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Title: The clinical significance of loss of DNA mismatch repair in ovarian cancer patients : an immunohistochemical study
Author: Mackean, Melanie
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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Loss of mismatch repair (MMR) and, in particular, loss of MLH1 is associated with acquired cisplatin resistance of ovarian tumour cell line models. The aim of this thesis is to examine in ovarian cancer patients the clinical prognostic significance of the MMR proteins MLH1 and MSH2 when measured at disease presentation. We have developed immunohistochemistry (IHC) and a scoring system for the expression of MLH1 and MSH2 in paraffin embedded tissues. We have scored both the intensity of staining (I-score) and percentage of cells staining (%-score). We have validated this technique with good agreement in scoring over time, between blocks and between observers (inter-observer kappa scores of ³ 0.629, intra-observer kappa scores of ³ 0.646 and intra-slide kappa scores of ³ 0.583). There was a positive correlation of Ki67, (a proliferation maker), with I-MLH1, %-MLH1 and %-MSH2 scores (p=0.002; <0.001 and 0.001) but not with p53 scores. We examined prechemotherapy samples from 58 patients with a histological diagnosis of advanced ovarian carcinoma, who were then treated with primary chemotherapy regimens containing cisplatin. Advanced stage was associated with increased percentage cells positive for MLH1, MSH2 and Ki67 (p = 0.0092, 0.0049 and 0.0054 respectively). We performed a multivariate analysis allowing for known clinical prognostic factors, (i.e. type of chemotherapy given, stage, performance status and residual disease). Patients with a loss of intensity of staining for MMR proteins prechemotherapy showed a poor survival (Hazard Ratio, HR=3.64; p=0.0012) and poor progression free survival (HR=2.37; p=0.016). Similarly patients showing a reduced intensity of MLH1 staining showed a poor overall survival (HR=2.17; p=0.031). There was no correlation of MMR proteins and tumour response to treatment. Although further prospective validation studies will be necessary, our observations support the proposal that low MLH1 and/or MSH2 expression is associated with resistance in vivo of ovarian tumours to cisplatin and hence poor survival of patients after cisplatin-based chemotherapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available