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      Prognostic values of DNA mismatch repair genes in ovarian cancer patients treated with platinum-based chemotherapy

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          Abstract

          Purpose

          DNA mismatch repair (MMR) is a highly conserved biological pathway that plays a key role in maintaining genomic stability. MMR has been reported as a prognostic marker in certain cancers; however, the results are controversial. Therefore, identification of the prognostic value of MMR genes in ovarian cancer based on a large sample size is pivotal.

          Methods

          In the current study, we systemically investigated the prognostic roles of seven MMR genes, MSH2, MSH3, MSH6, MLH1, MLH3, PMS1 and PMS2, in ovarian cancer patients treated with platinum-based chemotherapy through “The Kaplan–Meier plotter” (KM plotter) database, which contains gene expression data and survival information of ovarian cancer patients.

          Results

          Among seven MMR genes, high mRNA levels of MSH6, MLH1 and PMS2 were significantly associated with a better overall survival for all ovarian cancer patients treated with platinum-based chemotherapy, especially in late-stage and poor-differentiated ovarian cancer patients. Increased MSH6 and PMS2 mRNA expression was correlated with a favorable overall survival in serous ovarian cancer patients.

          Conclusions

          Our results indicate that sufficient MMR system is associated with an improved survival in ovarian cancer treated with platinum-based chemotherapy. MMR gene may be a potential prognosis predictor in ovarian cancer.

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          Most cited references31

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          Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.

          Valérie Bonadona, Bernard Bonaïti, Sylviane Olschwang … (2011)
          Providing accurate estimates of cancer risks is a major challenge in the clinical management of Lynch syndrome. To estimate the age-specific cumulative risks of developing various tumors using a large series of families with mutations of the MLH1, MSH2, and MSH6 genes. Families with Lynch syndrome enrolled between January 1, 2006, and December 31, 2009, from 40 French cancer genetics clinics participating in the ERISCAM (Estimation des Risques de Cancer chez les porteurs de mutation des gènes MMR) study; 537 families with segregating mutated genes (248 with MLH1; 256 with MSH2; and 33 with MSH6) were analyzed. Age-specific cumulative cancer risks estimated using the genotype restricted likelihood (GRL) method accounting for ascertainment bias. Significant differences in estimated cumulative cancer risk were found between the 3 mutated genes (P = .01). The estimated cumulative risks of colorectal cancer by age 70 years were 41% (95% confidence intervals [CI], 25%-70%) for MLH1 mutation carriers, 48% (95% CI, 30%-77%) for MSH2, and 12% (95% CI, 8%-22%) for MSH6. For endometrial cancer, corresponding risks were 54% (95% CI, 20%-80%), 21% (95% CI, 8%-77%), and 16% (95% CI, 8%-32%). For ovarian cancer, they were 20% (95% CI, 1%-65%), 24% (95% CI, 3%-52%), and 1% (95% CI, 0%-3%). The estimated cumulative risks by age 40 years did not exceed 2% (95% CI, 0%-7%) for endometrial cancer nor 1% (95% CI, 0%-3%) for ovarian cancer, irrespective of the gene. The estimated lifetime risks for other tumor types did not exceed 3% with any of the gene mutations. MSH6 mutations are associated with markedly lower cancer risks than MLH1 or MSH2 mutations. Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years.
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            Role of DNA mismatch repair defects in the pathogenesis of human cancer.

            Päivi Peltomäki (2003)
            The DNA mismatch repair (MMR) system is necessary for the maintenance of genomic stability. In a broad sense, all main functions of the MMR system, including the correction of biosynthetic errors, DNA damage surveillance, and prevention of recombination between nonidentical sequences serve this important purpose. Failure to accomplish these functions may lead to cancer. It is therefore not surprising that inherited defects in the MMR system underlie one of the most prevalent cancer syndromes in humans, hereditary nonpolyposis colon cancer (HNPCC). In addition, acquired defects of the same system may account for 15% to 25%, or even a higher percentage, of sporadic cancers of different organs of the "HNPCC spectrum," including the colon and rectum, uterine endometrium, stomach, and ovaries. Recent studies indicate that the MMR genes may be involved in the pathogenesis of even a broader spectrum of tumors in one way or another. An updated review of the different features of the human MMR system will be provided, with the emphasis on their implications in cancer development.
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              DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy.

              Greg Yothers, Sarah J Moore, Kevin R. Foster … (2011)
              Approximately 15% of colorectal cancers develop because of defective function of the DNA mismatch repair (MMR) system. We determined the association of MMR status with colon cancer recurrence and examined the impact of 5-fluorouracil (FU)-based adjuvant therapy on recurrence variables. We included stage II and III colon carcinoma patients (n = 2141) who were treated in randomized trials of 5-FU-based adjuvant therapy. Tumors were analyzed for microsatellite instability by polymerase chain reaction and/or for MMR protein expression by immunohistochemistry to determine deficient MMR (dMMR) or proficient MMR (pMMR) status. Associations of MMR status and/or 5-FU-based treatment with clinicopathologic and recurrence covariates were determined using χ(2) or Fisher Exact or Wilcoxon rank-sum tests. Time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) were analyzed using univariate and multivariable Cox models, with the latter adjusted for covariates. Tumors showing dMMR were categorized by presumed germline vs sporadic origin and were assessed for their prognostic and predictive impact. All statistical tests were two-sided. In this study population, dMMR was detected in 344 of 2141 (16.1%) tumors. Compared with pMMR tumors, dMMR was associated with reduced 5-year recurrence rates (33% vs 22%; P < .001), delayed TTR (P < .001), and fewer distant recurrences (22% vs 12%; P < .001). In multivariable models, dMMR was independently associated with delayed TTR (hazard ratio = 0.72, 95% confidence interval = 0.56 to 0.91, P = .005) and improved DFS (P = .035) and OS (P = .031). In stage III cancers, 5-FU-based treatment vs surgery alone or no 5-FU was associated with reduced distant recurrence for dMMR tumors (11% vs 29%; P = .011) and reduced recurrence to all sites for pMMR tumors (P < .001). The dMMR tumors with suspected germline mutations were associated with improved DFS after 5-FU-based treatment compared with sporadic tumors where no benefit was observed (P = .006). Patients with dMMR colon cancers have reduced rates of tumor recurrence, delayed TTR, and improved survival rates, compared with pMMR colon cancers. Distant recurrences were reduced by 5-FU-based adjuvant treatment in dMMR stage III tumors, and a subset analysis suggested that any treatment benefit was restricted to suspected germline vs sporadic tumors.
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                Author and article information

                Contributors
                Haiyan Zhu: +86 577 88002796 , zhuhaiyandoc@sina.com
                Xueqiong Zhu:
                ORCID: http://orcid.org/0000-0002-8389-928X
                +86 577 8800279 , zjwzzxq@163.com
                Journal
                Journal ID (nlm-ta): Arch Gynecol Obstet
                Journal ID (iso-abbrev): Arch. Gynecol. Obstet
                Title: Archives of Gynecology and Obstetrics
                Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )
                ISSN (Print): 0932-0067
                ISSN (Electronic): 1432-0711
                Publication date (Electronic): 23 October 2017
                Publication date PMC-release: 23 October 2017
                Publication date (Print): 2018
                Volume: 297
                Issue: 1
                Pages: 153-159
                Affiliations
                ISNI 0000 0004 1764 2632, GRID grid.417384.d, Department of Obstetrics and Gynecology, , The Second Affiliated Hospital of Wenzhou Medical University, ; No. 109 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang China
                Author information
                http://orcid.org/0000-0002-8389-928X
                Article
                Publisher ID: 4563
                DOI: 10.1007/s00404-017-4563-x
                PMC ID: 5762798
                PubMed ID: 29063235
                SO-VID: 8bf36f7e-d7b6-43b1-8661-d2ecf2179cec
                Copyright © © The Author(s) 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Date received : 7 December 2016
                Date accepted : 11 October 2017
                Funding
                Funded by: Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents
                Funded by: Wenzhou Science and Technology Grant
                Award ID: Y20140345
                Award Recipient :
                Categories
                Subject: Gynecologic Oncology
                Custom metadata
                issue-copyright-statement © Springer-Verlag GmbH Germany, part of Springer Nature 2018

                ScienceOpen disciplines: Obstetrics & Gynecology
                Keywords: mismatch repair,ovarian cancer,prognosis,km plotter
                Data availability:
                ScienceOpen disciplines: Obstetrics & Gynecology
                Keywords: mismatch repair, ovarian cancer, prognosis, km plotter

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