Reviewers' comments on manuscript entitled: "TNFR2 +676 T>G polymorphism predicts
survival of non-Small cell lung cancer patients treated with chemoradiotherapy" submitted to
BMC Cancer by Guan et al.
Reviewer 1's report:
The manuscript of Xiaoxiang Guan et al. describes a genetic association study of five potentially
functional polymorphisms in TNF-# and TNFR2 genes with prognosis of non-small cell lung
cancer (NSCLC) patients treated with chemoradiotherapy. The authors report that the TNFR2 +
676 GG genotype is an independent prognosis factor after multivariate regression analysis in
the presence of node status and tumor stage.
This study has a well justified aim and its methodology is sound. It has resulted in interesting
original findings and the well written manuscript merits publication.
Minor essential revision
It would be suggested to the authors to inquire whether there might be a possible connection of
their findings of TNFR2 role in lung cancer immunological response with the findings of TNFR2
role in lung immunological response to infection (Sainz J et al. “Variable number of tandem
repeats of TNF receptor type 2 promoter as genetic biomarker of susceptibility to develop
invasive pulmonary aspergillosis” Hum Immunol. 2007). A comment in Discussion might be
worthwhile.
Response:
Based on the paper by Sainz J et al., we have added to the revision the following sentences:
" Another possibility is that this SNP may change the expression level of TNFR2 and influence
the character of immunological response to infection in lung cancer patients, finally resulting in
the difference of survival in NSCLC[50]." (Page 14)
Reviewer 2's report:
Major Compulsory Revisions
1) Of the 225 patients 79 had adenocarcinoma, 71 squamous cell carcinoma, and 75 other type
of NSCLC. The authors have not evaluated if these three groups of patients differed in the
frequency of genotypes, or if the observed association between the TNFR2 genotype and
survival was restricted to a certain subtype of NSCLC. Although the numbers of patients may be
too small to reliably address these issues, it makes sense to make an effort to do an analysis on
this, as the biologic characteristics of adenocarcinoma and squamous cell carcinoma are likely
different, i.e., adenocarcinoma may be more resistant to radiotherapy.
Response:
Thanks for the suggestions. We have evaluated the association between the TNFR2 genotype
and survival in the stratification analysis by tumor types, but the numbers of patients were very
small and no significant results were found (Table A). In the revision, we have added a
sentence to describe such information (Page 11).
Table A. Stratification analysis for associations between TNFR2 rs1061622 genotypes and
survival of lung cancer patients by tumor types
TNFR2 +676 T>G (rs1061622)
Adjusted HR
(deaths /patients)
Genotypes
Adjusted P a
(95% CI)a
GT+TT
GG
Adenocarcinoma
48/77
0/2
-----
Squamous cell
48/66
3/5
0.62 (0.18-2.14)
0.450
Others
54/71
2/4
0.27 (0.06-1.26)
0.096
a
Adjusted for age, gender, ethnicity, smoking status, tumor histology, KPS, tumor stage, node status,
application of chemotherapy and radiotherapy dose.
2) Were the adenocarcimomas primary lung adenocarcinomas? Were there any
adenocarcinoma metastasis in the lungs with a primary tumor outside the lungs?
Response:
Yes, 35.1% of the patients had primary lung adenocarcinomas, and all our cases were newly
diagnosed primary lung cancer patients without any metastasis.
3) What were the 75 other types of NSCLC?
Response:
They included large cell, undifferentiated and mixed-cell carcinomas, or non-small cell lung
cancer, not otherwise specified. We have added this note in Table1 in the revision.
4) Not all patients received chemotherapy (163 out of 225 got platinum and taxane). The title
gives the impression that the observed association was restricted to patients who received
chemoradiotherapy. Was there an association between TNFR2 polymorphisms and survival in
patients who received only radiotherapy?
Response:
All cases were treated with chemoradiotherapy or radiotherapy alone. Among them, only 62
patients (27.6%) had received only radiotherapy. We further conducted the stratification analysis
by treatment and found no significant associations (Table B). In the revision, we have added a
sentence to describe such information (Page 11).
Table B. Stratification analysis for associations between TNFR2 rs1061622 genotypes and
survival of lung cancer patients by treatment
Genotypes
Chemotherapy and
radiotherapy
Only radiotherapy
TNFR2 +676 T>G (rs1061622)
(deaths /patients)
GT+TT
GG
Adjusted HR
(95% CI)a
Adjusted P a
110/157
3/6
0.34 (0.10-1.10)
0.071
40/57
2/5
0.35 (0.08-1.58)
0.174
Minor Essential Revisions
1) The authors should describe the dosing of platium and taxane based chemotherapy used at
their center and if chemotherapy was given concurrently with radiotherapy
Response:
The most commonly used concurrent chemotherapy regimen is Paclitaxel 50mg/m2 and
Carboplatin AUC 2.
2) Affiliation of Ritsuko Komaki (2) is not reported.
Response:
Sorry for missing the information. We had provided the affiliation in the revision.
3) The official gene symbols according to pubmed for TNF and TNFR2 (CD120b) are TNF and
TNFRSF1B as spelled in italics. These designations should be used consistently in the
manuscript.
Response:
The TNF and TNFRSF1B are used consistently in the revised manuscript.
Discretionary Revisions
1) It would be preferable to use rs numbering of the SNPs in the abstract.
Response:
We have added the rs # in the Abstract of the revision (Page 2).