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Journal of Clinical Oncology, Vol 25, No 7 (March 1), 2007: pp. 913-914 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.4227
Microsatellite Instability Testing in Genetically Heterogeneous PopulationsPost-Graduate Program in Gastroenterological Sciences, Federal University of Rio Grande do Sul, Brazil
Post-Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Brazil; and the Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Brazil
Post-Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Brazil; and the Department of Genetics, Federal University of Rio Grande do Sul, Brazil
Post-Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Brazil
Post-Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Brazil; and the Department of Genetics, Federal University of Rio Grande do Sul, Brazil
Post-Graduate Program in Gastroenterological Sciences, Federal University of Rio Grande do Sul, Brazil; and the Department of Internal Medicine, Federal University of Rio Grande do Sul, Brazil To the Editor: We read with great interest the article "Multipopulation Analysis of Polymorphisms in Five Mononucleotide Repeats Used to determine the Microsatellite Instability Status of Human Tumors" by Buhard and colleages1 that appeared in the Journal of Clinical Oncology. The authors analyze a comparable panel of five mononucleotide markers (BAT-25, BAT-26, NR-27, NR-21, and NR-24) in germline DNA from 1,206 individuals encompassing 55 different populations worldwide, two of them from Brazil (including 45 individuals from the Suruí and Karitiana native populations). They conclude that gastrointestinal tumor microsatellite instability (MSI) can be determined using the pentaplex reaction for human populations without the need for matching normal DNA.1 In general, microsatellite stability status (MSS) is determined by the comparison between normal and tumoral tissues from the same patient and instability is characterized by the difference in the amplification profile of specific markers between these tissues.2,3 The International Workshop on Microsatellite Instability and Replication Error Repair Phenotypes in Cancer Detection and Familial Predisposition has recommended that MS status be studied through a panel of five markers: the mononucleotide markers BAT-25 and BAT-26 and the dinucleotide markers D2S123, D5S346, and D17S250.2,3 Of these, BAT-26 and BAT-25 are considered quasimonomorphic in replication error-negative tumors or healthy tissue of European individuals.4,5 Nevertheless, Pyatt et al6 showed a high frequency of allelic variation at the BAT-25 and BAT-26 loci in a sample of African American individuals, suggesting that similar variations may be encountered in other populations. Polymorphic allelic variation of the BAT-25 and BAT-26 loci was also described in sporadic tumors such as endometrial adenocarcinomas.7 These studies indicate that the existence and distribution of allelic variants of these mononucleotide markers should be determined in specific populations before a decision is made on the most reliable clinical protocol for MSI screening. Little has been published on BAT-25 and BAT-26 allelic variants and MSS at these loci in sporadic and hereditary colorectal cancers of Brazilian patients.8 One of the most interesting characteristics of the Brazilian population is its heterogeneity. Apart from native populations, the "Amerindians," Brazil has received immigrants from different countries, including an important contribution from Southern European (Portuguese and Spanish colonizers in the 16th century), Africans (in the late 17th century), and Northern Europeans (in the 19th century). These very diverse geographical and ethnic backgrounds contributed to the formation of the contemporary Brazilian genetic pool.9 The high degree of admixture can be observed in the entire Brazilian territory and for this reason we believe that the data presented by Buhard et al, 1 that studied microsatellite stability (MSS) in a small number of individuals from two isolated native populations that certainly are not representative of the Brazilian population as it exists today, must be interpreted with caution. In an exploratory study of 216 healthy unrelated individuals from Southern Brazil that were not selected for ethnic background, we anonymously analyzed the frequency of constitutive polymorphic variation at the BAT-25 and BAT-26 loci. DNA was extracted from peripheral blood by a standard salting-out procedure, and the screening for constitutive polymorphic variation at the BAT-25 and BAT-26 loci was performed by polymerase chain reaction–single-strand conformation polymorphism (PCR-SSCP) as described previously.3,10 All samples were compared with a normal control (wild type size) and all those exhibiting a different size were considered allelic variants. Fifteen (7%) and 13 (6%) individuals showed variant alleles at the BAT-25 and BAT-26 loci, respectively,11 and allele sizing of the variants is currently under way to determine how many of these variants are without the quasimonomorphic range. Several evidences in the literature, including the article by Buhard et al suggest that BAT-25 and BAT-26 do have considerable allelic variation,6,12,13 especially in sub-Saharan populations. In Brazilians we expect variation to be high too because a significant proportion have African origins. It has been estimated that about 146 million of 188 million inhabitants of Brazil, independently of their physical appearance, show at least 10% of sub-Saharan ancestry.14 Not surprisingly, this portion of the African continent is also the region of the world where constitutive variation at these loci has been repeatedly described in a high number of its native individuals. The findings of our study and those of others, describing BAT-25 and BAT-26 variant alleles in a significant proportion of healthy individuals are important for clinical purposes. If a tumor sample of such individual would be analyzed for MSI without analysis of the healthy corresponding tissue, this constitutive variant could be misclassified as MSI. Taken together, these data reinforce that comparative analysis between healthy and tumoral tissue for MSS determination may be necessary to avoid false-positive results in certain populations, such as the Brazilian, where the contemporaneous genetic pool is too heterogeneus and where the precise ethnic background of an individual seen in routine clinical practice is difficult to determine. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. ACKNOWLEDGMENTS Supported by grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior (CAPES), and Fundação de Incentivo a Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE/HCPA), Brazil. REFERENCES
1. Buhard O, Cattaneo F, Wong YF, et al: Multipopulation analysis of polymorphisms in five mononucleotide repeats used to determine the microsatellite instability status of human tumors. J Clin Oncol 24:241-251, 2006 2. Boland CR, Thibodeau SN, Hamilton SR, et al: A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248-5257, 1998 3. Dietmaier W, Wallinger S, Bocker T, et al: Diagnostic microsatellite instability: Definition and correlation with mismatch repair protein expression. Cancer Res 57:4749-4756, 1997 4. Cravo M, Lage P, Albuquerque C, et al: BAT-26 identifies sporadic colorectal cancers with mutator phenotype: A correlative study with clinico-pathological features and mutations in mismatch repair genes. J Pathol 188:252-257, 1999[CrossRef][Medline] 5. Hoang J-M, Cottu PH, Thuille B, et al: BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines. Cancer Res 57:300-303, 1997 6. Pyatt R, Chadwick RB, Johnson CK, et al: Polymorphic variation at the BAT-25 and BAT-26 loci in individuals of African origin: Implications for microsatellite instability testing. Am J Pathol 155:349-353, 1999 7. Yu H-JA, Lin KM, Ota DM, et al: Hereditary nonpolyposis colorectal cancer: Preventive management. Cancer Treat Rev 29:461-470, 2003[CrossRef][Medline] 8. Fuzikawa AK, Hadad LA, da-Cunha-Melo JR, et al: Utilization of microsatellites for the analysis of genomic alterations in colorectal cancers in Brazil. Br J Med Biol Res 30:915-921, 1997[Medline] 9. Salzano FM, Bortolini MC: Evolution and Genetics of Latin American Populations. Cambridge, Cambridge University Press, 2002 10. Iacopetta B, Hamelin R: Rapid and nonisotopic SSCP-based analysis of the BAT-26 mononucleotide repeat for identification of the replication error phenotype in human cancers. Hum Mutat 12:355-360, 1998[CrossRef][Medline] 11. Cossio SL, Coura RS, Bortolini MC, et al: Polymorphic variation of mononucleotide microsatellites and its implication for microsatellite instability (MSI) screening. Arq Gastroenterol (in press) 12. MSH2 database. http://www.genecards.org/cgi-bin/carddisp.pl?gene=MSH2&search=MSH2 13. Alazzouzi H, Domingo E, González S, et al: Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis. Hum Mol Gen 14:235-239, 2005 14. Pena SD, Bortolini MC: Pode a genética definir quem deve se beneficiar das cotas universitárias e demais ações afirmativas [in Portuguese]? Est Avan ç (São Paulo) 18:1-20, 2004
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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