World Trade Center Exposure, DNA Methylation Changes, and Cancer: A Review of Current Evidence
, Nedim Durmus 3, Ramazan Alptekin 3, Muhammed Yilmaz 3, Maria Cecilia Crisanti 3, Matija Snuderl 4, Yu Chen 1,5, Yongzhao Shao 1,5, Joan Reibman 3,6, Emanuela Taioli 2,* and Alan A. Arslan 1,5,7,*
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis is an well conducted review regarding WTC exposure, DNA methylation Changes and Cancer.
Minor comments:
1. Regarding the prostate cancer responders: although the WTC-exposed males with prostate cancer have increased methylation GpG sites, what the consequence to the survival of these patients?
since the survival of prostate cancer is mainly related to the diagnosed Gleason score grade and clinical stages and the treatment modalities, the methylation status may related to cancer development, not impact to cancer survival.
Author Response
Response: Thank you for taking the time to review our manuscript and for your thoughtful insights. It is an interesting point that WTC-associated DNA methylation changes could play a role in cancer development or survival. We’ve not yet been able to investigate the impact of DNA methylation changes on survival among WTC exposed cancer patients using survival modeling, but this will be an objective of future studies. We’ve expended on the third paragraph of our discussion to address this, “It remains to be seen, however, what impact DNA methylation of these cancer-related genes may have on cancer survival. Resources like the WTC EHC Pan-Cancer Database will enable us to address this question in future work. Up to December 2022, there are 976 prostate cancer and 1,1213 breast cancer cases documented in the Pan Cancer Database.17,33 Demographic and treatment data, as well as specific tumor characteristics like Gleason score for prostate cancer, are included in the database, which is periodically linked to the National Death Index.33 By expanding on these EWAS studies and making use of this rich data source we will be able to tease apart the effects of WTC-associated DNA methylation on cancer development and survival.” [lines 263-271]
Reviewer 2 Report
Comments and Suggestions for Authors
1. The review manuscript of Dr. Shen Tuminello and colleagues extensively cover a highly relevant and interesting topic. This is an interesting review aimed in reviewing the published epigenetic data on the differentially methylated gene profiles identified in Epigenome-wide association analyses studies of World Trade Center exposure. Four studies which published epigenome data in terms of DNA methylation changes regarding World Trade Center exposure were evaluated. Main results indicate tha t dust exposure appears to be associated with DNA methylation changes across the human genomes and in particular cancer initiation and development. The role of World Trade Center exposure on long-term DN Amethyaltion changes is has therefore been hypothesized to play a role in cancer development
2. In my opinion the study is well written, well conducted, relevant and suitable for Epigenomes MDPI. Below some comment for improving the work
3. In order to increase the visibility of the work, may I suggest replacing the abbreviation WTC with World Trade Center in the title?
4. In line 60 Have these environmental pullulants been found in World Trade Center?
5. In lines 62-64 or 243-426, these additional supporting references on the role of DNA methylation in gene expression modulation and cancer onset should be included PMID: 27223861, PMID: 27826838
6. Several studies underlined the implication of dust/air pollutants in DNA methylation changes, although this topic is not closely related to the purpose of the study. I believe these studies deserve attention given the presence of a fraction of scientific literature that reported an association between dust/air pollutants and even explosions and epigenetic changes, including DNA methylation changes. Authors should mention these studies as a support of the study findings. Please check PMID: 31152171, PMID: 19136372, PMID: 30871143 and PMID: 33192958
Author Response
Comment 1: In order to increase the visibility of the work, may I suggest replacing the abbreviation WTC with World Trade Center in the title?
Response: Yes, thank you for this comment. The title has been changed to “World Trade Center Exposure, DNA Methylation Changes and Cancer: A Review of Current Evidence” as suggested.
Comment 2: In line 60 Have these environmental pullulants been found in World Trade Center?
Response: Yes, all the environmental pollutants mentioned were measured in the World Trade Center Dust. We’ve clarified the introduction to read “Environmental exposure to asbestos, VOCs, PAHs, PCBs, and dioxins, all of which were observed and measured in the WTC dust, have been shown to induce aberrant DNA methylation changes in tumor suppressors and oncogenes, such as OGG1, FOXF1, GAS1, TP53, PTEN, BCL3 and BRCA1 [now line 63].
Comment 3: In lines 62-64 or 243-426, these additional supporting references on the role of DNA methylation in gene expression modulation and cancer onset should be included PMID: 27223861, PMID: 27826838
Response: Thank you for bringing these helpful papers to our attention. We’ve cited PMID: 27826838 in line 252 (now reference # 54) and PMID: 27223861 in line 254 (now reference #55).
Comment 4: Several studies underlined the implication of dust/air pollutants in DNA methylation changes, although this topic is not closely related to the purpose of the study. I believe these studies deserve attention given the presence of a fraction of scientific literature that reported an association between dust/air pollutants and even explosions and epigenetic changes, including DNA methylation changes. Authors should mention these studies as a support of the study findings. Please check PMID: 31152171, PMID: 19136372, PMID: 30871143 and PMID: 33192958
Response: Thank you for suggesting these interesting and helpful articles. We’ve added to the first paragraph of the discussion illustrating how this work aligns with previous work on occupational exposures and DNA methylation alterations, which reads “This is in keeping with previous work investigating the long-term epigenetic impacts of occupational exposures to dust and fumes, whereby inhalation of small particulate matter induces DNA methylation changes.49–51 A history of exposure to explosive blasts among military members, for example, is encapsulated by DNA methylation profiling of genes linked to commonly reported symptomology such as chronic pain and sleep dysregulation.52” [lines 235-240]
The suggested articles have been cited PMID: 31152171 [reference # 49], PMID: 19136372 [reference # 50], PMID: 30871143 [reference # 51] and PMID: 33192958 [reference # 52]
Reviewer 3 Report
Comments and Suggestions for AuthorsTuminello et al., in the paper "WTC exposure, DNA methylation changes, and cancer: a review of current evidence" compare data obtained from four previous papers in which DNA methylation changes in people involved in the collapse of the WTC were evaluated.
In the discussion, the authors illustrate the limitations of the study, which were present a priori, however, they did not consider reducing them using other samples.
Unfortunately, the work performed is insufficient to result in a publication.
Author Response
Response: Thank you for taking the time to review our work. The association of complex environmental exposure such as World Trade Center dust on DNA methylation is an understudied topic. To-date only the four studies outlined in our review have attempted to address this topic. We note in the discussion that the reviewed articles were relatively small studies. However, this initial re-analysis shows consistent results reported in the individual pilot projects. We therefore think that we have contributed new information by strengthening some of the results found in the initial pilot studies, thus helping weed out results that are not relevant from those that deserve further studies.
In the interim, we’ve added to the discussion section, “The insights reported here will hopefully be validated and expanded upon in future work.” [lines 326-327]
Given the gap in understanding regarding the biological mechanisms of WTC-associated cancer development, and the rising cancer rates among WTC exposed persons, we feel this work, while exploratory in nature, offers useful insights for future projects. We hope that these edits can help to alleviate some of the reviewer’s concerns.
Round 2
Reviewer 3 Report
Comments and Suggestions for AuthorsI thank the authors for their comprehensive answers.
