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Mismatch repair deficiency in ovarian cancer — Molecular characteristics and clinical implications

  • Xue Xiao
    Affiliations
    University of Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road South, Edinburgh, UK
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  • David W. Melton
    Affiliations
    University of Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road South, Edinburgh, UK
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  • Charlie Gourley
    Correspondence
    Corresponding author at: University of Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, Crewe Road South, Edinburgh, UK. Fax: +44 1317773520.
    Affiliations
    University of Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road South, Edinburgh, UK
    Search for articles by this author
Published:December 30, 2013DOI:https://doi.org/10.1016/j.ygyno.2013.12.003

      Highlights

      • Both mutational and expression data suggest that MMR deficiency is more common in non-serous ovarian cancer than in serous subtypes.
      • The effect of MMR deficiency on ovarian cancer chemosensitivity remains unproven but synthetic lethal approaches offer hope of novel therapies.

      Abstract

      DNA mismatch repair (MMR) deficiency is associated with increased risk of developing several types of cancer and is the most common cause of hereditary ovarian cancer after BRCA1 and BRCA2 mutations. While there has been extensive investigation of MMR deficiency in colorectal cancer, MMR in ovarian cancer is relatively under-investigated. This review summarizes the mechanism of MMR, the ways in which MMR deficiency can promote carcinogenesis in general and then assesses the available studies regarding MMR deficiency in ovarian cancers with specific emphasis on implications for disease incidence and therapy. The incidence of germline MMR gene mutations in ovarian cancer is only 2% but other mechanisms of gene inactivation mean that loss of expression of one of the seven main genes (MSH2, MSH3, MSH6, MLH1, MLH3, PMS1 and PMS2) occurs in up to 29% of cases. Both mutational and expression data suggest that MMR deficiency is more common in non-serous ovarian cancer. Some studies suggest an improved survival for patients with MMR deficiency compared to historical controls but these do not account for the preponderance of non-serous tumors. A number of in vitro studies have suggested that MMR deficiency is a cause of platinum resistance. To date this has not been categorically demonstrated in the clinic. Larger studies that account for stage of presentation and immunohistochemical subtype are required to assess the effect of MMR deficiency on survival and chemosensitivity. Investigation of MMR related synthetic lethality in colorectal cancer has identified dihydrofolate reductase, DNA polymerase β and DNA polymerase γ and PTEN-induced putative kinase 1 as synthetic lethal to certain MMR defects by causing accumulation of oxidative DNA damage. These synthetic lethal targets require tested and others should be sought within the context of MMR deficient ovarian cancer in an attempt to provide novel therapeutic strategies for these patients.

      Keywords

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      References

        • NCI
        National Cancer Institute (NCI), Cancer Statistics > Cancer Stat Fact Sheets > Cancer of the Ovary.
        (Available from:)
        • Bashashati A.
        • et al.
        Distinct evolutionary trajectories of primary high‐grade serous ovarian cancers revealed through spatial mutational profiling.
        J Pathol. 2013; 231: 21-34
        • Colombo N.
        • et al.
        Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2010; 21: v23-v30
        • Conklin C.M.
        • Gilks C.B.
        Differential diagnosis and clinical relevance of ovarian carcinoma subtypes.
        Expert Rev Obstet Gynecol. 2013; 8: 67-82
        • Köbel M.
        • et al.
        Differences in tumor type in low-stage versus high-stage ovarian carcinomas.
        Int J Gynecol Pathol. 2010; 29: 203-211
        • Lalwani N.
        • et al.
        Histologic, molecular, and cytogenetic features of ovarian cancers: implications for diagnosis and treatment.
        Radiographics. 2011; 31: 625-646
        • Seidman J.D.
        • et al.
        The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin.
        Int J Gynecol Pathol. 2004; 23: 41-44
        • Holschneider C.H.
        • Berek J.S.
        Ovarian cancer: epidemiology, biology, and prognostic factors.
        in: Seminars in surgical oncology. Wiley Online Library, 2000
        • Alsop K.
        • et al.
        BRCA mutation frequency and patterns of treatment response in BRCA mutation—positive women with ovarian cancer: a report from the Australian ovarian cancer study group.
        J Clin Oncol. 2012; 30: 2654-2663
        • Risch H.A.
        • et al.
        Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada.
        J Natl Cancer Inst. 2006; 98: 1694-1706
        • Schrader K.A.
        • et al.
        Germline BRCA1 and BRCA2 mutations in ovarian cancer: utility of a histology-based referral strategy.
        Obstet Gynecol. 2012; 120: 235-240
        • Bandera C.A.
        Advances in the understanding of risk factors for ovarian cancer.
        J Reprod Med. 2005; 50: 399-406
        • Bewtra C.
        • Watson P.
        • Conway T.
        • Read-Hippee C.
        • Lynch H.T.
        Hereditary ovarian cancer: a clinicopathological study.
        Int J Gynecol Pathol. 1992; 11: 180
        • Malander S.
        • et al.
        The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer.
        Gynecol Oncol. 2006; 101: 238-243
        • Rubin S.C.
        • et al.
        BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: relationship to family history and implications for genetic testing.
        Am J Obstet Gynecol. 1998; 178: 670-677
        • Lynch H.T.
        • Casey M.J.
        • Lynch J.
        • White T.E.
        • Godwin A.K.
        Genetics and ovarian carcinoma.
        Semin Oncol. 1998; 25: 265-280
        • Li G.M.
        Mechanisms and functions of DNA mismatch repair.
        Cell Res. 2008; 18: 85-98
        • Macpherson P.
        • et al.
        8-Oxoguanine incorporation into DNA repeats in vitro and mismatch recognition by MutSα.
        Nucleic Acids Res. 2005; 33: 5094-5105
        • Pal T.
        • Permuth‐Wey J.
        • Sellers T.A.
        A review of the clinical relevance of mismatch‐repair deficiency in ovarian cancer.
        Cancer. 2008; 113: 733-742
        • Genschel J.
        • Littman S.J.
        • Drummond J.T.
        • Modrich P.
        Isolation of MutSbeta from human cells and comparison of the mismatch repair specificities of MutSbeta and MutSalpha.
        J Biol Chem. 1998; 273: 19895-19901
        • Modrich P.
        Mechanisms in eukaryotic mismatch repair.
        J Biol Chem. 2006; 281: 30305-30309
        • Kadyrov F.A.
        • Dzantiev L.
        • Constantin N.
        • Modrich P.
        Endonucleolytic function of MutLα in human mismatch repair.
        Cell. 2006; 126: 297-308
        • Gu L.
        • Hong Y.
        • McCulloch S.
        • Watanabe H.
        • Li G.M.
        ATP-dependent interaction of human mismatch repair proteins and dual role of PCNA in mismatch repair.
        Nucleic Acids Res. 1998; 26: 1173-1178
        • Hsieh P.
        • Yamane K.
        DNA mismatch repair: molecular mechanism, cancer, and ageing.
        Mech Ageing Dev. 2008; 129: 391-407
        • Seifert M.
        • Reichrath J.
        The role of the human DNA mismatch repair gene hMSH2 in DNA repair, cell cycle control and apoptosis: implications for pathogenesis, progression and therapy of cancer.
        J Mol Histol. 2006; 37: 301-307
        • Abdel-Rahman W.M.
        • Mecklin J.P.
        • Peltomäki P.
        The genetics of HNPCC: application to diagnosis and screening.
        Crit Rev Oncol Hematol. 2006; 58: 208-220
        • Boland C.R.
        • et al.
        A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.
        Cancer Res. 1998; 58: 5248-5257
        • Turnpenny P.D.
        • Ellard S.
        Emery's elements of medical genetics.
        Churchill Livingstone, 2011
        • Woerner S.M.
        • et al.
        Microsatellite instability of selective target genes in HNPCC-associated colon adenomas.
        Oncogene. 2005; 24: 2525-2535
        • Imai K.
        • Yamamoto H.
        Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics.
        Carcinogenesis. 2008; 29: 673-680
        • Shannon C.
        • et al.
        Incidence of microsatellite instability in synchronous tumors of the ovary and endometrium.
        Clin Cancer Res. 2003; 9: 1387-1392
        • Knudson Jr., A.G.
        Mutation and cancer: statistical study of retinoblastoma.
        Proc Natl Acad Sci U S A. 1971; 68: 820-823
        • Gras E.
        • et al.
        Microsatellite instability, MLH‐1 promoter hypermethylation, and frameshift mutations at coding mononucleotide repeat microsatellites in ovarian tumors.
        Cancer. 2001; 92: 2829-2836
        • Wajed S.A.
        • Laird P.W.
        • DeMeester T.R.
        DNA methylation: an alternative pathway to cancer.
        Ann Surg. 2001; 234: 10
        • Aarnio M.
        • Mecklin J.P.
        • Aaltonen L.A.
        • Nyström-Lahti M.
        • Järvinen H.J.
        Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome.
        Int J Cancer. 1995; 64: 430-433
        • Lynch H.T.
        • et al.
        Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management.
        Mol Oncol. 2009; 3: 97-137
        • Domanska K.
        • Malander S.
        • Måsbäck A.
        • Nilbert M.
        Ovarian cancer at young age: the contribution of mismatch‐repair defects in a population‐based series of epithelial ovarian cancer before age 40.
        Int J Gynecol Cancer. 2007; 17: 789-793
        • Pal T.
        • et al.
        Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.
        Br J Cancer. 2012; 107: 1783-1790
        • Cai K.Q.
        • et al.
        Microsatellite instability and alteration of the expression of hMLH1 and hMSH2 in ovarian clear cell carcinoma.
        Hum Pathol. 2004; 35: 552-559
        • Catasús L.
        • et al.
        Molecular genetic alterations in endometrioid carcinomas of the ovary: similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas.
        Hum Pathol. 2004; 35: 1360-1368
        • Jensen K.C.
        • et al.
        Microsatellite instability and mismatch repair protein defects in ovarian epithelial neoplasms in patients 50 years of age and younger.
        Am J Surg Pathol. 2008; 32: 1029
        • Watanabe Y.
        • Koi M.
        • Hemmi H.
        • Hoshai H.
        • Noda K.
        A change in microsatellite instability caused by cisplatin-based chemotherapy of ovarian cancer.
        Br J Cancer. 2001; 85: 1064
        • Rosen D.G.
        • Cai K.Q.
        • Luthra R.
        • Liu J.
        Immunohistochemical staining of hMLH1 and hMSH2 reflects microsatellite instability status in ovarian carcinoma.
        Mod Pathol. 2006; 19: 1414-1420
        • UEDA H.
        • et al.
        Microsatellite status and immunohistochemical features of ovarian clear-cell carcinoma.
        Anticancer Res. 2005; 25: 2785-2788
        • Liu J.
        • et al.
        Microsatellite instability and expression of hMLH1 and hMSH2 proteins in ovarian endometrioid cancer.
        Mod Pathol. 2004; 17: 75-80
        • Geisler J.P.
        • et al.
        Mismatch repair gene expression defects contribute to microsatellite instability in ovarian carcinoma.
        Cancer. 2003; 98: 2199-2206
        • Helleman J.
        • et al.
        Mismatch repair and treatment resistance in ovarian cancer.
        BMC Cancer. 2006; 6: 201
        • Popat S.
        • Hubner R.
        • Houlston R.
        Systematic review of microsatellite instability and colorectal cancer prognosis.
        J Clin Oncol. 2005; 23: 609-618
        • Radman M.
        • Wagner R.
        Carcinogenesis. Missing mismatch repair.
        Nature. 1993; 366: 722
        • Crijnen T.E.M.
        • et al.
        Survival of patients with ovarian cancer due to a mismatch repair defect.
        Fam Cancer. 2005; 4: 301-305
        • Scartozzi M.
        • et al.
        Loss of hMLH1 expression correlates with improved survival in stage III–IV ovarian cancer patients.
        Eur J Cancer. 2003; 39: 1144-1149
        • Grindedal E.M.
        • et al.
        Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds.
        J Med Genet. 2010; 47: 99-102
        • Kemp Z.
        • Ledermann J.
        Update on first-line treatment of advanced ovarian carcinoma.
        Int J Women's Health. 2013; 5: 45-51
        • Strathdee G.
        • MacKean M.J.
        • Illand M.
        • Brown R.
        A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer.
        Oncogene. 1999; 18: 2335
        • Zeller C.
        • et al.
        Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling.
        Oncogene. 2012; 31: 4567-4576
        • Plumb J.A.
        • Strathdee G.
        • Sludden J.
        • Kaye S.B.
        • Brown R.
        Reversal of drug resistance in human tumor xenografts by 2′-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter.
        Cancer Res. 2000; 60: 6039-6044
        • Ercoli A.
        • et al.
        hMSH2 and GTBP expression in advanced stage epithelial ovarian cancer.
        Br J Cancer. 1999; 80: 1665
        • Marcelis C.L.
        • van der Putten H.W.
        • Tops C.
        • Lutgens L.C.
        • Moog U.
        Chemotherapy resistant ovarian cancer in carriers of an hMSH2 mutation?.
        Fam Cancer. 2001; 1: 107-109
        • Samimi G.
        • et al.
        Analysis of MLH1 and MSH2 expression in ovarian cancer before and after platinum drug-based chemotherapy.
        Clin Cancer Res. 2000; 6: 1415-1421
        • Tucker C.L.
        • Fields S.
        Lethal combinations.
        Nat Genet. 2003; 35: 204-205
        • Bryant H.E.
        • et al.
        Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase.
        Nature. 2005; 434: 913-917
        • Farmer H.
        • et al.
        Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
        Nature. 2005; 434: 917-921
        • Martin S.A.
        • Hewish M.
        • Sims D.
        • Lord C.J.
        • Ashworth A.
        Parallel high-throughput RNA interference screens identify PINK1 as a potential therapeutic target for the treatment of DNA mismatch repair-deficient cancers.
        Cancer Res. 2011; 71: 1836-1848
        • Martin S.A.
        • et al.
        DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1.
        Cancer Cell. 2010; 17: 235-248
        • Martin S.A.
        • et al.
        Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2.
        EMBO Mol Med. 2009; 1: 323-337
        • Zhai Q.J.
        • Rosen D.G.
        • Lu K.
        • Liu J.
        Loss of DNA mismatch repair protein hMSH6 in ovarian cancer is histotype-specific.
        Int J Clin Exp Pathol. 2008; 1: 502-509
        • Aysal A.
        • et al.
        Ovarian endometrioid adenocarcinoma: incidence and clinical significance of the morphologic and immunohistochemical markers of mismatch repair protein defects and tumor microsatellite instability.
        Am J Surg Pathol. 2012; 36: 163-172
        • Coppola D.
        • et al.
        Uncertainty in the utility of immunohistochemistry in mismatch repair protein expression in epithelial ovarian cancer.
        Anticancer Res. 2012; 32: 4963-4969
        • Strathdee G.
        • et al.
        Primary ovarian carcinomas display multiple methylator phenotypes involving known tumor suppressor genes.
        Am J Pathol. 2001; 158: 1121
        • Willner J.
        • et al.
        Alternate molecular genetic pathways in ovarian carcinomas of common histological types.
        Hum Pathol. 2007; 38: 607-613