Review Reports - DNA Methylation and Micro-RNAs: The Most Recent and Relevant Biomarkers in the Early Diagnosis of Hepatocellular Carcinoma

Round 1

Reviewer 1 Report

Reviewing report for Medicina-550380: « DNA methylation and micro-RNAs: biomarkers in early diagnosis of hepatocellular carcinoma” from Cozma et alii

In this concise review, A. Cozma and coworkers analyzed the publications from PubMed published on a time frame of two years (2017-2018.) The authors focused their search on “hepatocellular carcinoma”, “DNA methylation” and “microRNA”. In addition, they targeted these molecular species and changes in body fluid and selected only case-control studies.

The paper is well written and the results examined are reviewed correctly.

There is, however several concerns with the content of the paper.

First the title gives the impression that the reader will find a general review. As it is not the case, the mention “recent results” or a similar expression will be welcomed and fair.

Understandably for a search of early biomarkers, the authors focused on molecules circulating in body fluids. But they did not indicate why they focused on DNA methylation and microRNA and not on mutations, or proteins or extracellular vesicles or other RNA species. One or two sentences to set the landscape up will be useful.

The way the bibliographic search was conducted for microRNA is puzzling. Table one gives the impression that the authors focused on only 6 different microRNA species. Is that the case? And if it is, what were the bases that led the authors to focus on those very species of miRNA? If there is justification to this apparently arbitrary choice, please, explain to the reader.

The authors should also make more clearly apparent the transition with the text from individual markers to compound tests that include several methylated targets or different microRNA

Author Response

Thank you very much for your pertinent review. We performed the indicated modifications.

The paper is well written and the results examined are reviewed correctly.

There is, however several concerns with the content of the paper.

First the title gives the impression that the reader will find a general review. As it is not the case, the mention “recent results” or a similar expression will be welcomed and fair.

Response: the title has been changed to: “DNA methylation and micro-RNAs: the most recent and relevant biomarkers in early diagnosis of hepatocellular carcinoma“

Response: we add the following paragraph in the “Context”, on second page (lines 44-47): “With the advent of biotechnology, multiple “omics” data, that include genomics, epigenomics, transcriptomics, proteomics, metabolomics has been used to discover molecular candidates with diagnostic value in HCC. In this article, due to extensive available data, we reviewed only the HCC biomarkers derived from epigenomic data”.

Response: An additional line has been added in table 1 and a paragraph in the body of the text (lines 203-205): “A total of 1126 records were retrieved by a primary PubMed search for microRNAs. After reviewing the titles and abstracts, we selected 6 microRNA that have proved significant diagnostic value for hepatocellular carcinoma”.

The authors should also make more clearly apparent the transition with the text from individual markers to compound tests that include several methylated targets or different microRNA

Response: the following paragraph has been added after the subtitle “MicroRNAs based score”, (lines 244-245) “Compared with single miRNAs, the combination of several miRNAs seems to have a better diagnostic accuracy.”

Reviewer 2 Report

The paper of Angela et al. “DNA methylation and micro-RNAs: biomarkers in early diagnosis of hepatocellular carcinoma” deals with description of epigenetic modifiers, especially miRNA and DNA methylation, in HCC. The Authors try to overview about biomarkers for early diagnosis in HCC. I considered that this review was very well and clear done. Moreover, I think that overall this manuscript can be very helpful to understand about relationship between epigenetic markers and HCC. Therefore, I can strongly recommend this manuscript to medicina.

Author Response

Thank you very much for your pertinent review. We performed the indicated modifications.

Reviewer 3 Report

This review describes the use of liquid biopsy for cancer driver, deregulated DNA methylation as well as aberrant expression of micro-RNAs levels in early diagnosis of HCC. However, this observation is not novel.

Author Response

Thank you very much for your pertinent review. We performed the indicated modifications.

Round 2

Reviewer 1 Report

In this version the authors took in account my remarks. The general structure of the paper is unchanged but the message of the paper has been nuanced (notably in the title).

I consider, therefore, with all the initial reserves I initially expressed, that the paper could be considered.

Reviewer 3 Report

This review describes the use of liquid biopsy for cancer driver, deregulated

DNA methylation as well as aberrant expression of micro-RNAs levels in early diagnosis of HCC. They review recently reported (January 2017-December 2018) HCC-associated molecules, including microRNAs and methylated gene promoters.

In this revision of the earlier version, authors have made attempt with something new. That is encouraging. The authors addressed most of my concerns. Therefore, I can strongly recommend this manuscript to Medicina.