: “Well defined regions in expression space is a fact in favor of the attractor paradigm of cancer” could be replaced by “Well defined regions in expression space support 6 the attractor paradigm of cancer”. Authors Reply: We thanks the referee for pointing this out, we have corrected it accordingly. Reviewer 1: 6. “sub-expression” should rather be termed “under-expression”, as opposed to over- expression, or “up-regulation” and “down-regulation” should be used (throughout the manuscript). Authors Reply: We thanks the referee for pointing this out, we have uniformized the notation. Reviewer 1: 7. The Formatting of the References apparently does not adhere to PLOS One style, in particular, the full first names of authors are provided. Authors Reply: We thanks the referee for pointing this out, we have corrected the format of the references and the manuscript accordingly. Reviewer 2: PCA has been used to analyze GE data from TCGA dataset. In detail, the results of the PCA of 15 different tumors seem to support 5 different facts or statements. Overall, the manuscript is well written and PCA well performed. Authors Reply: We thanks the referee for his/her very positive comments. Reviewer 2: I have some minor comments: - As authors stated: ”results are simple, general and unbiased, in the sense that no modeling or elaborated mathematical treatments are used”. 7 It would be better to describe the possible limits of this approach. - For example, could we use the pan-cancer genes (i.e, the genes common to all 15 tumors) in therapies designed to act in this group of tumors? Are these druggable targets? Authors Reply: We thanks the referee for raising these points. We have stressed in the new version of the manuscript that the results of our PCA analysis are limited mainly by the number of available samples. The second raised question on the pan-cancer genes is really interesting, but beyond the scope of the paper. Druggable targets are defined as those molecules (i.e. proteins, peptides, nucleic acids) which levels and/or specific activities can by modulated by a drug, which can consist of a small molecular weight chemical compound (SMOL) or a biologic (BIOL), such as an antibody or a recombinant protein. Two issues need to be considered on the putative druggability of these reported pan-cancer genes: 1) Gene expression changes highlighted here need to be corroborated at the protein level if we attempt to develop a target therapy against the final protein product. 2) Usually, protein down-regulation and/or diminished activity, are harder to tackle than protein over-expression and/or activity inhibition. However, as described below, there are experimental and approved drugs for 2/3 up-regulated pan-cancer genes, whereas there are recent reported drugs aiming at the three down-regulated genes: a) MMP11 (Up, Matrix Metallopeptidase 11): at least two experimental drugs are re- ported at https://www.genecards.org/cgi-bin/carddisp.pl?gene=MMP11 b) C7 (Down, Complement Component C7): at least one experimental drug is reported at https://www.genecards.org/cgi-bin/carddisp.pl?gene=C7&keywords=C7 c) ANGPTL1 (Down,Angiopoietin Like 1): one inferred drug is reported at https://www.genecards.org/cgi-bin/carddisp.pl?gene=ANGPTL1&keywords= ANGPTL1#drugs_compounds d) UBE2C (Up, Ubiquitin Conjugating Enzyme E2 C): at least three approved drugs are reported at https://www.genecards.org/cgi-bin/carddisp.pl?gene=UBE2C&keywords= UBE2C#drugs_compounds e) IQGAP3 (Up, IQ Motif Containing GTPase Activating Protein 3): no reported or in- ferred drug so far at https://www.genecards.org/cgi-bin/carddisp.pl?gene=IQGAP3& keywords=IQGAP3 8 f) ADH1B (Down, Alcohol Dehydrogenase 1B (Class I), Beta Polypeptide): there are more than 5 approved drugs and another handful under developmental stages. Of note, in a former comprehensive redefinition of the druggable genome (doi: 10.1126/sc- itranslmed.aag1166), the authors stratified the druggable gene set into three tiers corre- sponding to position in the drug development pipeline. Tier 1 (1427 genes) included efficacy targets of approved small molecules and bio-therapeutic drugs as well as clinical-phase drug candidates. Tier 2 was composed of 682 genes encoding targets with known bioactive drug- like small-molecule binding partners as well as those with ≥ 50% identity (over ≥ 75% of the sequence) with approved drug targets. Tier 3 contained 2370 genes encoding secreted or extracellular proteins, proteins with more distant similarity to approved drug targets, and members of key druggable gene families not already included in tier 1 or 2. Furthermore, the more frequent Pfam-A domain content in three tiers of druggable genes were also described. After inspecting this data we noted that ADH1B was positioned into Tier 1, whereas MMP11, C7 and ANGPTL1 were located to Tier 3B. Overall, only IQGAP3 remains elusive as a putative druggable target within the six pan-cancer genes. IQGAP3 contains the Rho GTPase activation prot domains not included in tiers 1-3. Attachments Attachment Submitted filename: plosone_response_vT.pdf https://doi.org/10.1371/journal.pone.0277786.r002
3 Nov 2022 Decision Letter - Elingarami Sauli, Editor On the gene expression landscape of cancer PONE-D-22-21174R1 Dear Dr. Dario Alejandro Leon Valido, 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. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Elingarami Sauli, PhD 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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes ****** 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 ****** 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 ****** 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: My comments have been all addressed and the manuscript improved. I suggest accepting the manuscript. ****** 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: No ******** https://doi.org/10.1371/journal.pone.0277786.r003
Formally Accepted
11 Nov 2022 Acceptance Letter - Elingarami Sauli, Editor PONE-D-22-21174R1 On the gene expression landscape of cancer Dear Dr. Leon Valido: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Elingarami Sauli Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0277786.r004

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