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Departments of Medical Genetics [A. L., K. E., P. L., R. S., P. K., V. L., L. A. A.] and Pathology [R. S.], Biomedicum Helsinki, FIN-00014 University of Helsinki, Finland; Second Department of Surgery, Helsinki University Central Hospital, FIN-00029 Helsinki, Finland [H. J.]; Department of Surgery, Jyväskylä Central Hospital, FIN-40620 Jyväskylä, Finland [J-P. M.]; and Department of Oncology, Helsinki University Central Hospital, FIN-00029 Helsinki, Finland [L. A. A.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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A total of 85–90% of HNPCC patients show MSI, and this proportion is even higher in mutation-positive families (7 , 11 , 12) , whereas only 10–15% of sporadic colorectal tumors do so (7, 8, 9) . Thus, MSI is a relatively sensitive but unspecific marker for HNPCC. In 1997, the International Workshop on MSI and RER Phenotypes in Cancer Detection and Familial Predisposition proposed a panel of five microsatellite markers to be used in MSI analysis (13) . For the purpose of providing some uniformity, two mononucleotide repeats (BAT25 and BAT26) and three dinucleotide repeats (D2S123, D5S346, and D17S250) were recommended. Using this reference panel (known as the Bethesda markers), tumors with instability in two or more markers are defined as MSI-H, tumors with instability in one marker are defined as MSI-L, and tumors in which none of the markers exhibit MSI are defined as MSS. Arguments in favor of combining the MSI-L and MSS groups include the facts that the baseline mutation rate for microsatellites in apparently stable CRCs is not precisely known and that the clinical features in the two groups are similar (14 , 15) . The distinction between these two groups is dependent on both the type and the number of microsatellites analyzed. If a large number of markers are used, all CRCs may exhibit some level of MSI (13) .
Nevertheless, MSI-L CRCs seem to be distinct from both MSI-H and MSS CRC. They appear to have more in common with MSS cancers (16) , although they can be distinguished on the basis of a higher frequency of K-ras mutations (16 , 17) and reduced expression of BCL-2 (16 , 18) . MSI-L may represent a subtype of CRC combining features of the common chromosomal instability and mild mutator pathways (16 , 19) . However, MLH1 and MSH2 do not appear to be implicated in the MSI-L subset (20, 21, 22) ; thus, for the purpose of identifying patients with defects in these two genes, MSI-L and MSS cases may not need to be distinguished.
BAT26 has some advantages over many other markers in MSI analysis. It is extremely sensitive in detecting tumors with instability (20 , 23, 24, 25, 26) and shows negligible size variation either between both alleles of one individual or among individuals (23) . Several studies support the use of BAT26 on tumor DNA alone (23 , 24 , 27) . However, a germ-line polymorphism in the BAT26 locus has been detected in 7.7–12.6% of African Americans (26 , 28) and in 0.8% of Caucasians (26) . The presence of allelic variations, although rare in some populations, emphasizes the need for matching normal DNA in MSI-positive cases to avoid misclassifications.
This work was performed to test MSI analysis using the Bethesda panel of five markers in a series of 494 CRCs including 27 patients with identified MLH1 or MSH2 mutations. This series is part of a larger population-based study (24 , 29) . The MSI status of these samples had already been determined using BAT26 alone. The aim of this study was to evaluate the possible benefit of using the Bethesda set, as compared with using BAT26 alone, to identify MLH1 or MSH2 mutation-positive HNPCC patients.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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MSI Analysis.
All 494 samples had already been analyzed for MSI using BAT26 and tumor DNA (24
, 29)
. In this study, these tumor DNAs and respective normal tissue DNAs were used to independently study MSI status using five fluorescence-labeled microsatellite markers (BAT25, BAT26, D2S123, D5S346, and D17S250, the Bethesda panel). Primer sequences are presented in Table 1
. PCR reactions were carried out in a 10-µl reaction volume containing 50–100 ng of genomic DNA, 1x PCR buffer (Perkin-Elmer Applied Biosystems Division, Foster City, CA), 250 µM each deoxynucleotide triphosphate (Finnzymes, Espoo, Finland), 0.5 µM each primer, and 1 unit of AmpliTaq Gold polymerase (Perkin-Elmer). The MgCl2 concentration was 2.5 mM for BAT25 and 2.75 mM for BAT26, D2S123, D5S346, and D17S250. The PCR cycles for each marker are indicated in Table 1
. Predenaturation was performed at 95°C for 10 min, and final extension was performed at 72°C for 10 min in all reactions. PCR products were loaded on a 5% Long Ranger 6 M urea gel (FMC BioProducts, Rockland, ME) and run in an ABI PRISM 377 DNA Sequencer (Perkin-Elmer) according to the manufacturer’s instructions. The data were collected automatically and analyzed by GeneScan 3.1 software (Perkin-Elmer).
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In 16 cases, the distinction between MSI-positive and MSS in individual markers was difficult to perform visually, and in these cases, a previously described (30) mathematical model for the calculation of a RER score was used. The RER or MSI score was calculated individually for each dinucleotide marker and used to determine the MSI status of each marker separately. A MSI score of 25% or higher was used as a cutoff level for positivity (30) .
Immunohistochemistry.
Immunohistochemistry for MLH1, MSH2, and MSH6 was performed for MSI-L cases and novel MSI-H cases. Paraffin-embedded surgical resection specimens were collected from the files of pathology departments in different hospitals.
The tissue sections were mounted on ChemMate Capillary Gap microscopy slides (DAKO A/S, Glostrup, Denmark; BioTek Solutions) and dried at 37°C. The sections were deparaffinized in xylene and rehydrated through a graded alcohol series to distilled water. The samples were then microwaved at high power four times (5 min each) in citrate buffer and then cooled and washed in PBS.
The following monoclonal antibodies were used: (a) MLH1 (clone G168-15; catalogue number 13271; PharMingen); (b) MSH2 (clone FE 11; catalogue number NA27; Oncogene Sciences); and (c) MSH6 (clone 44; G70220; Transduction Laboratories). For immunohistochemical analysis, avidin-biotin complex immunoperoxidase technique was performed by using a commercial ChemMate detection kit (DAKO A/S) in a Techmate automate machine. Endogenous peroxidase was blocked by incubation in hydrogen peroxide with methanol. Incubation with nonimmune horse serum was followed by incubation with primary antibody. The sections were then incubated in biotinylated second antibody and peroxidase-labeled avidin-biotin complex. All dilutions were made in PBS (pH 7.2). The stainings were visualized with diaminobenzidine tetrahydrochloride solution. The sections were counterstained in Mayer’s hematoxylin, rinsed with water, and mounted in an aqueous mounting media (Aquamount, BDH, Poole, United Kingdom). The percentage of positive nuclei was evaluated and scored as follows: (a) -, 0%; (b) +, 1–10%; (c) ++, 11–50%; (d) +++, 51–80%; and (e) ++++, 81% or more. The slides were analyzed by one pathologist (R. S.).
Detection of Germ-line Mutations.
All 494 patients had been scrutinized previously for the two most common mismatch repair gene mutations in Finland (24
, 29) . Founder mutation 1 is a 3.5-kb genomic deletion of MLH1 comprising exon 16, and founder mutation 2 is MLH1 exon 6 splice site mutation G
A at 454-1 (last intronic base before exon 6). If neither founder mutation was detected, but the patient’s tumor displayed MSI (analyzed using BAT26 alone), mutation analysis of MLH1 and MSH2 was performed by direct genomic sequencing of the coding exons including the flanking intronic regions and promoter region, as described previously (24
, 29)
.
The new MSI-H cases appearing after MSI analysis using the Bethesda markers were similarly analyzed for mutations in MLH1 and MSH2. To exclude the possibility of large deletions of MLH1 and MSH2, the new MSI-H cases were analyzed by Southern blotting according to standard procedures. Genomic DNA was digested with EcoRI and analyzed with two different cDNA probes encompassing MLH1 exons 11–19 and MSH2 exons 1–8. The new MSI-H cases were also screened for MSH6 mutations by direct sequencing covering 98% of the coding region. Primer sequences and PCR conditions are available on request. Direct sequencing of the PCR products was performed using cycle sequencing with Big Dye Terminator kit (Perkin-Elmer), and reactions were run on an ABI 3100 capillary sequencer (Perkin-Elmer) according to the manufacturer’s instructions.
A total of 182 cancer-free control individuals and 83 CRC patients were analyzed for a MSH6 variant in exon 2 by single-strand conformational polymorphism analysis using mutation detection enhancement gel solution (BioWhittaker Molecular Applications, Rockland, ME). PCR products were run on 0.6x mutation detection enhancement gels at 4 W for 22 h. The running buffer was 0.6x Tris-borate EDTA. Single-strand conformational polymorphism gels were silver-stained according to standard procedures.
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RESULTS AND DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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). The cutoff level for MSI positivity for the mononucleotide markers was set at shifts of 3 bp or greater. The cutoff level of 3 bp was chosen because all 10 cases displaying such deviation also had instability at other loci. Eight and seven patients showed 1–2-bp deviations at BAT25 and BAT26, respectively, and none of these cases displayed additional evidence of MSI at other loci. In 31 individual cases, the three reviewers had discrepancies when scoring dinucleotide markers, whereas not a single scoring discrepancy occurred with BAT25 and BAT26.
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. A total of 95 of 494 patients (19.2%) were classified as MSI with the Bethesda panel; 75 patients (15.2%) were classified as MSI-H, and 20 patients (4.0%) were classified as MSI-L (Table 2)
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). Germ-line mutation analysis of MLH1 and MSH2 was performed for the two new MSI-H cases. No mutations were found in the coding regions, exon-intron boundaries, or the promoter region of these genes. Neither case had a family history of cancer, and the ages at diagnosis were 64 and 65 years. To examine the molecular background of the observed MSI-H phenotype in more detail, additional experiments were performed on the two cases. Because direct genomic sequencing cannot detect defects such as genomic deletions affecting whole exons, we examined both MLH1 and MSH2 by Southern hybridization. No aberrations were detected. Direct genomic sequencing of MSH6 revealed a missense change in one case; MSH6 exon 2 S144I (AGCATC). The tumor DNA showed no loss of heterozygosity at this change. This variant has been reported previously as a pathogenic mutation (34)
. We analyzed 182 cancer-free controls and 83 individuals with CRC for the change and found it in 1 control sample. It thus appears to be a rare polymorphism, although additional studies are needed to confirm its nature. Five additional microsatellite markers (TGF-ßRII, D18S363, D18S1156, D5S318, and TP53) were used to confirm the status of the 20 MSI-L cases. Three samples showed further instability with one of the markers. This degree of instability (2 of 10 or 20%) should be considered as MSI-L (13) .
In addition, immunohistochemistry of MLH1, MSH2, and MSH6 was performed for the 20 MSI-L and the 2 new MSI-H cases. Because no lack of expression was revealed in the MSI-L cases (all scored ++, +++, or ++++), no further procedures were performed. Also, previous studies have confirmed that the expression of MLH1 and MSH2 is not altered in MSI-L cases, whereas loss of expression in one of them, typically MLH1, can be seen in most MSI-H cases (20 , 21) . However, because MLH1 antibody has a tendency to show a weak positive staining even in cases harboring deleterious mutations (35) , we must acknowledge the possible involvement of a gene defect even in cases showing MLH1 immunostaining. Importantly, the two new MSI-H cases expressed MLH1, MSH2, and MSH6 (all scored +++ or ++++). This result, together with their BAT26 negativity, implies that they are possibly MSI-L despite the two unstable dinucleotide markers.
All 27 mutation-positive CRCs in the series of 494 tumors showed instability at both the BAT26 and BAT25 loci. However, in other studies, we have detected one sample derived from a mutation-positive patient with no instability at BAT26. The patient was diagnosed at 37 years of age with a proximal tumor, has Finnish founder mutation 1, and has a strong family history of CRC. Thus, the lesion is most likely a HNPCC tumor. The degree of MSI in tumors is related to past patterns of tumorigenesis, primarily to mutation rate and the number of divisions since loss of mismatch repair. Relatively young lesions are likely to show less MSI, and rare cases of HNPCC may display MSI at relatively few loci (36) . In this study, D2S123, D5S346, and D17S250 identified 24 (89%), 16 (59%), and 22 (81%) of 27 mutation-positive individuals, respectively. Despite negative results in genomic sequencing, some of the 46 cases that showed BAT26 instability may have had a MSH2 or MLH1 mutation that was not detected by the method. Of these 46 individuals, 35 had no family history of CRC or endometrial cancer, but undetected mutations may underlie a subset of the 11 cases with some HNPCC features (1–3 relatives with CRC or endometrial cancer). None of the 11 pedigrees fulfilled the Amsterdam criteria for HNPCC (2) .
It is possible that the two common founder mutations in Finland cause a bias toward MSI-H phenotypes in our HNPCC series. Together, these two mutations accounted for 18 of 27 (67%) mutations in this series. However, all of the nine other patients with five different mutations exhibited MSI-H phenotypes, supporting the notion that deleterious MLH1 and MSH2 mutations tend to cause MSI-H phenotypes. A minority of HNPCC tumors are MSS. The genes responsible for HNPCC are not yet fully known, and some of these appear to be associated with more attenuated phenotypes (13) . It is possible that MSH6, TGF-ßRII, and perhaps other currently unidentified predisposing genes cause a MSI-L or MSS phenotype (34) .
Relying on BAT26 alone in MSI analysis has prompted the question of possible loss of sensitivity and specificity. The proposed panel of five microsatellite markers (13) aims at dividing tumors into categories of MSI-H, MSI-L, and MSS, of which typically only MSI-H tumors are considered as candidates for MLH1/MSH2 mutation analysis (20, 21, 22) . When relying on one marker, distinguishing between MSI-H and MSI-L is impossible. According to this study, BAT26 detects MSI-H cases with high sensitivity because 73 of 75 (97%) MSI-H cases were BAT26 positive. The sensitivity in detecting MLH1/MSH2 mutation-positive individuals was 100% (27 of 27).
Only 2 of 421 (0.5%) BAT26-negative tumors were found to be MSI-H, and no MLH1/MSH2 mutations could be found in these patients. Twenty of 421 (4.8%) BAT26-negative tumors were found to be MSI-L. These 22 BAT26-negative tumors expressed MLH1, MSH2, and MSH6 according to immunohistochemistry and are unlikely to represent HNPCC. The specificity of BAT26 in detecting mutation-positive individuals (27 of 73 cases, 37%) was very similar to the specificity of the Bethesda panel (27 of 75 cases, 36%). The data suggest that there is little loss of specificity when relying on BAT26 alone.
On the basis of analyzing 494 CRC patients for MSI using the Bethesda markers, we conclude that BAT26 alone was sufficient to identify 97% of MSI-H cases but seemingly fails to detect MSI-L cases. Thus, additional markers are needed when aiming at distinguishing MSI-L and MSS subgroups. However, this may not be necessary when prescreening patients for MLH1/MSH2 germ-line mutations. It seems that BAT26 identifies MLH1 or MSH2 mutation-positive CRC patients with high sensitivity. Whereas utilization of more markers may be useful if extensive resources are available, the benefit appears marginal and may not be cost effective. Utilization of numerous markers resulted in increased workload and expense, as well as difficulties in scoring even in experienced hands. Our data indicate that BAT26 alone can be used as a tool in detection of MLH1/MSH2-associated HNPCC in circumstances where resources and experience in interpretation are limited.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by grants from the Finnish Cancer Society, the Academy of Finland, Sigrid Juselius Foundation, Duodecim, Ida Montin Foundation, Jalmari and Rauha Ahokas Foundation, Emil Aaltonen Foundation, Finnish-Norwegian Medical Foundation, Nordisk Cancer Union, Paulo Foundation, and Helsinki University Central Hospital and carried out at the Center of Excellence in Disease Genetics of the Academy of Finland (Project 44870). 
2 A. L., K. E., and P. L. contributed equally to this work.
3 To whom requests for reprints should be addressed, at Department of Medical Genetics, Haartman Institute, P. O. Box 63, FIN-00014 University of Helsinki, Finland. Phone: 358-9-19125595; Fax: 358-9-19125105; E-mail: lauri.aaltonen{at}helsinki.fi
4 The abbreviations used are: HNPCC, hereditary nonpolyposis colorectal cancer; CRC, colorectal cancer; MSI, microsatellite instability; MSI-H, high MSI; MSI-L, low MSI; MSS, microsatellite stable; RER, replication error; TGF-ßRII, transforming growth factor ß receptor II.
Received 11/20/00. Accepted 3/26/01.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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