Originally published as JCO Early Release 10.1200/JCO.2005.04.1574 on March 20 2006

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Clinicopathologic Significance of Defective DNA Mismatch Repair in Endometrial Carcinoma

Destin Black, Robert A. Soslow, Douglas A. Levine, Carmen Tornos, Shirley C. Chen, Amanda J. Hummer, Faina Bogomolniy, Narciso Olvera, Richard R. Barakat, Jeff Boyd

From the Departments of Surgery, Pathology, Epidemiology and Biostatistics, and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

Address reprint requests to Jeff Boyd, PhD, Department of Surgery, Box 201, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: boydj{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 
PURPOSE: Defective DNA mismatch repair is commonly present in sporadic manifestations of gastrointestinal, endometrial, and other cancers. The pathognomonic molecular manifestation of this repair defect is microsatellite instability (MSI). Here, we test the hypothesis that MSI predicts the clinicopathologic features of endometrial carcinoma.

PATIENTS AND METHODS: A retrospective cohort of 473 patients treated for endometrial carcinoma at this institution was identified. All cases were reviewed by a gynecologic pathologist, and clinical information was abstracted from medical records. Using consensus criteria, DNA samples from nontumor and tumor tissue pairs were genotyped for MSI. Associations between MSI status and pathologic and clinical variables were assessed.

RESULTS: Ninety-three (20%) of 473 tumors were MSI+. In the MSI+ tumor group compared with the MSI– tumor group, the proportion of advanced compared with early-stage tumors was higher (92% v 81%; P = .01), as was the proportion of tumors of endometrioid compared with nonendometrioid histologic subtype (94% v 23%; P = .001), and the proportion of tumors with myometrial invasion compared with those with none (92% v 78%; P = .01). By multivariate analyses, disease-free survival (hazard ratio, 0.3; 95% CI, 0.2 to 0.7) and disease-specific survival (hazard ratio, 0.3; 95% CI, 0.1 to 0.8) were significantly improved in patients with MSI+ tumors.

CONCLUSION: In endometrial carcinoma, the presence of MSI was independently associated with a more favorable clinical outcome.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 
Endometrial carcinoma is the most common gynecologic malignancy in the United States, with 41,200 new cases and 7,350 deaths estimated in 2005.¹ During the last 15 years, several important advances have been made in defining the molecular genetic alterations that contribute to endometrial tumorigenesis.² Among the most well characterized of these is a defect in the DNA mismatch repair system, affecting approximately 20% of tumors, which occurs predominantly in the type I class of endometrial cancers.² Defective mismatch repair was initially described in sporadic colorectal tumors and those associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome.^3-5 The HNPCC syndrome is associated with autosomal dominant cancer predisposition characterized by the development of colorectal carcinoma at an early age, as well as tumors of the upper urologic, gastrointestinal, and female reproductive tracts.⁶ Endometrial carcinoma is the most common extracolonic cancer in HNPCC, with an estimated frequency of 40% to 60% in female mutation carriers.^7-9

Germline mutation of one or another of the mismatch repair genes MSH2, MLH1, or MSH6 is believed to account for the great majority of HNPCC kindreds,¹⁰ whereas somatic promoter hypermethylation and silencing of the MLH1 gene appears to be the primary mechanism for loss of mismatch repair in endometrial and other sporadic cancers.¹¹ In either case, failure of this system leads to the accumulation of single base-pair mismatches, as well as small insertions and deletions in tandem repeats known as microsatellites, which manifests as microsatellite instability (MSI). This phenomenon is readily quantitated by gel electrophoresis of polymerase chain reaction (PCR) products containing microsatellites, and the observation of mobility shifts present in tumor compared with normal DNA products from the same individual. A specific panel of microsatellite markers has been adopted through National Cancer Institute (NCI; Bethesda, MD) –sponsored consensus recommendations, and found to have high sensitivity for the detection of defective mismatch repair.¹²

In colorectal carcinoma, several studies have demonstrated that tumors exhibiting MSI have distinctive molecular and clinicopathologic profiles. These tumors are associated with preferential proximal colon location, poorly differentiated histology, and extensive peritumoral lymphocyte infiltration.^3,4,13,14 In addition, studies have consistently demonstrated that colorectal cancers with MSI are associated with an improved prognosis compared with tumors with intact mismatch repair.^9,15-18 In contrast, the clinicopathologic significance of MSI in endometrial cancer has not yet been clarified.

From the period 1995 to 2004, we identified 13 publications^19-31 that reported on a range of 42 to 259 unselected endometrial carcinoma cases that included data on MSI status and any correlation with clinicopathologic characteristics of the cases. The most consistent findings were related to tumor grade and histology, with five studies^{19,20,26,28,29} reporting higher grade in MSI+ tumors compared with MSI– tumors and four studies^22,23,27,30 reporting no difference, while tumors of endometrioid histology were overrepresented among MSI+ tumors in three studies^21,22,24 and no correlation seen in one.²⁷ Neither age at diagnosis nor extent of myometrial invasion were associated with MSI status in seven^19-23,26,27 and four^20,26,27,30 studies, respectively. Two studies examined race and tumor MSI status, with one finding no assocation,²⁷ and a second finding a significantly increased incidence of MSI+ tumors, by multivariate analysis, in white patients.²⁴

More conflicting are reported associations of tumor MSI status with stage and clinical outcome. Disease stage was not significantly associated with MSI status in seven studies,^19-23,27,30 whereas MSI+ tumors were associated with advanced stage disease in two studies,^28,29 and with lower stage disease, by multivariate analysis, in one study.²⁴ With respect to clinical outcome, disease-free survival was not associated with MSI status in four studies,^24,25,28,29 but MSI+ tumors were associated with worse disease-free survival, by multivariate analysis, in one study.²⁶ In terms of overall survival, MSI+ tumors were associated with improved survival in one study,²⁷ but worse survival (although not independent of tumor grade) in another study,²⁰ and there was no correlation observed in six studies.^23-25,28-30 The purpose of this study was to perform a comprehensive investigation of the possible associations of all of these clinical and pathologic variables with tumor MSI status in a large group of unselected patients with endometrial carcinoma.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 
Study Participants
This study was approved by the institutional review board of the Memorial Sloan-Kettering Cancer Center (New York, NY). Endometrial carcinomas and corresponding nontumor tissues were obtained from 473 patients, unselected for age or personal or family history of cancer, treated at this institution from 1992 to 2003. The 946 nontumor and tumor tissue samples consisted of snap-frozen tissue and peripheral blood lymphocyte samples from 190 patients, and paraffin-embedded tissue samples from 283 patients. Only patients with carcinomas were included in the study. All patients underwent exploratory laparotomy for diagnosis and staging followed by adjuvant radiation and chemotherapy if indicated. Standard post-treatment surveillance included serial physical examination with Pap smears. Recurrence of disease was confirmed by biopsy. Clinical information was abstracted from hospital records and included age at diagnosis, race, surgical stage, adjuvant treatment, and disease status. The patients were staged according to International Federation of Gynecology and Obstetrics (FIGO) criteria. When complete surgical staging had not been performed, a clinical stage was assigned using FIGO criteria from 1971. All tumors were subjected to additional review by a gynecologic pathologist for tumor grade (based on 1994 WHO criteria), histologic subtype, depth of myometrial invasion, and presence of lymphovascular invasion.

DNA Isolation and Genotyping Procedures
DNA was isolated from formalin-fixed, paraffin-embedded tissue specimens after the tumor area was identified by a pathologist on hematoxylin and eosin–stained sections. Tumor cells and nontumor cells were macroscopically dissected with a discoid-cleoid instrument (American Eagle Instruments, Missoula, MT). Genomic DNA was isolated using a DNeasy Tissue Kit (Qiagen, Valencia, CA). Tumor DNA from frozen tissue specimens and corresponding normal DNA from peripheral blood lymphocytes were isolated in a similar fashion.

Paired DNA samples from endometrial carcinoma and nontumor tissues were genotyped for MSI using five microsatellite markers: BAT25, BAT26, D2S123, D5S346, D17S250. These markers were chosen on the basis of the consensus recommendation of the NCI workshop on the development of international guidelines for the evaluation of MSI in colorectal cancer.¹² Reactions for PCR amplification were carried out in a volume of 10 µL containing 50 ng of genomic DNA, and 200 µmol/L each deoxynucleotide triphosphate, 1.6 µmol/L each primer, 1 µL of 10x PCR buffer (Applied Biosystems, Foster City, CA), and 0.1 µL of Gold Taq polymerase (Applied Biosystems). The forward primer was end-labeled with [-³³P]. Amplification was then performed using a Perkin-Elmer (San Francisco, CA) 9600 thermal cycler with the following settings: 1 cycle at 95°C for 10 minutes, followed by 35 cycles at 95°C for 20 seconds, 55°C for 20 seconds, and 72°C for 30 seconds, and 1 cycle at 72°C for 7 minutes. PCR products were diluted 1:4 in denaturing loading buffer (95% formamide, 10 mmol/L EDTA [pH, 8.0], 0.02% xylene cyanol FF, and 0.02% bromphenol blue), heated at 95°C for 5 minutes, and placed on ice. Electrophoresis was performed in a 6% polyacrylamide gel for 2.5 hours at 80 W. Gels were dried and exposed to Hyperfilm MP autoradiography film (Amersham Corp, Louisville, CO) for 24 to 48 hours. Determination of MSI status was made according to the presence of mutant alleles in tumor DNA compared with nontumor tissue DNA. Tumors were classified as MSI+ if at least two (40%) of five markers displayed evidence of mutant alleles in tumor DNA when compared with nontumor tissue DNA.¹²

Statistical Analyses
Comparisons between MSI status and categoric clinicopathologic characteristics were performed using the ² test statistic. Test of association of MSI status and age was performed using the t test. Disease-free survival (DFS) was defined as time to progression of disease. Disease-specific survival (DSS) was defined as time to cancer-related death. To estimate DFS and DSS, competing risk methods were used to control for non–cancer-related deaths. Competing risks analysis was performed using Gray’s method.^32,33 The univariate hazard ratios were estimated using the competing risk model. For each end point, only those variables with a P value of less than .05 by Gray's method in univariate analysis were included in the initial multivariate model. The final model was determined by backward stepwise regression procedures using the Cox proportional hazards competing risk model including only the significant variables. Statistical analyses were performed using SAS Software (SAS Institute, Cary, NC) and the cmprsk R package (http://biowww.dfci.harvard.edu/gray).

	RESULTS

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Of 473 endometrial cancer patients included in the study, the mean age was 63 years (range, 27 to 89 years for those with MSI– tumors and 34 to 88 years for those with MSI+ tumors), with a median follow-up time for living patients of 5 years (range, 0.02 to 12.2 years). Clinical and pathologic information associated with these patients is summarized in Table 1. Ninety-three (20%) of 473 tumors were classified as MSI+. A representative example of MSI in an endometrial carcinoma is illustrated in Figure 1. After controlling for those clinicopathologic variables associated with MSI status, we did not observe a disproportionate ratio of MSI+ to MSI– cases in paraffin-embedded compared with frozen tissues.

View larger version (30K): [in this window] [in a new window]   Fig 1. Representative examples of microsatellite instability (MSI) in endometrial carcinoma. Shown are autoradiographic images of polymerase chain reaction (PCR) products after gel electrophoresis, demonstrating MSI at the five microsatellite markers used in this study: (A) BAT 25, (B) BAT 26, (C) D17S250, (D) D2S123, (E) D5S346. N, PCR product from nontumor tissue DNA; T, PCR product from corresponding tumor DNA. The arrows to the right indicate product mobility shifts characteristic of MSI.

View larger version (10K): [in this window] [in a new window]   Fig 2. Disease-free survival by microsatellite instability (MSI) status. Solid black, disease progression, MSI–; solid red, disease progression, MSI+; dashed black, non–disease-specific death, MSI–; dashed red, non–disease-specific death, MSI+.

View larger version (10K): [in this window] [in a new window]   Fig 3. Disease-specific survival by microsatellite instability (MSI) status for all patients. Solid black, disease-specific death, MSI–; Solid red, disease-specific death, MSI+; dashed black, non–disease-specific death, MSI–; dashed red, non–disease-specific death, MSI–.

View larger version (8K): [in this window] [in a new window]   Fig 4. Disease-specific survival by microsatellite instability (MSI) status for advanced stage disease patients. Solid black, disease-specific death, MSI–; Solid red, disease-specific death, MSI+; dashed black, non–disease-specific death, MSI–; dashed red, non–disease-specific death, MSI+.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

Although the clinical and pathologic features commonly associated with colorectal cancers arising from defective DNA mismatch repair are relatively well established, the available data related to endometrial carcinomas affected by this molecular genetic alteration remain equivocal, as discussed in the Introduction. The present study represents the largest series of MSI-genotyped endometrial cancer patients reported to date, and revealed several significant clinicopathologic relationships. There were significant associations of MSI+ tumors with myometrial invasion and advanced pathologic stage. It is not readily apparent why myometrial invasion and advanced stage would correlate with MSI+ tumor status, the latter of which is an independent predictor of improved prognosis, when myometrial invasion and advanced stage are both independent predictors of poor prognosis. However, this observation is analogous to that made with respect to MSI+ colorectal carcinomas, which also have an improved prognosis compared with MSI–tumors, and are more likely to present with a significantly greater depth of tumor invasion.¹⁷

Among the other clinicopathologic features examined, there was a strong association of MSI with endometrioid histology, a relationship that has been noted consistently in studies that examined this characteristic.^21,22,24 This is one factor that contributes to the general consensus that MSI+ endometrial carcinomas are appropriately classified as type I tumors.² No significant associations were observed between MSI status and age, tumor grade, race, or lymphovascular invasion.

Although the data on colorectal carcinomas clearly indicate an improved prognosis for patients with MSI+ tumors, there are fewer data on the impact of this molecular alteration on prognosis from endometrial cancer, and those that have been reported are equivocal. In this study, multivariate analyses indicated that the presence of tumor MSI was an independent predictor of improved DFS and DSS. For DSS, the substantial reduction in hazard ratio associated with MSI+ tumor status appeared to be driven by a strong effect on advanced-stage cases; when the data were analyzed separately according to early or advanced stage, tumor MSI status lost prognostic significance for early-stage tumors. Not unexpectedly, other well-established risk factors for endometrial cancer also achieved independent prognostic significance in this study, including tumor grade, stage, and presence of myometrial invasion for DFS, and tumor grade and stage for DSS. These data on improved prognosis associated with MSI+ tumors warrant a discussion of the mechanistic rationale for this phenomenon.

There are at least two potential, and possibly overlapping, genetic explanations for this association. Genetic instability is believed to represent a hallmark of most human cancers, and MSI (also known as MIN) is one of two well characterized forms of genetic instability, the other being chromosomal instability (CIN), which leads to aneuploidy.^34,35 These defects in the maintenance of genetic stability occur in a mutually exclusive fashion with high frequency in colorectal and other cancers, including endometrial carcinoma. Unlike cancers affected by CIN that develop aneuploidy, cancer cells that display MSI invariably have a diploid or near-diploid karyotype, but a nucleotide mutation rate two to three orders of magnitude higher than in mismatch repair proficient cells.^36-39 Although some form of genetic instability is a likely requirement for cells to overcome the many intrinsic cellular barriers to neoplastic progression, the accumulated MSI-induced damage to the genome that ensues after many cancer cell divisions may ultimately rise above the threshold for cell viability, leading to the activation of apoptotic pathways or perhaps increased susceptibility to particular antineoplastic therapeutic agents.⁴⁰ Thus, cancer cells with defective mismatch repair may behave in a more indolent fashion and/or ultimately lose their evolutionary fitness for survival before the host dies as a result of disease.

A related hypothesis is that MSI+ endometrial cancers acquire a unique spectrum of additional somatic molecular genetic alterations that contributes to a less aggressive biologic behavior in this class of tumors. Among the well-characterized somatic mutations that occur in endometrial tumorigenesis, mutation and/or overexpression of the TP53 gene, hallmarks of type II endometrial cancers and associated with a poor prognosis, are consistently low or absent in MSI+ endometrial carcinomas.^22,27,41-43 Conversely, mutational inactivation of the PTEN tumor suppressor gene, generally associated with type I endometrial cancers and an improved prognosis, is more common in endometrial cancers with MSI.^27,41,43-45 Mutational activation of the KRAS oncogene, which has proven more difficult to classify with respect to relative incidence in type I versus type II endometrial cancers, is similarly subject to inconsistent correlation with MSI status; three studies found no correlation,^20,43,45,46 whereas two reported a higher frequency in MSI+ tumors.^42,47 Mutation in the CTNNB1 gene, encoding ß-catenin, is consistently reported not to correlate with MSI status in endometrial cancers.^45,48,49

Finally, it is axiomatic that MSI+ endometrial cancers have a high frequency of inactivating frameshift mutations in genes with coding region microsatellite repeats (eg, TGFßRII, IGFIIR, BAX), and that this may represent the major mechanism through which MSI contributes to tumorigenesis.^43,50 However, there are a large number of such genes in the genome, and it is not clear which of these, when mutated, play a causal or bystander role in tumorigenesis.⁵¹ A statistical meta-analysis of MSI+ human cancers revealed that most of the putative targets of MSI are probably bystanders, and that for endometrial carcinoma, the most highly-ranked Real Common Targets of MSI are TAF1B, AIM2, and SLC23A1.⁵² In addition, the ATR (ataxia telangiectasia and Rad3-related) gene was recently shown to undergo frameshift mutations in MSI+ endometrial tumors, with the functional consequence of abrogation of ATR-dependent Chk1 phosphorylation and cell cycle arrest following DNA damage.⁵³

With respect to DNA content and global gene expression profiles, all studies that have examined the correlation of ploidy with MSI status consistently find that MSI+ tumors are predominantly diploid,^{30,43,45,49,54} and conversely, that aneuploid endometrial cancers do not exhibit MSI, consistent with the MSI (MIN)/CIN dichotomy observed in colorectal carcinoma.^34,35 The unsupervised analysis of global gene expression profiles of early stage endometrioid endometrial carcinomas reveals two distinct classes of tumors that segregate according to MSI status, implicating the alterations of discrete molecular pathways in these two categories of tumors.⁵⁵

In summary, the existing literature together with data from this report provide sufficient evidence to warrant the inclusion of a majority of MSI+ tumors in the type I category of endometrial carcinomas and further, to conclude that MSI+ endometrial tumors have a unique biologic behavior compared with MSI–tumors. The classification of MSI as an independent prognostic variable is one of a very small number of instances in which a specific molecular marker has achieved this standard in endometrial carcinoma, and this finding warrants further study with respect to translational potential in the clinical management of this disease.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 

Conception and design: Destin Black, Douglas A. Levine, Amanda J. Hummer, Jeff Boyd Financial support: Richard R. Barakat, Jeff Boyd Administrative support: Richard R. Barakat, Jeff Boyd Provision of study materials or patients: Robert A. Soslow, Douglas A. Levine, Carmen Tornos, Shirley C. Chen, Narciso Olvera, Richard R. Barakat Collection and assembly of data: Destin Black, Robert A. Soslow, Carmen Tornos, Shirley C. Chen, Faina Bogomolniy, Narciso Olvera Data analysis and interpretation: Destin Black, Robert A. Soslow, Douglas A. Levine, Carmen Tornos, Shirley C. Chen, Amanda J. Hummer, Faina Bogomolniy Manuscript writing: Destin Black, Amanda J. Hummer, Jeff Boyd Final approval of manuscript: Destin Black, Robert A. Soslow, Douglas A. Levine, Carmen Tornos, Shirley C. Chen, Amanda J. Hummer, Faina Bogomolniy, Narciso Olvera, Richard R. Barakat, Jeff Boyd

 

	GLOSSARY

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions GLOSSARY REFERENCES

 
HNPCC (hereditary nonpolyposis colorectal cancer): Accounting for 5% of all colorectal cancer, HNPCC arises due to a hereditary defect in one of the mismatch repair genes. Cancer of the uterus (ie, womb or endometrium), gastrointestinal tract (ie, stomach, small intestine, or pancreas), urinary system (ie, kidney or ureter), and female reproductive organs (ie, ovary) may be cancers seen in some HNPCC families. A family history, colon examination, and genetic testing for mutations in DNA mismatch repair genes are helpful in identifying HNPCC.

Microsatellite instability: Microsatellites are repeating units in DNA of 1–5 basepairs that are ubiquitous, abundant, and repeated several times in eukaryotic genomes. The presence of microsatellites is associated with genomic instability, giving rise to mutations that involve the addition or subtraction of one or two repeat units.

Mismatch repair: One of four major pathways of DNA repair in mammalian cells. Mismatch repair recognizes and corrects errors in DNA replication leading to single base-pair mismatches or insertions/deletions in small repetitive tracts of DNA known as microsatellites.

Oncogene: Oncogenes are normal cellular genes whose protein products may function in any number of critical molecular pathways (and are referred to as proto-oncogenes when functioning in a nonmutated state) that are subject to activating, or gain-of-function mutations, which stimulate tumorigenesis.

Tumor suppressor gene: The products of tumor suppressor genes normally function to inhibit aspects of the neoplastic phenotype, and are subject to inactivating, or loss-of-function mutations, which contribute to tumorigenesis.

	NOTES

 
Supported by Grant No. R01 CA100272 from the National Institutes of Health, Bethesda, MD.

Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted September 6, 2005; accepted December 19, 2005.

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