Review for 10.1186/1471-230X-9-51 (2009)

Reviewer's report
Title:Associations of a PTPN11 G/A polymorphism at intron 3 with Helicobactor
pylori seropositivity, gastric atrophy and gastric cancer in Japanese
Version: 1Date:23 October 2008
Reviewer: Uday Ghoshal
Reviewer's report:
Associations of a PTPN11 G/A polymorphism at intron 3 with Helicobactor pylori
seropositivity, gastric atrophy and gastric cancer in Japanese (BMC
Gastroenterology)
Major issues
1. The aim of the present study was to examine the formerly reported association
between G/A polymorphism of PTPN11 (protein-tyrosine phosphatase,
nonreceptor-type, 11) (rs2301756) gene encoding SHP-2 protein in a large
population of Japanese patients with gastric cancer and control and risk of
gastric atrophy. In a previous study authors have investigated the association of
this polymorphism (SNP; JST057927; G-to-A) in the PTPN11 gene with gastric
atrophy and gastric cancer. In this study gastric atrophy was assessed by
measuring serum pepsinogen I and II levels. The subjects comprised 454 healthy
controls and 202 gastric cancer cases (Goto Y et al. Association between serum
pepsinogens and polymorphismof PTPN11 encoding SHP-2 among Helicobacter
pylori seropositive Japanese. Int J Cancer. 2006 Jan 1;118(1):203-8). The point
of concern is that how much is the overlap between the study population and the
data presented in the two studies?
2. Authors have mentioned that G/A SNP at intron 3 (rs2301756) was selected
as a representative of the linked SNPs. What was the basis for selection of this
particular SNP as the representative? What are the data to support that this SNP
can be used as representative of all the 9 linked SNPs?
3. Authors have mentioned that “subjects were participants of HERPACC
(Hospital-based Epidemiologic Research Program at Aichi Cancer Center) study,
in which first-visit outpatients were consecutively invited to provide lifestyle data
and blood sample after informed consent”. What was the purpose of taking
lifestyle data in the present study?
4. In the study 1,591 age-sex-frequency matched cancer free outpatients
(controls) were included. Authors should present more data on controls. What for
the visited hospital? It is not specified whether control subjects were free from
other gastrointestinal pathologies such as peptic ulcer, non-ulcer dyspepsia etc
as presence of these conditions may affect the outcome of the study.
5. In the result section authors have mentioned “When H. pylori seropositive
subjects and seronegative subjects with gastric atrophy were regarded as H.
pylori infected subjects, the age-sex-adjusted OR of severe gastric atrophy
among the H. pylori infected was further reduced; 0.64 (95% CI 0.44-0.93,
P=0.020) for G/A+A/A”. Authors need to clarify that why both H. pylori
seronegative and seropositive subjects with gastric atrophy were regarded as H.
pylori infected.
6. It seems that authors have strongly concluded based on the previous studies
in Japanese population that all the gastric cancer patients were H. pylori positive.
It may not be appropriate for an original article. It should be based on the current
data.
7. In the present study the AA genotype was associated with reduced risk of
severe gastric atrophy but was not associated with gastric cancer. Authors have
mentioned that “Since the biological processes in infection, atrophy development,
and carcinogenesis are different, the association of this polymorphism with only
atrophic development seemed biologically plausible.” However, gastric atrophy is
a precancerous gastric lesion and an established risk factor for gastric
carcinogenesis; therefore, the authors need to provide a satisfactory explanation
for this observation. This point becomes more relevant because authors have
themselves pointed out that though in the present study gastric atrophy was not
determined in patients with gastric cancer “…but almost all the gastric cancer
cases seemed to be H. pylori positive cases with gastric atrophy”.
8. “Figure 1 depicts the distributions of pepsinogen I/II ratio according to PTPN11
rs2301756 genotype among H. pylori infected subjects with PG I<70 ng/ml”: Why
were only H. pylori infected subjects with PG I<70 ng/ml were and not all H. pylori
infected subjects included in this analysis?
9. Abstract: “This study aimed to examine the formerly reported association
between a G/A PTPN11 (protein-tyrosine phosphatase, nonreceptor-type, 11)
polymorphism (rs2301756) and risk of gastric atrophy in Japanese with a large
sample including gastric cancer patients.” This gives a false impression as if the
gastric atrophy was diagnosed in gastric cancer patients also which is not the
case. Therefore, it should be written as “association of G/A PTPN11
(protein-tyrosine phosphatase, nonreceptor-type, 11) polymorphism (rs2301756)
with gastric cancer and gastric atrophy in a Japanese population using a large
sample size.”
10. Please give p values in table 2 for G/A and A/A genotypes.
11. Only genotypic frequencies were calculated. Please give data of the allelic
frequencies and the risk associated with the 2 alleles (G and A).
Minor revision
12. The authors need to carefully edit the manuscript for typographical and
grammatical errors. Some of the errors are as mentioned below:
• Abstract: “The biological roles of this PTPN11 polymorphism require further to
be investigated” Should be replaced with “The biological roles of this PTPN11
polymorphism requires further investigation”
• At all the places in the manuscript “gastric cancer patients” should be replaced
by “patients with gastric cancer”
• Background: “cytotoxin-associated gene A (cagA) gene”. Delete “gene” at the
end.
• Background: “This study aimed to confirm the formerly reported association
between the PTPN11 polymorphism (rs2301756) and gastric atrophy measured
with serum pepsinogens in a large Japanese sample”. Delete sample.
• Methodology: “The amplified DNA was 201bp for G allele, 339bp for A allele,
and 490bp for common band.” The band pattern does not represent allele but
genotype. Therefore it should be corrected accordingly. It would be better if
authors provide a representative gel picture.
• Results: “There were no A/A subjects” replace with “there were no subjects with
A/A genotype”
• Results: “In consistent with the finding that those with the A allele was at
significantly lower risk of severe gastric atrophy, the proportion of the subjects
with PG I/II ratio no more than 2 was lower in subjects with A allele than those
with G/G genotype” should replace with “In accordance with the finding that
subjects with A allele were at significantly reduced risk of severe gastric atrophy,
the frequency of subjects with PG I/II ratio less than 2 was lower in subjects with
A allele than those with G/G genotype”
• There are some more spelling and grammatical mistakes.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I declare that I have no competing interests