Review for 10.1186/s12876-021-01864-9 (2021)

Title: Prognostic role and clinicopathological features of SMAD4 gene mutation in colorectal
cancer: a systematic review and meta-analysis
Version: 0 Date: 30 Apr 2021
Reviewer's report:
The manuscript is a standard and thorough meta-analysis of the role of SMAD4 mutations in
CRC prognosis and related clinical factors.
I have some doubts about the interpretation of the OR reported in the manuscript which seems
to be backwards. I may have misunderstood something, but these look like serious mistakes, so
in either case, I would like to receive a good explanation about them.
While the meaning of the text is usually clear, the English could be improved. I made some
corrections to the text, but many other sentences are a bit strange. The authors should check the
text again or have a native speaker proofread the text.
---Page 3, line 7
"publication bias was not observed in all studies" means that publication bias could have been
observed in some studies (but not in all). Probably the author meant: "publication bias was not
observed in any study"
---Page 3, line 12
"indicated" by whom?
---Page 3, line 15
"their relationship was worth further investigating" -> "their relationship warrants further
investigation"
---Page 4, line 9
"SMAD4 is the established tumor suppressor gene locating on chromosome 18q21" -> "SMAD4
is an established tumor suppressor gene located in chromosome band 18q21"
---Page 6, line 2
What do you mean by "gives or provides computable data"?
---Page 6, line 3
This part is written incorrectly and unclear: "does not include patients with CRC patients who".
Please fix and clarify
---Page 7, line 4
"I2 > 50%" -> "I2 > 0.5", since you just wrote that I2 ranges from 0 to 1
---Page 7
I found the whole "Selection of studies" section confusing and understood correctly what had
been done looking at fig1. Can you improve the clarity of this section?
---Page 8, line 3
"were review, letter and case port" -> "were reviews, letters or case reports"
---Page 10, line 4
It is not clear to me that SMAD4 mutation is associated with higher TNM stages? The OR=0.78
is lower than 1, so mutation should be associated with lower TNM stages.
Also in the next line, if the association is correct you should write:
"patients with SMAD4 mutation are more likely to occur distant metastasis" -> "distant
metastasis is more likely to occur in patients with SMAD4 mutations"
---Page 10, line 10
Also here the OR for RAS mutations is 0.47, so it should be less prone to harbour concurrent
RAS mutation. Why do you say it is more?
---Page 10, line 13
Also, tumor grade is not significantly associated with SMAD4 mutations, is there a reason for
not mentioning it here?
---Page 10, line 14
Here the other study reports an OR=2.04 while you report (same page, line 4) an OR=0.78, so
the two results appear to be not consistent to me. Can you explain this?
Also, the syntax is weird, it should be like this (if the results are consistent like you claim):
"There is a meta-analysis showed that SMAD4 mutation (combined OR 2.04, 95% CI 1.41-2.95)
were at a higher risk of distant metastasis[14], which is consistent with our results." ->
"Another meta-analysis[14] showed that SMAD4-mutated patients were at a higher risk of
distant metastasis (combined OR 2.04, 95% CI 1.41-2.95), which is consistent with our results."
---Figures 6 and 7
The study names should be written instead of the row number.