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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina; and the Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
Address reprint requests to: Andrew Berchuck, MD, Department of Obstetrics and Gynecology, Duke University Medical Center, Box 3079, Durham, NC 27710, E-mail: berch001{at}mc.duke.edu
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Abstract |
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Methods: Microsatellite instability analysis was performed in 131 patients with endometrioid endometrial cancer using three polymorphic markers in paired cancer and normal DNA. Logistic regression and multivariable analyses calculated the relation between microsatellite instability, clinical features, and survival.
Results: Microsatellite instability was detected in 29 of 131 (22%) endometrioid endometrial cancers. There was no correlation between microsatellite instability and age, race, grade, stage, or depth of myometrial invasion. Microsatellite instability was associated with better survival in univariate and multivariable analyses after controlling for confounding influences (P = .03). The 5-year survival rate of those with microsatellite instability was 77% (95% confidence interval 55%, 90%) compared with only 48% (95% confidence interval 39%, 57%) in other cases. Microsatellite instability was associated with other molecular features that predict favorable outcome including PTEN mutation (P = .002) and the absence of p53 overexpression (P = .01).
Conclusion: Microsatellite instability is a molecular alteration associated with favorable outcome in endometrioid endometrial cancers, even when accounting for other prognostic factors. This association might be explained by the finding that the pathway of molecular carcinogenesis characterized by loss of DNA mismatch repair favors alteration of genes that result in a less virulent clinical phenotype.
Microsatellites are repetitive DNA sequences that are widely dispersed throughout the genome. Because of their repetitive structure, microsatellites are particularly susceptible to slippage errors by DNA polymerase during replication, resulting in insertion or deletion mutations.1 The proteins encoded by mismatch repair genes normally recognize and repair these genetic mutations. Alterations in mismatch repair genes such as MLH1, MLH6, MSH2, MSH3, and PMS2 lead to accumulation of mutations in microsatellite sequences throughout the genome, a phenomenon known as microsatellite instability.2 Microsatellite instability was initially noted in colorectal cancers of patients with hereditary nonpolyposis colorectal cancer syndrome.3,4 Endometrial cancer is the second most common malignancy observed in hereditary nonpolyposis colorectal cancer, and genetic analysis of these tumors showed microsatellite instability in 75% of cases.5 Affected individuals in these families carried germline mutations in the DNA repair genes, primarily MLH1 or MSH2.6
Microsatellite instability also was found in some sporadic cancers: approximately 20% of endometrial7–9 and 17% of colon10 nonfamilial cancers. Most sporadic colon and endometrial cancers with microsatellite instability do not have acquired mutations in mismatch repair genes11; microsatellite instability in these cancers might be caused by hypermethylation of the MLH1 promoter, leading to the absence of expression of this DNA repair protein.12–16 A population-based study of 607 patients with colon cancer found that microsatellite instability, regardless of the underlying cause, is a strong independent predictor of favorable survival even when accounting for other prognostic factors such as stage.10 We investigated whether endometrial cancers with microsatellite instability have a similarly favorable outcome.
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Materials and Methods |
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AbstractMaterials and MethodsResultsDiscussionReferences |
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Analysis of microsatellite instability was done as described6 using polymerase chain reaction to amplify three polymorphic markers (BAT 26, [An]; D14S65, [CAn]; and D14S297, [GATAn]) in paired endometrial cancer and normal DNA samples. Cancer cases were designated as positive when two of the three markers showed alleles of aberrant mobility when compared with corresponding normal tissue.
Proportions among unordered categories were compared using the Fisher two-tailed exact test, and those for ordered categories were compared using the chi-square test for trend.19 The logistic regression model analyzed the association between microsatellite instability and more than one clinical feature.20 The Cox proportional hazards regression model analyzed the relation between survival and study variables.21 In a stepwise method, each variable entered into the model was adjusted for those variables already in the model. Survival was defined as the interval from diagnosis to death from any cause. When evaluating individual study variables in the survival analysis, if fewer than 50% of the patients had not died, the median was not defined and a minimum possible time was determined. Patients still alive were censored in the analysis. Survival curves were constructed using the Kaplan–Meier method and differences were tested using the log-rank statistic.22,23 Survival times were truncated at 10 years for the figures, but all statistics were based on the complete data. Estimated median follow-up time was 6.3 years and the minimum was 3 years.
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Results |
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. The relation between microsatellite instability and clinicopathologic features is shown in Table 1. Microsatellite instability was not associated with age, race, grade, depth of myometrial invasion, or stage but was associated with p53 expression (P = .01) and PTEN mutation (P = .002). Endometrial cancers with microsatellite instability were found more often to have normal p53 expression and PTEN mutation.
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. In this analysis, extent of disease, depth of invasion, and grade predicted survival. Survival was worse in older women and blacks, but these differences were not statistically significant. Improved survival was associated with microsatellite instability, mutant PTEN, and normal p53 expression. In a multivariable analysis of all patients, microsatellite instability still predicted survival (P = .03) after controlling for stage and grade. Kaplan–Meier survival curves of the relation between microsatellite instability and survival are shown in Figure 2. In the entire group of endometrioid endometrial cancers (Figure 2A), microsatellite instability associated with more favorable survival (P = .03). The 5-year survival rate of those with microsatellite instability was 77% (95% confidence interval 55%, 90%) compared with only 48% (95% confidence interval 39%, 57%) in other cases. The favorable effect of microsatellite instability on outcome was more pronounced in those with nonmetastatic disease (Figure 2B) than in those with metastatic disease (Figure 2C), but these differences were not statistically significant.
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Discussion |
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Microsatellite instability also was found in approximately 20–30% of endometrial cancers. Most studies did not associate microsatellite instability with pathologic features of endometrial cancers such as grade26–28 or depth of myometrial invasion.29 Despite the lack of correlation with clinical prognostic factors, some small studies predicted favorable outcome with the presence of microsatellite instability. In a study of 51 endometrial cancers, Tibiletti et al noted a trend toward better outcome in cases with microsatellite instability in the subset with endometrioid histology.26 Similarly, in a study of 50 patients with endometrial cancer, Wong et al found that disease-related deaths occurred in three patients without microsatellite instability, whereas all patients with microsatellite instability were alive at 40 months.30 Conversely, Caduff et al analyzed 109 endometrial cancers and found that 60% of patients whose cancers had microsatellite instability died of disease 1–60 months after diagnosis compared with 25% of other patients.29 Its frequency in this study (10%) was significantly lower than described in other reports.
In a study of advanced stage III/IV endometrial cancers, we had found that microsatellite instability was exclusively a feature of endometrioid cancers and not of papillary serous or clear cell cancers.18 The association of microsatellite instability with endometrioid histology suggested a favorable outcome because these cases have much better survival than those with serous or clear cell histology. A strong link between microsatellite instability and favorable outcome also was suggested because microsatellite instability predicted better survival in the endometrioid subset of advanced stage cases. This stimulated us to examine endometrial cancers of all stages; in the present study, microsatellite instability remained predictive of improved survival, even when accounting for stage in a multivariate model. Similar to the large population-based study of colorectal cancers in Ontario, we found that 5-year survival rate of endometrioid endometrial cancers with microsatellite instability was about 20% better than that of cases without it.
Several factors might contribute to differences between the results of our study and those reported. There is no consistent standard with respect to the number of microsatellite markers examined and the thresholds that define microsatellite instability differ. Although we used three markers to assess microsatellite analysis, a subset of 73 cancers had been evaluated using 19 additional markers with no resultant increase in the fraction of cases with instability. All of the studies in the literature, including the present report, are hospital based and subject to biases dependent on referral patterns. In the present study, about 40% of cases had metastatic disease, which is somewhat higher than one would expect in the general population.
Our study has several notable strengths. It specifically focused on endometrioid cases. Other studies included nonendometrioid cases, which do not exhibit instability, which confounded analysis of the relation between microsatellite instability and survival. Unlike those reports, our patients were followed for at least 3 years after initial surgery. None of the studies correlating microsatellite instability and clinical features distinguished between women with inherited mutations in DNA repair genes and those with acquired alterations.
Although all human cancers arise from genetic mutations, loss of DNA repair capability leading to microsatellite instability might represent a fundamentally different mechanism of carcinogenesis relative to the more common pathway of chromosome instability characterized by gene loss or amplification. Microsatellite instability in endometrial cancers occurs almost exclusively in type I endometrioid tumors and was found in endometrial hyperplasias, their premalignant precursors.31 Cancers with microsatellite instability are more likely to have PTEN mutations (also associated with endometrioid histology) and less likely to have p53 overexpression, a molecular event frequently found in type II nonendometrioid cancers. Loss of DNA repair efficiency might be an early event that increases the likelihood of malignant progression to an endometrioid endometrial cancer with alterations in specific oncogenes and tumor suppressor genes that confer a more favorable prognosis. Japanese investigators showed that lymphocytic infiltration is more significant in endometrial cancers with microsatellite instability, suggesting augmentation of the host response in these tumors.32 Mutations that accompany microsatellite instability might affect not only growth regulatory genes but also those immunologic factors important in the recognition of cancer cells.
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Footnotes |
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Received June 21, 2000. Received in revised form August 28, 2000. Accepted September 28, 2000.
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