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:24 October 2008
Reviewer: charles S rabkin
Reviewer's report:
Reviewer's report
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Please number your comments and divide them into
- Major Compulsory Revisions
The author must respond to these before a decision on publication can be
reached. For example, additional necessary experiments or controls, statistical
mistakes, errors in interpretation.
The SHP-2 protein is necessary for the morphological cell transformation
resulting from infection with cagA positive H. pylori infection. As such
polymorphisms in PTPN11, the gene encoding SHP-2 might influence the degree
of gastric atrophy and risk of developing gastric cancer for those individuals
infected with cagA positive strains of the H. pylori. The authors sought to
examine the association between a single polymorphism in the PTPN11 gene
and risk of atrophy in a cohort of gastric cancer patients and matched controls.
Major Comment:
Table 5 presents the null association of a PTPN11 SNP with gastric cancer vs. all
gastric atrophy controls. However, the association with gastric cancer vs. severe
gastric atrophy has crude OR of 1.59 for G/A, 1.62 for A/A, and 1.59 for G/A+A/A,
indicating significantly increased risk for progressing from the most advanced
pre-cancerous state (see table below). Furthermore, a more revealing
comparison would be gastric cancer vs. H. pylori-infected subjects without
atrophy, for which the crude OR are 1.00 for G/A, 0.66 for A/A, and 0.97 for
G/A+A/A. While consistent with possible counter-balancing effects on
progression from infection to atrophy and then atrophy to cancer, a simpler
interpretation is that this polymorphism is unrelated to these outcomes of H.
pylori infection.
PTPN11 HP-infected* Normal PGI/PGratio Low PGI/PGratio Very low
PGI/PGratio Gastric cancer
GG 843 (69%) 462 (67%) 381 (71%) 148 (77%) 396 (68%)
GA 343 (28%) 203 (30%) 140 (26%) 41 (21%) 174 (30%)
AA 37 (3%) 23 (3%) 14 (3%) 3 (2%) 13 (2%)
GA+AA 380 (31%) 226 (33%) 154 (29%) 44 (23%) 187 (32%)
Comparisons to HP-infected without atrophy as controls:
ODDS OR ODDS OR ODDS OR ODDS OR ODDS OR
GG - ref. - ref. - ref. - ref. -
GA 0.41 0.44 1.00 0.37 0.84 0.28 0.63 0.44 1.00
AA 0.04 0.05 1.00 0.04 0.74 0.02 0.41 0.03 0.66
GA+AA 0.45 0.49 1.00 0.40 0.83 0.30 0.61 0.47 0.97
Comparison to severe atrophy as controls:
ODDS OR ODDS OR
GG ref. - ref. -
GA 0.28 1.00 0.44 1.59
AA 0.02 1.00 0.03 1.62
GA+AA 0.30 1.00 0.47 1.59
*seropositive or low PG1/PGratio
- Minor Essential Revisions
The author can be trusted to make these. For example, missing labels on figures,
the wrong use of a term, spelling mistakes.
Minor comments:
In general the paper is well written with good flow, though it would benefit from
some copy-editing to correct minor language errors.
Given the central hypothesis of the study focuses on H. pylori infection and cagA
positivity I think the authors could have gone to greater lengths in establishing H.
pylori status, they used a single measure (IgG assays) where they might also
have used histology, Clo testing etc to support the results of the serological
testing. Some statement in defense of their single test for H. pylori should be
made in the Discussion. Similarly, histological diagnosis of atrophy would
strengthen the author’s classification of their study group.
The authors chose to examine a single SNP in PTPN11. They explain that a
number of SNPs in this gene are in complete linkage disequilibrium the authors
might have supported this statement with a clear figure showing LD in the region.
Given the number of stages involved in post-cagA infection cell transformation
the authors might also explain why they chose to investigate a single
polymorphism in a single gene which apparently codes for a single protein. Do
they plan, in future studies, to investigate other proteins/genes/polymorphisms
which might modulate transformation (as listed in the Discussion) ? Some type of
pathway analysis might be an interesting way with which to move forward.
Some further detail should be added to the description of statistical analysis in
the Methods section. Did the authors consider the use of polytomous regression
when looking at atrophic gastritis and gastric cancer?
The first paragraph of the Results section should only highlight any significant
results from Table 1. Where differences are significant please quote p values.
Did the authors carry out a test for trend across genotypes? In the second last
paragraph of the section the authors say they compared genotype frequency
“between gastric atrophy subjects and gastric cancer cases” but list ORs rather
than frequency differences – do they have chi squared estimates for the
differences in frequencies? Were the ORs from the groups compared directly and
if so, how?
The opening paragraph of the Discussion should be a succinct review of the
main findings and a reminder of the original study hypothesis.
The discussion of the possible functional nature of the polymorphism is
necessary and the authors are applauded for it’s inclusion, however, it could be
shortened dramatically and rewritten for clarity.
Level of interest: An article of limited interest
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:
We declare that we have no competing interests