Review for 10.1186/1471-230X-13-32 (2013)

Reviewer's report
Title:Genetic polymorphisms of epidermal growth factor in relation to risk of
hepatocellular carcinoma: two case-control studies
Version: 1Date:21 October 2012
Reviewer: Pierre Nahon
Reviewer's report:
The study by Yuan et al aimed to assess the influence of EGF 61A>G SNP on
the risk of HCC. For this purpose, they genotyped two small sample-size
case-control cohorts from the USA and China and compared genotypic
distributions between patients with HCC and healthy controls in each cohort.
They were able to observe a limited influence of the G allele that was restricted
to Caucasians with chronic alcohol consumption.
The strength of this report is that it was conducted in two different cohorts from
different ethnicities that were rather well phenotyped. The main limitation is
related to low power analyses due to small sample-size efectives, an issue that is
underlined by the authors themselves.
Here are my specific comments:
1) As all cases of HCC seem to have been histologically proven, the authors
need to provide pathological data regarding non-tumoral liver samples. Were all
HCC developed in cirrhotic livers? This issue is pivotal as both the cause of liver
disease and ethnicity (for example HBV-related HCC without cirrhosis in Asia
versus alcohol-induced HCC developed in cirrhosis in the West) might modulate
the influence of EGF variants on liver carcinogenesis: the degree of liver injury
could thus explain the observed differences and downplay the role of EGF on
liver carcinogenesis.
2) As well, the authors should discuss the pertinence of selecting healthy
individuals as controls for a cancer that develops in almost 90% of cases in
cirrhotic liver. In this setting, case-control studies should assess comparison of a
given parameter between patients with the disease (ie HCC developed in
cirrhosis) and patients exposed to the disease (cirrhosis without HCC).
3) As a whole, the influence of EGF variants on HCC has already been reported
by other reports that were more accurate (ref 16), particularly one that was
conducted in a large prospective cohort of HCV-infected patients from the
HALT-C trial that is surprisingly not mentioned (Gastroenterology. 2011
Jul;141(1):141-9.) The results reported by the authors should be put in
perspective regarding these two major studies, and discrepancies carefully
discussed, particularly with respect to the role of EGF variants according to the
cause of liver disease.
4) As well, two recent meta-analyses published in 2012 have already reported
the influence of this SNP on the risk of HCC in both Caucasians and
non-Caucasians individuals (PLoS One. 2012;7(3):e32159. Epub 2012 Mar 5.)
How do the authors integrate their results in this already extensively studied
topic?
5) Table 4 is difficult to read. My suggestion is to report the combined influence of
both genetic heterogeneities in bar graphs. My prediction is that cytokines
variants will be the most discriminate in this population.
Level of interest: An article of limited interest
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests