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      Methylation of MGMT Is Associated with Poor Prognosis in Patients with Stage III Duodenal Adenocarcinoma

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          Abstract

          Background

          O 6 -methylguanine-DNA methyltransferase ( MGMT) methylation status has not been extensively investigated in duodenal adenocarcinoma (DA). The aim of this study was to evaluate the MGMT methylation status and examine its possible prognostic value in patients with stage III DA.

          Methods

          Demographics, tumor characteristics and survival were available for 64 patients with stage III DA. MGMT methylation was detected by using MethyLight. A Cox proportional hazard model was built to predict survival, adjusted for clinicopathological characteristics and tumor molecular features, including the CpG island methylator phenotype (CIMP), microsatellite instability (MSI), and KRAS mutations.

          Results

          MGMT methylation was detected in 17 of 64 (26.6%) patients, and was not correlated with sex, age, tumor differentiation, CIMP, MSI, or KRAS mutations. MGMT methylation was the only one factor associated with both overall survival (OS) and disease-free survival (DFS) on both univariate and multivariate analyses. In patients treated with surgery alone, MGMT-methylated group had worse OS and DFS when compared with MGMT-unmethylated group. However, in patients treated with chemotherapy/radiotherapy, outcomes became comparable between the two groups.

          Conclusions

          Our results demonstrate MGMT methylation is a reliable and independent prognostic factor in DAs. Methylation of MGMT is associated with poor prognosis in patients with stage III DAs.

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          Most cited references40

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          CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.

          Daniel Weisenberger, Kimberly D. Siegmund, Mihaela Campan … (2006)
          Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'. However, the existence of CIMP has been challenged. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1 . We propose a robust new marker panel to classify CIMP+ tumors.
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            Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

            Roger Stupp, Monika E Hegi, Thierry Gorlia … (2014)
            Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter.
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              Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression.

              S Wallinger, R Fishel, J Rüschoff … (1997)
              Alterations of the length of simple repetitive genomic sequences (microsatellite instability, MSI) characterize a distinct mechanism of colorectal carcinogenesis. Such MSI has been found to be associated with hereditary nonpolyposis colorectal cancer (HNPCC) that involves mutation of the human mismatch repair genes hMSH2 and hMLH1 as well as many sporadic cancers of most tissue types. Although the study of MSI status is a useful tool for HNPCC screening and for the determination of tumor prognosis in sporadic cases of colorectal cancer, the reliability of MSI diagnosis is still a subject of debate. Here we have examined 58 primary colorectal tumors (selected from a cohort of 200) using 31 microsatellite markers that comprised the most frequent simple repeat types. The expression of the hMSH2 and hMLH1 mismatch repair proteins was studied by immunohistochemistry, and most patients were surveyed for at least 2 years. Reproducibility of gel interpretation, as well as diagnostic sensitivity and specificity of the MSI status, were determined. We found that unambiguous determination of band shifts as well as MSI diagnosis were closely related to the type of the marker repeat and that MSI could be subdivided into "high" MSI (>20% unstable loci), "low" MSI (<10% unstable loci), and microsatellite stable (0% unstable loci). One-half of the patients with high MSI tumors (n = 8) fulfilled either the Amsterdam criteria (n = 4), had at least one relative with HNPCC-related carcinoma (n = 2), or were diagnosed with colorectal cancer at an age below 45 years (n = 2). Fourteen of the 15 high MSI tumors had lost either hMSH2 (n = 8) or hMLH1 (n = 6) protein expression. In contrast, all of the low MSI tumors and the MSI-negative tumors displayed normal expression of hMSH2 and hMLH1. These studies provide a clear recommendation for the uniform use of a panel of 10 microsatellites and a definition of at least 40% instability (using these defined marker loci) in the diagnostic analysis of MSI.
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                Author and article information

                Contributors
                Dajun Deng: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 19 September 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 9
                Electronic Location Identifier: e0162929
                Affiliations
                [1 ]Department of Gastrointestinal Surgery II, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital, Wuhan University, Wuhan, China
                [2 ]Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [3 ]Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [4 ]Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                Beijing Cancer Hospital, CHINA
                Author notes

                Competing Interests: Stephen B. Baylin has commercial grant funding and serves on the advisory board for MDx Health Inc. and BioNumerik Pharmaceuticals Inc. Nita Ahuja has grant funding from Astex and has licensed biomarkers to Cepheid Inc. She has served as consultant for Ethicon. No potential conflicts of interest were disclosed by the other authors.

                • Conceptualization: TF NA.

                • Data curation: TF NA.

                • Formal analysis: TF.

                • Funding acquisition: TF NA.

                • Investigation: TF AS FX YL KL WW CLW NA.

                • Methodology: TF NA.

                • Project administration: TF NA.

                • Resources: AS CLW NA.

                • Software: TF.

                • Supervision: TF SBB CLW NA.

                • Validation: TF SBB CLW NA.

                • Visualization: TF NA.

                • Writing – original draft: TF.

                • Writing – review & editing: TF AS FX YL KL WW SBB CLW NA.

                Author information
                http://orcid.org/0000-0003-4713-7269
                Article
                Publisher ID: PONE-D-16-26856
                DOI: 10.1371/journal.pone.0162929
                PMC ID: 5028050
                PubMed ID: 27643594
                SO-VID: d66d88e6-e721-402b-8b3a-542f7a552d97
                Copyright © © 2016 Fu et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 12 July 2016
                Date accepted : 30 August 2016
                Page count
                Figures: 3, Tables: 3, Pages: 13
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: CA140599
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: CA127141
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81000898
                Award Recipient :
                ORCID: http://orcid.org/0000-0003-4713-7269
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81472289
                Award Recipient :
                ORCID: http://orcid.org/0000-0003-4713-7269
                This work was supported by National Institutes of Health grants CA140599 and CA127141, National Natural Science Foundation of China grants 81000898 and 81472289, and sponsored by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry of China.
                Categories
                Subject: Research Article
                Subject: Biology and life sciences
                Subject: Cell biology
                Subject: Chromosome biology
                Subject: Chromatin
                Subject: Chromatin modification
                Subject: DNA methylation
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: Epigenetics
                Subject: Chromatin
                Subject: Chromatin modification
                Subject: DNA methylation
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: Gene expression
                Subject: Chromatin
                Subject: Chromatin modification
                Subject: DNA methylation
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: DNA
                Subject: DNA modification
                Subject: DNA methylation
                Subject: Biology and life sciences
                Subject: Biochemistry
                Subject: Nucleic acids
                Subject: DNA
                Subject: DNA modification
                Subject: DNA methylation
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: Epigenetics
                Subject: DNA modification
                Subject: DNA methylation
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: Gene expression
                Subject: DNA modification
                Subject: DNA methylation
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Chemotherapy
                Subject: Combination Chemotherapy
                Subject: Chemoradiotherapy
                Subject: Medicine and Health Sciences
                Subject: Clinical Medicine
                Subject: Clinical Oncology
                Subject: Chemotherapy
                Subject: Combination Chemotherapy
                Subject: Chemoradiotherapy
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Clinical Oncology
                Subject: Chemotherapy
                Subject: Combination Chemotherapy
                Subject: Chemoradiotherapy
                Subject: Medicine and Health Sciences
                Subject: Pharmaceutics
                Subject: Drug Therapy
                Subject: Chemotherapy
                Subject: Combination Chemotherapy
                Subject: Chemoradiotherapy
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Radiation Therapy
                Subject: Chemoradiotherapy
                Subject: Medicine and Health Sciences
                Subject: Clinical Medicine
                Subject: Clinical Oncology
                Subject: Radiation Therapy
                Subject: Chemoradiotherapy
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Clinical Oncology
                Subject: Radiation Therapy
                Subject: Chemoradiotherapy
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Carcinomas
                Subject: Adenocarcinomas
                Subject: Medicine and Health Sciences
                Subject: Surgical and Invasive Medical Procedures
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Chemotherapy
                Subject: Adjuvant Chemotherapy
                Subject: Medicine and Health Sciences
                Subject: Clinical Medicine
                Subject: Clinical Oncology
                Subject: Chemotherapy
                Subject: Adjuvant Chemotherapy
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Clinical Oncology
                Subject: Chemotherapy
                Subject: Adjuvant Chemotherapy
                Subject: Medicine and Health Sciences
                Subject: Pharmaceutics
                Subject: Drug Therapy
                Subject: Chemotherapy
                Subject: Adjuvant Chemotherapy
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Prognosis
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Colorectal Cancer
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