Association of O6-Methylguanine-DNA Methyltransferase Protein Expression With Postoperative Prognosis and Adjuvant Chemotherapeutic Benefits Among Patients With Stage II or III Gastric Cancer
Authors: Heng Zhang
Songyang Wu
Hongyong He
Weijuan Zhang
Hao Liu
Jiejie Xu
Ruochen Li
Yifan Cao
He Li
Chao Lin
Journal: JAMA surgery (2017)
Discipline: CLINICAL MEDICINE
Keywords: MGMT; gastric cancer; prognosis; adjuvant chemotherapy; overall survival
Affiliations: School of Basic Medical Sciences, Department of Biochemistry and Molecular Biology, Fudan University, Shanghai, China., Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China., School of Basic Medical Sciences, Department of Immunology, Fudan University, Shanghai, China.

Abstract:  Importance: Loss of O6-methylguanine-DNA methyltransferase (MGMT) protein expression has been reported in several malignant tumors and predicts dismal survival outcomes. In gastric cancer, existing studies on this topic are limited and the association between MGMT and fluorouracil-based adjuvant chemotherapy remains obscure. Objective: To investigate the postoperative prognostic significance of MGMT in patients with resectable gastric cancer and its responsiveness to fluorouracil-based adjuvant chemotherapy. Design, setting, and participants: This study recruited 445 consecutive patients with resectable gastric cancer who underwent radical gastrectomy between August 1, 2007, and December 30, 2008, at Zhongshan Hospital at Fudan University in Shanghai, China. Patients were randomly divided into a discovery data set (n = 200) and a validation data set (n = 245), and the range of follow-up time was from 2 to 76 months for the discovery group and 2 to 79 months for the validation group. The immunoreactivity for MGMT in cancer cells was reviewed under a light microscope by 2 pathologists who were blinded to the clinicopathological data. The association of MGMT expression with clinicopathological characteristics and measures and prognosis was inspected. Data and specimens were collected from patients from the date of surgery to April 25, 2014. Data analysis took place from May 9, 2016, to July 15, 2016. Main outcomes and measures: Estimates of overall survival on the basis of MGMT expression and hazard ratio (HR) for estimates of overall mortality risk. Results: Of the 445 patients included in the study, 315 (70.8%) were men, and the mean (SD) age of all patients was 60 (12) years. Positive expression of MGMT indicated better overall survival for patients with stage II or III gastric cancer in both the discovery data set (HR, 0.52; 95% CI, 0.32-0.84; P = .003) and the validation data set (HR, 0.63; 95% CI, 0.43-0.93; P = .01). Multivariate analysis identified MGMT expression and TNM stage as 2 independent prognostic factors for overall survival. In stage II disease, the benefit from fluorouracil-based adjuvant chemotherapy was superior among MGMT-positive patients (HR, 0.35; 95% CI, 0.13-0.95; P = .007 for interaction) compared with MGMT-negative patients. Conclusions and relevance: Positive expression of MGMT in gastric cancer was identified as an independent, favorable prognostic factor. Incorporating MGMT expression into the current TNM staging system could lead to better prognostic accuracy. These findings should be confirmed within the framework of randomized clinical trials associated with genomic DNA sequencing studies. 

Retracted: No

PubPeer comments:
 A letter of explanation has been published, which looks like a point-to-point response to this pubpeer post: [10.1001 jamasurg.2018.5755](http: 10.1001 jamasurg.2018.5755). I write on behalf of my coauthors to explain several important reporting failures in our article, u201cAssociation of O6-Methylguanine-DNA Methyltransferase Protein Expression With Postoperative Prognosis and Adjuvant Chemotherapeutic Benefits Among Patients With Stage II or III Gastric Cancer,u201d that was published online on September 13, 2017, and in the November 2017 issue of JAMA Surgery.1 This included failure to cite related articles with similar study designs that included many patients from the same overall sample. In our JAMA Surgery article, we examined O6-methylguanine-DNA methyltransferase protein expression as a prognostic factor among patients with gastric cancer who had undergone gastrectomy with D2 lymphadenectomy. This study was conducted at Zhongshan Hospital at Fudan University in Shanghai, China, between August 1, 2007, and December 30, 2008. We had conducted similar studies on different biomarkers in many of the same patients at this hospital.2-10 We should have informed the editors of these related studies and should have discussed and cited these studies in our JAMA Surgery article as is required by the journal.11 In addition, we failed to report complete information on the patients and tissue samples included in this study. The study began with a sample of 496 patients with resectable gastric cancer who underwent surgery at Zhongshan Hospital. However, 468 of 496 patients had comprehensive information about chemotherapy, clinicopathological data, and survival outcomes for complete analysis. For these 468 patients, we included assessment of tissue microarrays (TMAs) that were initially constructed by the Department of Pathology at Zhongshan Hospital. However, the quality of these TMAs was inadequate for analysis. Thus, we sent tissue specimens for the 468 patients to Shanghai Outdo Biotech Co, Ltd, which constructed new TMAs. Two pathologists at this company evaluated the immunohistochemistry scores, and then 2 coauthors confirmed these scores. We paid for this commercial service. After immunohistochemistry had been assessed, data for the specimens for 15 patients were lost, and we excluded an additional 8 patients with TNM stage IV gastric cancer. Thus, the final sample in our study comprised 445 patients. In our JAMA Surgery article, we failed to report on the role of Shanghai Outdo Biotech Co, Ltd, in creating the TMAs and evaluating the immunohistochemistry scores. Finally, we did not fully explain that our use of the R software, version 3.3.2, to compute area under the receive operating curves was needed owing to the limitations of previous versions of the R software. We have requested that our article be corrected to address these failures: to add citations to and description of the previously published and related 9 studies; a more complete explanation of the role of Shanghai Outdo Biotech Co, Ltd, in creating the TMAs and evaluating the immunohistochemistry scores; and a better explanation of the rationale for use of R software, version 3.3.2.12 These corrections affect text in the Abstract, Introduction and Methods sections, and eMethods 1 and eMethods 2 in the online Supplement of the original article. With these corrections, we confirm that none of the findings, interpretations, or conclusions of the study are affected and that there are no other omissions. We regret these failures in reporting and scholarship and apologize for any confusion that this has caused readers, other researchers, and the editors of the journal. The JAMA Surgery editors have asked us to report this study to the editors of other journals that have published any related studies from the same or portions of same patient sample included in this study, and we plan to do so. , 
 ![file] Though the authors investigated a prognostic factor in gastric cancer which might be of clinical importance, a deeper look into this article and the related works has revealed a list of similar studies and a number of inconsistencies, making me skeptical. Here I present some of what I have found: ## 1. The authors published many articles with almost identical study design. Starting in 2014, the authors of this JAMA Surgery paper, who are from Zhongshan Hospital and School of Basic Medical Sciences of Fudan University, published at least 19 articles of similar topic and of almost identical study design (See attached picture). In almost every article, the authors investigated the prognostic value of a different biomarker in gastric cancer; patients all received standard gastrectomy with D2 lymph node resection in Zhongshan Hospital; the authors mainly looked at immunohistochemistry results of tissue microarray, together with clinical outcome data, to draw conclusions. Interestingly, although the surgery dates of the studies were identical or shared considerable overlap (by this I mean the different studies were likely utilizing the samples and clinical information of same groups of patients), the number of patients were not identical in each study. ## 2. There are no pathologists in author lists. In each of the listed papers including the JAMA Surgery paper, the authors claimed that two pathologists independently assessed the specimens. However, there is not a single pathologist or doctor working in the Pathology Department in the author list. (The list of pathologists working at Zhongshan Hospital is available at http: www.zs-hospital.sh.cn) ## 3. Statistical analysis was done using R software v3.0.3. Although in the JAMA Surgery paper, the authors stated the statistical analysis was done by R software v3.3.2, in almost all other papers by the same group of authors they claimed that they used rms package on R software v3.0.3(See attached picture), including the most recent article published in 2018 (PMID:29872564). However, in practice, it is very unlikely for these analyses to be conducted under R v3.0.3 (which was released in 2014) since many dependencies of the rms package can only be run on R version 3.1. This is rather disturbing. Did the authors actually run rms package on R v3.0.3? Or they did not perform statistical analysis at all and just copy-pasted the previously published articles? ,