Reviewer’s report
Title: Analysis of the Relationship between MIR155HG Variants and Gastric Cancer Susceptibility
Version: 0 Date: 01 Nov 2019
Reviewer: Jose Saenz
Reviewer's report:
In this manuscript, Zou et al. describe a case-control study looking at the correlation between genetic
variants of a miRNA, MIR155HG, and gastric cancer. In particular, they analyzed single nucleotide
polymorphisms (SNPs) within this gene using a MassARRAY platform to identify particular SNPs that
correlated  with  either  increased  or  decreased  gastric  cancer  risk.  While  I  found  that  the  overall
approach of attempting to identify gastric cancer susceptibility loci is worthwhile, I believe that, in
general,  the  authors  did  not  adequately  describe  their  methods  and  seemed  to  overstate  certain
conclusions. Some of their association analyses failed to show correlations between certain SNPs,
which decreased the overall impact of the manuscript. In addition, it remains unclear whether some of
their conclusions can be applied to different populations aside from the Han population in China.
Perhaps the biggest weakness is that it remains to be seen how clinically and physiologically relevant
the SNPs identified in this study are to gastric cancer. The authors make little to no mention of the
possible functions or genetic targets of MIR155HG and how these might contribute to or prevent the
progression to gastric cancer. Some additional comments are listed below:
  
*The introduction of the various inheritance models seems problematic to me. That the χ2 test
showed no statistical difference in the frequencies of any of the SNPs in the MIR155HG gene between
the gastric cancer cases and controls makes it seem that the authors needed to turn to another statistical
test to find an association. The authors rely on a previously published inheritance model but do not
introduce the model or explain why they chose this model. What are the limitations of this model, and
why would it better explain the association than the χ2 test? This model appears to be central to
validating the association between the SNPs and gastric cancer, so it needs to be discussed in more
detail, and a more rigorous explanation of its utility needs to be made.
*The abstract presents too many loci and SNPs and no clear explanation of how these might
contribute to gastric cancer. Along these lines, on p.8, lines 45-53, how are the functions of these SNPs
predicted and/or validated? Are there any references to substantiate these hypothetical functions? In
addition, it seems like the functions listed are fairly broad and non-specific (e.g., protein binding).
*In Table 1, what does "absence" mean for staging and LNM?
*On p.8, lines 17-23, the authors claim that "the gender distribution was statistically different
between the case and control groups (p<0.05)." Is this accurate? They look nearly identical, certainly
not different enough for a p value of 0.001, as shown in Table 1.
*Why are only two SNPs shown in Table 3? How did the inheritance models fare for the other
SNPs shown in Table 2?
*On p. 9, lines 9-23, the authors claim that the identified SNP genotypes either increase or
decrease the risk of gastric cancer. This statement, as it is worded, is not accurate. The SNP genotypes
are associated with, or correlate with, an increased/decreased risk of gastric cancer, but the SNPs
themselves do not increase or decrease the risk of gastric cancer. No functional validation of these
SNPs was done in this study, so the authors cannot conclude that these SNPs increase or decrease the
cancer risk.
*To appeal  to  a broader audience, the authors  may want to  briefly discuss  the differences
between the dominant, recessive, and additive models. What does it mean for some genotypes to be
correlated to gastric cancer in one model but not the other? Does this have clinical significance?
*Haplotype association analysis showed no association between specific haplotypes and risk of
gastric cancer, significantly weakening the authors' conclusions.
*Are these SNPs specific to the Han population? Were other Chinese ethnicities studied or used
as controls?
*No validation of the effects of these SNPs on miR-155 levels was demonstrated.
*Minor edit: On p.11, line 50, it should read "gastric cancer," not "CRC (colorectal cancer)."
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
Yes
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you recommend an additional
statistical review?
If  an  additional  statistical  review  is  recommended,  please  specify  what  aspects  require  further
assessment in your comments to the editors.
I recommend additional statistical review
Quality of written English
Please indicate the quality of language in the manuscript:
Acceptable
Declaration of competing interests
Please complete a declaration of competing interests, considering the following questions:
1. Have you in the past five years received reimbursements, fees, funding, or salary from an
organisation that may in any way gain or lose financially from the publication of this
manuscript, either now or in the future?
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose
financially from the publication of this manuscript, either now or in the future?
3. Do you hold or are you currently applying for any patents relating to the content of the
manuscript?
4. Have you received reimbursements, fees, funding, or salary from an organization that holds
or has applied for patents relating to the content of the manuscript?
5. Do you have any other financial competing interests?
6. Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If
your reply is yes to any, please give details below.
I declare that I have no competing interests.
I agree to the open peer review policy of the journal. I understand that my name will be included on my
report to the authors and, if the manuscript is accepted for publication, my named report including any 
attachments I upload will be posted on the website along with the authors' responses. I agree for my 
report to be made available under an Open Access Creative Commons CC-BY license 
(http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments which I do not wish to 
be included in my named report can be included as confidential comments to the editors, which will not
be published.
I agree to the open peer review policy of the journal
Reviewer’s report
Title: Analysis of the Relationship between MIR155HG Variants and Gastric Cancer Susceptibility
Version: 0 Date: 01 Nov 2019
Reviewer: Jose Saenz
Reviewer's report:
In this manuscript, Zou et al. describe a case-control study looking at the correlation between genetic
variants of a miRNA, MIR155HG, and gastric cancer. In particular, they analyzed single nucleotide
polymorphisms (SNPs) within this gene using a MassARRAY platform to identify particular SNPs that
correlated  with  either  increased  or  decreased  gastric  cancer  risk.  While  I  found  that  the  overall
approach of attempting to identify gastric cancer susceptibility loci is worthwhile, I believe that, in
general,  the  authors  did  not  adequately  describe  their  methods  and  seemed  to  overstate  certain
conclusions. Some of their association analyses failed to show correlations between certain SNPs,
which decreased the overall impact of the manuscript. In addition, it remains unclear whether some of
their conclusions can be applied to different populations aside from the Han population in China.
Perhaps the biggest weakness is that it remains to be seen how clinically and physiologically relevant
the SNPs identified in this study are to gastric cancer. The authors make little to no mention of the
possible functions or genetic targets of MIR155HG and how these might contribute to or prevent the
progression to gastric cancer. Some additional comments are listed below:
  
*The introduction of the various inheritance models seems problematic to me. That the χ2 test
showed no statistical difference in the frequencies of any of the SNPs in the MIR155HG gene between
the gastric cancer cases and controls makes it seem that the authors needed to turn to another statistical
test to find an association. The authors rely on a previously published inheritance model but do not
introduce the model or explain why they chose this model. What are the limitations of this model, and
why would it better explain the association than the χ2 test? This model appears to be central to
validating the association between the SNPs and gastric cancer, so it needs to be discussed in more
detail, and a more rigorous explanation of its utility needs to be made.
*The abstract presents too many loci and SNPs and no clear explanation of how these might
contribute to gastric cancer. Along these lines, on p.8, lines 45-53, how are the functions of these SNPs
predicted and/or validated? Are there any references to substantiate these hypothetical functions? In
addition, it seems like the functions listed are fairly broad and non-specific (e.g., protein binding).
*In Table 1, what does "absence" mean for staging and LNM?
*On p.8, lines 17-23, the authors claim that "the gender distribution was statistically different
between the case and control groups (p<0.05)." Is this accurate? They look nearly identical, certainly
not different enough for a p value of 0.001, as shown in Table 1.
*Why are only two SNPs shown in Table 3? How did the inheritance models fare for the other
SNPs shown in Table 2?
*On p. 9, lines 9-23, the authors claim that the identified SNP genotypes either increase or
decrease the risk of gastric cancer. This statement, as it is worded, is not accurate. The SNP genotypes
are associated with, or correlate with, an increased/decreased risk of gastric cancer, but the SNPs
themselves do not increase or decrease the risk of gastric cancer. No functional validation of these
SNPs was done in this study, so the authors cannot conclude that these SNPs increase or decrease the
cancer risk.
*To appeal  to  a broader audience, the authors  may want to  briefly discuss  the differences
between the dominant, recessive, and additive models. What does it mean for some genotypes to be
correlated to gastric cancer in one model but not the other? Does this have clinical significance?
*Haplotype association analysis showed no association between specific haplotypes and risk of
gastric cancer, significantly weakening the authors' conclusions.
*Are these SNPs specific to the Han population? Were other Chinese ethnicities studied or used
as controls?
*No validation of the effects of these SNPs on miR-155 levels was demonstrated.
*Minor edit: On p.11, line 50, it should read "gastric cancer," not "CRC (colorectal cancer)."
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
Yes
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you recommend an additional
statistical review?
If  an  additional  statistical  review  is  recommended,  please  specify  what  aspects  require  further
assessment in your comments to the editors.
I recommend additional statistical review
Quality of written English
Please indicate the quality of language in the manuscript:
Acceptable
Declaration of competing interests
Please complete a declaration of competing interests, considering the following questions:
1. Have you in the past five years received reimbursements, fees, funding, or salary from an
organisation that may in any way gain or lose financially from the publication of this
manuscript, either now or in the future?
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose
financially from the publication of this manuscript, either now or in the future?
3. Do you hold or are you currently applying for any patents relating to the content of the
manuscript?
4. Have you received reimbursements, fees, funding, or salary from an organization that holds
or has applied for patents relating to the content of the manuscript?
5. Do you have any other financial competing interests?
6. Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If
your reply is yes to any, please give details below.
I declare that I have no competing interests.
I agree to the open peer review policy of the journal. I understand that my name will be included on my
report to the authors and, if the manuscript is accepted for publication, my named report including any 
attachments I upload will be posted on the website along with the authors' responses. I agree for my 
report to be made available under an Open Access Creative Commons CC-BY license 
(http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments which I do not wish to 
be included in my named report can be included as confidential comments to the editors, which will not
be published.
I agree to the open peer review policy of the journal
Please review this paper.
user
Reviewer’s report
Title: Analysis of the Relationship between MIR155HG Variants and Gastric Cancer Susceptibility
Version: 0 Date: 01 Nov 2019
Reviewer: Jose Saenz
Reviewer's report:
In this manuscript, Zou et al. describe a case-control study looking at the correlation between genetic
variants of a miRNA, MIR155HG, and gastric cancer. In particular, they analyzed single nucleotide
polymorphisms (SNPs) within this gene using a MassARRAY platform to identify particular SNPs that
correlated  with  either  increased  or  decreased  gastric  cancer  risk.  While  I  found  that  the  overall
approach of attempting to identify gastric cancer susceptibility loci is worthwhile, I believe that, in
general,  the  authors  did  not  adequately  describe  their  methods  and  seemed  to  overstate  certain
conclusions. Some of their association analyses failed to show correlations between certain SNPs,
which decreased the overall impact of the manuscript. In addition, it remains unclear whether some of
their conclusions can be applied to different populations aside from the Han population in China.
Perhaps the biggest weakness is that it remains to be seen how clinically and physiologically relevant
the SNPs identified in this study are to gastric cancer. The authors make little to no mention of the
possible functions or genetic targets of MIR155HG and how these might contribute to or prevent the
progression to gastric cancer. Some additional comments are listed below:
  
*The introduction of the various inheritance models seems problematic to me. That the χ2 test
showed no statistical difference in the frequencies of any of the SNPs in the MIR155HG gene between
the gastric cancer cases and controls makes it seem that the authors needed to turn to another statistical
test to find an association. The authors rely on a previously published inheritance model but do not
introduce the model or explain why they chose this model. What are the limitations of this model, and
why would it better explain the association than the χ2 test? This model appears to be central to
validating the association between the SNPs and gastric cancer, so it needs to be discussed in more
detail, and a more rigorous explanation of its utility needs to be made.
*The abstract presents too many loci and SNPs and no clear explanation of how these might
contribute to gastric cancer. Along these lines, on p.8, lines 45-53, how are the functions of these SNPs
predicted and/or validated? Are there any references to substantiate these hypothetical functions? In
addition, it seems like the functions listed are fairly broad and non-specific (e.g., protein binding).
*In Table 1, what does "absence" mean for staging and LNM?
*On p.8, lines 17-23, the authors claim that "the gender distribution was statistically different
between the case and control groups (p<0.05)." Is this accurate? They look nearly identical, certainly
not different enough for a p value of 0.001, as shown in Table 1.
*Why are only two SNPs shown in Table 3? How did the inheritance models fare for the other
SNPs shown in Table 2?
*On p. 9, lines 9-23, the authors claim that the identified SNP genotypes either increase or
decrease the risk of gastric cancer. This statement, as it is worded, is not accurate. The SNP genotypes
are associated with, or correlate with, an increased/decreased risk of gastric cancer, but the SNPs
themselves do not increase or decrease the risk of gastric cancer. No functional validation of these
SNPs was done in this study, so the authors cannot conclude that these SNPs increase or decrease the
cancer risk.
*To appeal  to  a broader audience, the authors  may want to  briefly discuss  the differences
between the dominant, recessive, and additive models. What does it mean for some genotypes to be
correlated to gastric cancer in one model but not the other? Does this have clinical significance?
*Haplotype association analysis showed no association between specific haplotypes and risk of
gastric cancer, significantly weakening the authors' conclusions.
*Are these SNPs specific to the Han population? Were other Chinese ethnicities studied or used
as controls?
*No validation of the effects of these SNPs on miR-155 levels was demonstrated.
*Minor edit: On p.11, line 50, it should read "gastric cancer," not "CRC (colorectal cancer)."
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
Yes
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you recommend an additional
statistical review?
If  an  additional  statistical  review  is  recommended,  please  specify  what  aspects  require  further
assessment in your comments to the editors.
I recommend additional statistical review
Quality of written English
Please indicate the quality of language in the manuscript:
Acceptable
Declaration of competing interests
Please complete a declaration of competing interests, considering the following questions:
1. Have you in the past five years received reimbursements, fees, funding, or salary from an
organisation that may in any way gain or lose financially from the publication of this
manuscript, either now or in the future?
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose
financially from the publication of this manuscript, either now or in the future?
3. Do you hold or are you currently applying for any patents relating to the content of the
manuscript?
4. Have you received reimbursements, fees, funding, or salary from an organization that holds
or has applied for patents relating to the content of the manuscript?
5. Do you have any other financial competing interests?
6. Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If
your reply is yes to any, please give details below.
I declare that I have no competing interests.
I agree to the open peer review policy of the journal. I understand that my name will be included on my
report to the authors and, if the manuscript is accepted for publication, my named report including any 
attachments I upload will be posted on the website along with the authors' responses. I agree for my 
report to be made available under an Open Access Creative Commons CC-BY license 
(http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments which I do not wish to 
be included in my named report can be included as confidential comments to the editors, which will not
be published.
I agree to the open peer review policy of the journal
assistant