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[Cancer Research 61, 2124-2128, March 1, 2001]
© 2001 American Association for Cancer Research

Molecular Biology and Genetics

Microsatellite Instability Occurs in Distinct Subtypes of Pediatric but not Adult Central Nervous System Tumors1

Michelle Alonso, Richard Hamelin, Mimi Kim, Kara Porwancher, Tammy Sung, Preeti Parhar, Douglas C. Miller and Elizabeth W. Newcomb2

Departments of Pathology [M. A., K. P., T. S., P. P., D. C. M., E. W. N.] and Environmental Medicine [M. K.], Division of Neuropathology [D. C. M.], and the Kaplan Comprehensive Cancer Center [M. K., D. C. M., E. W. N.], New York University School of Medicine, New York, New York 10016, and Institut National de la Santé et de la Recherche Médicale U434-Centre d’Etude de Polymorphisme Humane, 75010 Paris, France [R. H.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Length alterations in microsatellite repeats, termed microsatellite instability (MSI), are found in 10–15% of sporadic colon, endometrial, and gastric cancers harboring defects in DNA mismatch repair (MMR) genes. We used the microsatellite markers Big Adenine Tract (BAT) 26 and BAT-25 from the reference panel of five markers recommended by the National Cancer Institute to evaluate the incidence of MSI in 206 central nervous system tumors. We screened 102 pediatric and 104 adult cases representing 165 astrocytic and 41 nonastrocytic tumors. The overall incidence of MSI was 8% (16 of 206). All 16 tumors with MSI were found in pediatric rather than adult patients. MSI was associated with two distinct subtypes of pediatric tumors occurring in 27% (12 of 45) of WHO grade III and grade IV astrocytomas and 24% (4 of 17) of gangliogliomas. We evaluated the difference in clinicopathological and genetic features among 45 high-grade pediatric astrocytomas by MSI status. The median survival for pediatric patients with MSI (n = 12) was 8 months compared with 15 months for those patients without MSI (n = 33; P = 0.18). The frequency of p53 gene mutations was 13% for pediatric patients with MSI (n = 8) compared with 47% for those patients without MSI (n = 19; P = 0.19). These results revealed a trend between MSI status and prognosis and MSI status and frequency of p53 gene mutations. Our data suggest that pediatric high-grade astrocytomas can be attributed to two different genetic pathways: a MMR-deficient pathway and a MMR-proficient pathway.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Microsatellites are short, tandemly repeated nucleotide sequences that are widely distributed throughout the genome (1) . Length alterations in mono-, di-, tri-, tetra-, and pentanucleotide repeats, termed MSI3 , are used as a diagnostic criterion of the defective RER phenotype. Defective RER is most commonly caused by a deficiency of DNA MMR attributable to mutation in one of the human DNA MMR genes: hMLH1, hMSH2, hMSH3, hMSH6, hPMS1, and hPMS2 (2, 3, 4, 5, 6, 7, 8) . Because of their repetitive nature, microsatellites are particularly prone to errors during replication. Thus, the RER phenotype, characterized by frequent somatic variations in the size of microsatellites in tumor DNA, results in MSI (9) .

MSI was initially described in a minority (~15%) of nonselected colon tumors (9 , 10) and in a majority (>90%) of HNPCC tumors (11) . MSI has also been described in other sporadic tumors such as gastric and endometrial cancers (8 , 12) . Nonselected tumors necessarily contain both sporadic and hereditary cases, if a sufficient number is analyzed. Several studies have assessed gliomas for MSI using different panels of microsatellite loci, with conflicting results concerning the prevalence of the RER phenotype: reported incidences ranged from 1.8 to 45% (13, 14, 15, 16, 17) . The difference in frequency of MSI noted in gliomas among these studies may be related to the sensitivity of the methods used to detect the status of MSI.

To assess the incidence of MSI in tumors of the CNS for which we did not have matching normal DNA, we used the mononucleotide microsatellite markers BAT-26 and BAT-25 from the reference panel of five markers recommended by the NCI Workshop on International Criteria for the Determination of Microsatellite Instability (12) . Recent studies have shown that deletions within the mononucleotide microsatellite marker BAT-26, a poly(A) tract localized within intron 5 of the hMSH2 gene, is sufficient to establish the MSI status of most tumors in the absence of matching germline DNA (18, 19, 20) . Deletions in BAT-26 were examined in 542 tumors from various organs, including colorectal, gastric, and endometrial cancers that had previously been assessed for MSI using di- and tetranucleotide microsatellite repeat markers; the MSI status was identified by BAT-26 deletion unambiguously in 99% (539 of 542) of the tumors (19) . A recent study using BAT-26 as one of five microsatellite markers to evaluate MSI in 22 gliomas from a selected subgroup of young adult Chinese patients found that 18% (4 of 22) showed high rates of instability at >40% of microsatellites tested, and all of these tumors showed deletions in BAT-26 (21) . These results suggest that deletions in the BAT-26 marker can be used to define MSI in tumors of the CNS, as has been documented in other cancers (18 , 19) .

By using the microsatellite markers BAT-26 and BAT-25, tumors can be categorized as having MSI if both of the markers show variation in length. The aims of this study were (a) to evaluate a large series of primary tumors of the CNS for the incidence of MSI; (b) to compare the MSI status in adult and pediatric CNS tumors; (c) to determine the clinicopathological and genetic features associated with MSI-positive tumors; and (d) to determine the relevance of MSI to patient prognosis.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tumor Samples.
Tumor samples were obtained from 206 patients who had surgery at New York University School of Medicine between 1977 and 1995. Histopathological grading for astrocytomas used the revised WHO classification scheme except that necrosis was required for a diagnosis of glioblastoma (22) . This study included 165 astrocytic [12 grade I (all pilocytic), 10 grade II, 48 grade III, and 95 grade IV] and 41 nonastrocytic tumors (17 gangliogliomas, 5 neurocytomas, and 3 ganglioglioneurocytomas, 10 PNETs, 3 ependymomas, 1 meningioma, 1 anaplastic oligoastrocytoma, and 1 fibrosarcoma) from 102 pediatric (<21 years of age) and 104 adult patients. Histological evaluation of the tumor sections estimated that tumor samples consisted of >90% tumor cells. DNA was extracted from frozen or paraffin-embedded tissues as previously described (23 , 24) .

DNA Amplification by PCR.
PCR was performed using a 1-µl sample of DNA in 10 µl of reaction mixture containing 10 mM Tris (pH 8.3), 1.5 mM MgCl2, 50 mM KCl, 200 µM dNTPs, 0.5 U of Platinum Taq polymerase (Life Technologies, Inc., Rockville, MD), 1.0 µmol of each primer, and 0.02 µmol of the forward primer labeled with [{gamma}-32P]dATP (NEN Life Science Products, Boston, MA) using T4 polynucleotide kinase (Life Technologies, Inc.). The PCR conditions for amplification of BAT-26 and BAT-25 primers used an initial denaturation at 95°C for 10 min followed by 40 cycles consisting of denaturation at 95°C for 1 min, annealing at 60°C for 1 min, and extension at 72°C for 1 min. A final extension cycle at 72°C for 10 min was performed for completion of all of the PCR reactions.

The primer sequences for amplification were as follows: BAT-26: sense, 5'-TGACTACTTTTGACTTCAGCC-3'; antisense, 5'-AACCATTCAACATTTTTAACCC-3', which amplify a 121-bp DNA fragment containing a poly(A)26 tract of intron 5 of the hMSH2 gene (25) and BAT-25: sense, 5'-TCGCCTCCAAGAATGTAAGT-3'; antisense; 5'-TCTGCATTTTAACTATGGCTC-3', which amplify a 125-bp DNA fragment containing a poly(A) tract of an intron in the c-kit oncogene (25) .

Analysis of Microsatellite Markers.
The PCR products were denatured by heating for 15 min at 95°C in formamide loading buffer (94% formamide, 0.05% bromphenol blue, 0.05% xylene cyanol, 20 mM EDTA, 0.08 M NaOH), cooled on ice for 20 min and loaded onto a 6% (for BAT-26) or 8% (for BAT-25) denaturing polyacrylamide gel (Life Technologies, Inc.). Gels were run on a sequencing electrophoresis apparatus (Life Technologies, Inc.) at room temperature for ~2 h 30 min at 65 W without cooling. Gels were dried for 30 min at 80°C on a gel dryer (Bio-Rad, Hercules, CA). Radiolabeled DNA fragments were visualized using a Bio-Rad Personal Molecular FX apparatus with Quantity One (Version 4.0.3) software.

Detection of Microsatellite Instability.
The presence or absence of MSI was based on the detection of length alterations in both of the mononucleotide microsatellite markers BAT-26 and BAT-25. The colon cancer cell line, LS174T, and four primary colon tumors previously scored as MSI served as positive controls for deletions in both markers (26) . The glioma cell line, U87 MG, in which both microsatellite markers remained unaltered in length, served as a negative control. Tumor samples were scored positive for MSI if the tumors exhibited additional, faster migrating BAT-26 and BAT-25 bands that demonstrated deletions in both of these microsatellite markers. Experiments to ascertain MSI were done independently two to three times for each genetic locus.

Immunohistochemistry.
Tumor tissue from 15 high-grade spinal cord astrocytomas were immunostained and evaluated for levels of expression of p53, MDM2, p16INK4a, and EGFR proteins as described (27) . The immunohistochemistry and p53 gene mutation data for the 27 high-grade pediatric astrocytomas have been reported previously (28) .

Statistical Analysis.
Proportions were compared between groups using Fisher’s exact test, and continuous variables were compared using the two-sample t test. For the survival analysis, duration of follow-up was defined as the interval from initial diagnosis through patient death or the last official contact (scheduled follow-up or personal contact) as of July 1999. Survival distributions were estimated according to the method of Kaplan and Meier and compared by means of the log-rank test.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Frequency of MSI in Tumors of the CNS.
We screened 102 pediatric and 104 adult tumors representing 165 astrocytic and 41 nonastrocytic tumors of the CNS for deletions in the mononucleotide microsatellite markers BAT-26 and BAT-25. Figure 1Citation shows representative tumor DNAs with and without length alterations for both the BAT-26 and BAT-25 microsatellite markers. The overall frequency for MSI was 8% (16 of 206; Table 1Citation ). A similar incidence for MSI occurred in 7% (12 of 165) of astrocytic as well as 10% (4 of 41) of nonastrocytic tumors (P = 0.53). A significant association was found between younger age and the presence of MSI. Among high-grade astrocytic tumors, no adult patients showed MSI compared with an incidence of 27% (12 of 45) in pediatric patients (P < 0.001).



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  		Fig. 1. Detection of MSI in CNS tumors. Tumor DNAs were screened for length alterations in both of the mononucleotide microsatellite markers BAT-26 and BAT-25. Primary colon tumor samples (H1, H2, H3, and H4), previously scored for MSI, served as positive controls (26) . The control (C) consisted of 20% DNA from the MSI colon carcinoma cell line LS174T and 80% DNA from the glioblastoma cell line U87 MG without MSI to monitor the sensitivity of detection of BAT-26 and BAT-25 bands showing altered mobility in primary CNS tumor samples. Tumor samples were scored positive for MSI if the tumors exhibited additional, faster migrating BAT-26 and BAT-25 bands indicating deletion in that microsatellite marker. Arrowheads, position of wild-type and mutant BAT-26 and BAT-25 PCR products demonstrating a characteristic ladder of bands that differ in size by 1 bp. Note that the four primary MSI colon tumor samples, H1–H4, show mutant BAT-26 and BAT-25 PCR products that differ in length from each other, demonstrating that BAT deletions may be unique for a given tumor. Representative pediatric CNS tumors scored with MSI (P18, SC2, SC4, SC10, SC11, GG1, and GG4) showed deletions in both BAT-26 and BAT-25 microsatellite markers compared with those tumors scored without MSI (P17 and P134).

 

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  		Table 1 Frequency of MSI in tumors of the central nervous system

 
Among nonastrocytic tumors, there were 37 pediatric and 4 adult cases screened for MSI. Twenty-four percent (4 of 17) of the gangliogliomas were positive for BAT-26 and BAT-25 deletions. The 4 tumors occurred in pediatric patients ranging in age from 1 to 11 years. No deletions of BAT-26 and BAT-25 were detected in 24 other nonastrocytic tumors including 10 PNETs, 5 neurocytomas, 3 ganglioglioneurocytomas, 3 ependymomas, a meningioma, an anaplastic oligoastrocytoma, and a fibrosarcoma (Table 1)Citation . Presence of MSI was associated with younger age in the nonastrocytic tumors because no adult showed deletions of BAT-26 and BAT-25 (0 of 4) compared with 11% (4 of 37) of the pediatric patients. However, this difference was not statistically significant (P = 1.00) because of the small sample size.

Clinicopathological and Genetic Features of Pediatric High-grade Astrocytic Tumors by MSI Status.
Table 2Citation gives the clinicopathological and genetic features of each of the 12 MSI high-grade astrocytic tumors. Figure 2Citation shows the Kaplan-Meier survival estimates. The median survival among patients with MSI (n = 12) was 8 versus 15 months for the patients without MSI (n = 33; P = 0.18).


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  		Table 2 Profile of genetic alterations in the MSI pediatric high-grade astrocytic tumors

 


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  		Fig. 2. Kaplan-Meier plot for survival of pediatric patients with high-grade astrocytomas by MSI status. Survival of patients with (solid line; n = 12) or without (broken line; n = 33) MSI.

 
Tumor tissue from 42 pediatric high-grade astrocytomas were evaluated for p53 gene mutations and levels of expression of EGFR, MDM2, and p16INK4a proteins using immunohistochemistry as described (27) . The results for p53 gene mutations, EGFR and MDM2 protein overexpression, and loss of p16INK4a expression have been reported previously for 27 cases (28) . The frequency of p53 gene mutation was 13% (1 of 8) for pediatric patients with MSI compared with 47% (9 of 19) of those patients without MSI (P = 0.19). For other clinical and genetic parameters such as gender, age, and levels of protein expression for EGFR, MDM2, and p16INK4a, no statistical significance was observed by MSI status (data not shown).


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Several studies have assessed gliomas, mainly adult fibrillary astrocytomas, for MSI using different panels of microsatellite loci with conflicting results. One aim of this study was to evaluate CNS tumors for the incidence of MSI using the microsatellite markers BAT-26 and BAT-25 from the reference panel of five markers recommended by the NCI for determining MSI (12) . In this study, the presence or absence of MSI was based on the detection of bands with altered mobility, which indicate a deletion in both of the mononucleotide microsatellite markers BAT-26 and BAT-25. Recent studies suggest that in most instances in the absence of normal DNA, MSI can be determined by the analysis of a single microsatellite marker, BAT-26 (18, 19, 20) . However, among healthy individuals of African origin, a polymorphic variation results in length alterations of BAT-26 and BAT-25 in ~3% of individuals at both loci (29) . As far as we could determine, none of our patients were of African origin. We screened 102 pediatric and 104 adult tumors of the CNS for MSI. The overall incidence of MSI was 8% (16 of 206). There was a significant association between MSI status and patient age among both astrocytic and nonastrocytic tumors. Among patients with high-grade astrocytic tumors, no MSI was detected in adults compared with MSI in 27% (12 of 45) of pediatric patients (P < 0.001). Among patients with nonastrocytic tumors, no adult showed deletions of BAT-26 and BAT-25 (0 of 4) compared with deletions of BAT-26 and BAT-25 in 11% (4 of 37) of pediatric patients (P = 1.00).

MSI was present in two pediatric tumor subtypes: 27% (12 of 45) of high-grade astrocytomas and 24% (4 of 17) of gangliogliomas. Only three other studies have looked at these tumor subtypes. One reported screening 22 pediatric high-grade astrocytomas for MSI and finding an incidence of 9% (2 of 22; Ref. 30 ), another reported screening 6 pediatric high-grade astrocytomas for MSI and finding an incidence of 33% (2 of 6; Ref. 31 ), and a third reported screening 6 gangliogliomas for MSI, all from adults, and finding none positive for MSI (15) .

Among the 16 MSI tumors, 12 were pediatric high-grade astrocytomas arising in patients ranging in age from 3 to 19 years (mean, 10.9 years). Turcot’s syndrome is a rare hereditary disease affecting children and young adults that is characterized by the presence of a brain tumor followed by the appearance of colorectal cancer (32 , 33) . Recent genetic studies have stratified Turcot’s syndrome patients into two distinct clinical subtypes based on the kind of colorectal cancer polyp and the type of brain tumor detected (33) . One clinical subtype consists of patients with a median age of 18 years who present with glioblastoma multiforme and colorectal adenomas with polyposis (non-FAP cases). Tumors from these patients show MSI similar to those from HNPCC patients with germline mutations in the DNA MMR genes hMSH2, hMLH1, and hPMS2 (32, 33, 34) . Since 1949 there have been only 160 cases of Turcot’s syndrome reported (22) . Given the extreme rarity of glioblastomas associated with this syndrome, it is highly unlikely that the 12 cases of pediatric high-grade astrocytomas with MSI identified in this study are attributable to Turcot’s syndrome.

Another aim of this study was to evaluate the clinicopathological and genetic features of the 45 pediatric high-grade astrocytomas by MSI status. Some of the clinical features associated with MSI colon and gastric cancers are less frequent lymph node metastases, decreased wall invasiveness, and lower clinical aggressiveness of tumor growth with improved prognosis (35, 36, 37) . We found that the median survival for pediatric patients with MSI (n = 12) was 8 months compared with 15 months for those patients without MSI (n = 33; P = 0.18). These results indicate a trend between MSI status and prognosis. A much larger study will be required to further examine the relevance of MSI status to prognosis of pediatric patients with high-grade astrocytomas.

Studies of colorectal cancer have found that MSI status and p53 mutations are mutually exclusive genetic events (10 , 38 , 39) . In this study, we found the frequency of p53 gene mutations was 13% for pediatric patients with MSI (n = 8) compared with 47% for those patients without MSI (n = 19; P = 0.19). This result reveals a trend between the presence of MSI and absence of p53 gene mutations, consistent with findings in other MSI tumors (38 , 39) .

Various sporadic cancers have been screened for MSI using criteria similar to the NCI panel of markers (12) . Table 3Citation is a review of the published literature of sporadic tumors evaluated for MSI. For adult tumors of the CNS, MSI has been reported in 2% of astrocytic and nonastrocytic CNS tumors (13, 14, 15 , 17 , 19 , 40, 41, 42, 43) . Thus, CNS tumors in adults show a low to zero incidence of MSI (15 , 17 , 19 , 40 , 42 , 43) . In contrast, for pediatric tumors of the CNS, MSI has been reported in 21% of astrocytic and 11% of nonastrocytic tumors (30 , 31) . MSI occurs in 10–15% of sporadic colon (19 , 44, 45, 46, 47, 48, 49, 50) , endometrial (51, 52, 53) , and gastric (35 , 54 , 55) cancers compared with <5% of sporadic prostate (19 , 56 , 57) , breast (44 , 58) , esophageal (59 , 60) , lung (55 , 61 , 62) , and melanoma (63) tumors.


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  		Table 3 Frequency of MSI in sporadic tumors

 
In summary, we have identified two distinct subtypes of pediatric CNS tumors that exhibit a high frequency of MSI compared with other sporadic cancers (Table 3)Citation . Overall, MSI occurred in 27% (12 of 45) of pediatric high-grade astrocytomas and 24% (4 of 17) of gangliogliomas. Future studies will investigate the genetic mechanism(s) associated with MSI in these tumors. Such mechanisms might include inactivating mutations of the MMR genes hMLH1 or hMSH2, promoter methylation of hMLH1, mutations leading to a dominant negative phenotype as has been demonstrated for the hPMS2 gene (4) , or an imbalance in the levels of expression of one of the MMR genes such as hMSH3 (64) , all of which result in MMR deficiencies. Glioblastoma formation in the adult has been attributed to two main genetic pathways: the p53-dependent "progressive" pathway ("secondary glioblastoma") versus the p53-independent "de novo" pathway ("primary glioblastoma"; Refs. 24 , 27 , and 65 ). Using molecular genetic approaches, the constellation of altered target genes underlying the pathogenesis of different adult tumor variants are becoming known and thus can be exploited as potential therapeutic targets. In this study, we show that formation of high-grade astrocytomas in pediatric patients can be attributed also to two different genetic pathways: a MMR-deficient pathway versus a MMR-proficient pathway. A challenge for the future will be to identify the genetic differences between these pediatric astrocytoma tumor variants.


   ACKNOWLEDGMENTS
 
We thank Drs. George Teebor and Vittorio Defendi for helpful discussions and advice.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by the Children’s Brain Tumor Foundation (to E. W. N.). Back

2 To whom requests for reprints should be addressed, at Department of Pathology, New York University School of Medicine and Kaplan Comprehensive Cancer Center, New York, NY 10016. Phone: (212) 263-8757; Fax: (212) 263-8211; E-mail: newcoe01{at}med.nyu.edu Back

3 The abbreviations used are: MSI, microsatellite instability; RER, replication error repair; MMR, mismatch repair; HNPCC, hereditary nonpolyposis colorectal cancer; CNS, central nervous system; BAT, Big Adenine Tract; poly(A), polyadenine; NCI, National Cancer Institute; FAP, familial adenomatous polyposis; MDM2, mouse double minute-2; EGFR, epidermal growth factor receptor. Back

Received 12/20/99. Accepted 12/22/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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