High level of microsatellite instability but not hypermethylation of mismatch repair genes in therapy-related and secondary acute myeloid leukaemia and myelodysplastic syndrome
H. Mohammad Sheikhha,
Khalid Tobal,
A. Liu John Yin,
H. Mohammad Sheikhha
Molecular Oncology Group, University Department of Haematology, Manchester Royal infirmary, Manchester, UK
Search for more papers by this authorKhalid Tobal
Molecular Oncology Group, University Department of Haematology, Manchester Royal infirmary, Manchester, UK
Search for more papers by this authorA. Liu John Yin
Molecular Oncology Group, University Department of Haematology, Manchester Royal infirmary, Manchester, UK
Search for more papers by this authorH. Mohammad Sheikhha,
Khalid Tobal,
A. Liu John Yin,
H. Mohammad Sheikhha
Molecular Oncology Group, University Department of Haematology, Manchester Royal infirmary, Manchester, UK
Search for more papers by this authorKhalid Tobal
Molecular Oncology Group, University Department of Haematology, Manchester Royal infirmary, Manchester, UK
Search for more papers by this authorA. Liu John Yin
Molecular Oncology Group, University Department of Haematology, Manchester Royal infirmary, Manchester, UK
Search for more papers by this author K. Tobal, Molecular Oncology Group, University Department of Haematology, Manchester Royal infirmary, Cobbett House, Oxford Road, Manchester, M13 9WL, UK. E-mail:[email protected]
Abstract
Summary. Microsatellite instability (MSI) is associated with defects in the DNA mismatch repair (MMR) system, such as mutation or epigenetic silencing of the genes by promoter hypermethylation. We investigated the presence of MSI and promoter hypermethylation of hMLH1 and hMSH2 genes in 82 patients (68 acute myeloid leukaemia, AML; 14 myelodysplastic syndromes, MDS). Twelve separate microsatellite loci, including three mononucleotide repeat markers, were used. Mutator phenotype (RER+) was detected in 20 AML (29·4%) and 3 MDS (21·4%) patients. RER+ rate was much higher in the therapy-related and secondary cases compared with the de novo cases. Three out of 7 (42·9%) secondary (s-AML) and 8 out of 17 (47·1%) therapy-related (t-AML) showed RER+ in comparison with 9 out of 44 (20·5%) de novo cases. Similar rates were detected in MDS patients (2/2 therapy-related and 1/12 de novo). The promoter hypermethylation was found in three hMLH1 (3·7%) and two hMSH2 (2·4%) genes. All these five patients had AML and were older than 60 years of age. Two of them had s-AML and one had t-AML. RER+ was detected in three of these five patients. Our data suggest that genetic instability is associated with AML and MDS, especially t-AML and s-AML. In addition, our results indicate that the hMSH2 and hMLH1 promoter hypermethylation is not a common event in these malignancies, but may play a role in the development of AML in elderly patients.
References
- Auner, H.W., Olipitz, W., Hoefler, G., Bodner, C., Konard, D., Crevenna, R., Linkesch, W. & Sill, H. (1999) Mutational analysis of the DNA mismatch repair gene hMLH1 in myeloid leukaemias. British Journal of Haematology, 106, 706 – 708.
- Ben-Yehuda, D., Krichevsky, S., Caspi, O., Rund, D., Polliack, A., Abeliovich, D., Zelig, O. & Yahalom, V. (1996) Microsatellite instability and p53 mutation in therapy-related Leukemia suggest mutator phenotype. Blood, 11, 4296 – 4303.
- Bevilacqua, R.A. & Simpson, A.J. (2000) Methylation of the hMLH1 promoter but no hMLH1 mutations in sporadic gastric carcinomas with high-level microsatellite instability. International Journal of Cancer, 87, 200 – 203.DOI: 10.1002/1097-0215(20000715)87:2<200::AID-IJC7>3.3.CO;2-9
- Coleman, W.B. & Tsongalis, G.J. (1999) The role of genomic instability in human carcinogenesis. Anticancer Research, 19, 4645 – 4664.
- Cunningham, J.M., Christensen, E.R., Tester, D.J., Kim, C.Y., Roche, P.C., Bugar, L.J. & Thibodeau, S.N. (1998) Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Research, 58, 3455 – 3460.
- Das-Gupta, E.P., Seedhouse, C.H. & Russell, N.H. (2001) Microsatellite instability occurs in defined subsets of patients with acute myeloblastic leukaemia. British Journal of Haematology, 114, 307 – 312.DOI: 10.1046/j.1365-2141.2001.02920.x
- Deng, G., Chen, A., Hong, J., Chae, H.S. & Young, S.K. (1999) Methylation of CPG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression. Cancer Research, 59, 2029 – 2033.
- Harada, S., Komatsu, H., Seto, M., Ni, H., Xu, J.H., Hayami, Y., Tsubui, K., Wakita, A., Nitta, M., Kato, T. & Ueda, R. (1998) Microsatellite instability is rare in the clinical course of myelodysplastic syndrome studied with DNA from fresh and paraffin-embedded tissue. Journal of Cancer Research in Clinical Oncology, 124, 231 – 235.
- Hoang, J.M., Cottu, P.H., Thuille, B., Salmon, R.J., Thomas, G. & Hamelin, R. (1997) BAT-26 an indicator of the replication error phenotype in colorectal cancers and cell lines. Cancer Research, 57, 300 – 303.
- Honchel, R., Halling, K.C., Schaid, D.J., Pittelkow, M. & Thibodeau, S.N. (1994) Microsatellite intractability in Muir–Torre syndrome. Cancer Research, 54, 1159 – 1163.
- Horiike, S., Misawa, S., Kaneko, H., Sasai, Y., Kobayashi, M., Fujii, H., Tanaka, S., Yagita, M., Abe, T., Kashima, K. & Taniwaki, M. (1999) Distinct genetic involvement of the TP53 gene in therapy-related leukemia and myelodysplasia with chromosomal losses of Nos 5 and/or 7 and its possible relationship to replication error phenotype. Leukemia, 13, 1235 – 1242.
- Horrigan, S.K., Westbrook, C.A., Kim, A.H., Banerjee, M., Stock, W. & Larson, R.A. (1996) Polymerase chain reaction-based diagnosis of del (5q) in acute myeloid leukemia and myelodysplastic syndrome identifies a minimal deletion interval. Blood, 7, 2665 – 2670.
- Inoue, K., Kohno, T., Takakura, S., Hayashi, Y., Mizoguchi, H. & Yokota, J. (2000) Frequent microsatellite instability and BAX mutations in T cell acute lymphoblastic leukemia cell lines. Leukemia Research, 24, 255 – 262.
- Kane, M.F., Loda, M., Gaida, G.M., Lipman, J., Mishra, R., Goldman, H., Jessup, J.M. & Kolodner, R. (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell line. Cancer Research, 57, 808 – 811.
- Kaneko, H., Horiike, S., Inazawa, J., Nakai, H. & Misawa, S. (1995) Microsatellite instability is an early genetic event in myelodysplastic syndrome. Blood, 86, 1236 – 1237.
-
Kodera, T.,
Kohno, T.,
Takakura, S.,
Morishita, K.,
Hamaguchi, H.,
Hayashi, Y.,
Sasaki, T. &
Yokota, J. (1999) Microsatellite instability in lymphoid leukemia and lymphoma cell lines but not in myeloid leukemia cell lines.
Genes Chromosomes Cancer, 26, 267
–
269.
10.1002/(SICI)1098-2264(199911)26:3<267::AID-GCC13>3.0.CO;2-V CAS PubMed Web of Science® Google Scholar
- Krichevsky, S., Siegfried, F., Asimakopoulos, F.A., Shteper, P.J., Goldschmidt, N., Rachmilewitz, E.A., Rund, D. & Ben-Yehuda, D. (1999) Methylation of the promoter regions of DNA repair and genotoxic stress response genes in therapy-related but not primary leukemia. Blood, 94, 594a.
- Lerer, I., Meiner, V., Pashut-Lavon, I. & Abeliovich, D. (1994) Molecular diagnosis of Prader–Willi syndrome: Parent-of-Origin dependent methylation sites and non-isotopic detection of (CA)n dinucleotide repeat polymorphisms. American Journal of Medical Genetics, 52, 79 – 84.
-
Liu, T.,
Wahlberg, S.,
Burek, E.,
Lindblom, P.,
Rubio, C. &
Lindblom, A. (2000) Microsatellite instability as a predictor of a mutation in a DNA mismatch repair gene in familial colorectal cancer.
Gene Chromosomes and Cancer, 27, 17
–
25.
10.1002/(SICI)1098-2264(200001)27:1<17::AID-GCC3>3.0.CO;2-Y CAS PubMed Web of Science® Google Scholar
- Ma, S.K., Kong, C.T., Wan, T.S., Au, Ww.Y., Chan, J.C., Yip, S.F. & Chan, L.C. (2000) Absence of microsatellite instability in primary myelodysplastic syndrome. International Journal of Molecular Medicine, 5, 159 – 163.
- Maeck, L., Haase, D., Schoch, C., Hiddenmann, W. & Alves, F. (2000) Genetic instability in myelodysplasic syndrome: detection of microsatellite instability and loss of heterozygosity in bone marrow samples with karyotype alteration. British Journal of Haematology, 109, 842 – 846.
- Mori, N., Morosetti, R., Lee, S., Spira, S., Ben-Yehuda, D., Schiller, G., Landolfi, R., Mizoguch, H. & Koeffler, H.P. (1997) Allelotype analysis in the evolution of chronic myelocytic leukemia. Blood, 90, 2010 – 2014.
- Olipitz, W., Tilz, G.P., Beham-Schmid, C., Eibinger, C., Kerzina, P. & Sill, H. (2001) Microsatellite analysis in acute myeloid leukaemia evolving from myelodysplastic syndrome. British Journal of Haematology, 112, 248 – 253.DOI: 10.1046/j.1365-2141.2001.02497.x
- Pabst, T., Schwaller, J., Bellomo, M.J., Oestreicher, M., Muhlematter, D., Tichelli, A., Tobler, A. & Fey, M.F. (1996) Frequent clonal loss of heterozygosity but scarcity of microsatellite instability at chromosomal breakpoint cluster regions in adult leukemias. Blood, 88, 1026 – 1034.
- Parson, R., Li, G.M., Longley, M., Modrich, P., Liu, B., Berk, T., Hamilton, S.R., Kinzler, K.W. & Vogelstein, B. (1995) Mismatch repair deficiency in phenotypically normal human cells. Science, 268, 738 – 740.
- Rimsza, L.M., Kopecky, K.J., Ruschulte, J., Chen, I.M., Slovak, M.L., Karanes, C., Godwin, J., List, A. & Willman, C.L. (2000) Microsatellite instability is not a defining genetic feature of acute myeloid leukemogenesis in adults: results of a retrospective study of 132 patients and review of the literature. Leukemia, 14, 1044 – 1051.
- Roblrdo, M., Martinez, B., Arranz, E., Trujillo, M.J., Gonzalez, A.A., Rivas, C. & Benitez, J. (1995) Genetic instability of microsatellites in hematological neoplasms. Leukemia, 9, 960 – 964.
- Shin, K.H. & Park, J.G. (2000) Microsatellite instability is associated with genetic alteration but not with low levels of expression of the human mismatch repair proteins hMSH2 and Hmlh1. European Journal of Cancer, 36, 925 – 931.
- Stone, J.G., Tomlinson, I.P. & Houlston, R.S. (2000) Optimising methods for determining RER status in colorectal cancers. Cancer Letter, 149, 15 – 20.
- Takeuchi, S., Seriu, T., Tasaka, T., Koike, M., Cho, S.K., Park, S., Slater, J., Mufti, I., Hatta, Y., Miyoshi, I., Bartram, C.R. & Koeffler, H.P. (1997) Microsatellite instability and other molecular abnormalities in childhood acute lymphoblastic leukaemia. British Journal of Haematology, 98, 134 – 139.
- Tasaka, T., Lee, S., Spira, S., Takeuchi, S., Hatta, Y., Nagai, M., Takahara, J. & Koeffletr, P. (1996) Infrequent microsatellite instability during the evolution of the myelodysplastic syndrome to acute myeloid leukemia. Leukemia Research, 20, 113 – 117.
- Tasaka, T., Lee, S., Spira, S., Takeuchi, S., Nagai, M., Takahara, J. & Koeffletr, P. (1997) Microsatellite instability during the progression of acute myeloid leukemia. British Journal of Haematology, 98, 219 – 221.
- Thibodeau, S.N., Bren, G. & Schaid, D. (1993) Microsatellite instability in cancer of the proximal colon. Science, 260, 816 – 819.
- Wada, C., Shionoya, S., Fujino, Y., Tokuhiro, H., Akahoshi, T., Uchida, T. & Ohtani, H. (1994) Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia. Blood, 83, 3449 – 3456.
- Webb, J.C., Golovleva, I., Simpkins, A.H., Kempski, H., Reeves, B., Sturt, N., Chessells, J.M. & Brickell, P.M. (1999) Loss of heterozygosity and microsatellite instability at the MLL locus are common in childhood acute leukemia, but not in infant acute leukemia. Blood, 94, 283 – 290.
- Weber, J.L. & May, P.E. (1989) Abundant class of human DNA polymorphism which can be typed using the polymerase chain reaction. American Journal of Human Genetics, 44, 388 – 396.
- Wong, I.H.N., Ng, M.H.L., Huang, D.P. & Lee, J.C.K. (2000) Aberrant p15 promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications. Blood, 95, 1942 – 1949.
-
Zhou, X.P.,
Hoang, J.M.,
Li, Y.J.,
Seruca, R.,
Carneiro, F.,
Sobrinho-Simoes, M.,
Lothe, R.A.,
Gleeson, C.M.,
Russell, S.E.,
Muzeau, F.,
Flejou, J.F.,
Hoang-Xuan, K.,
Lidereau, R.,
Thomas, G. &
Hamelin, R. (1998) Determination of the replication of the replication error phenotype in human tumors without the requirement for matching normal DNA by analysis of mononucleotide repeat microsatellites.
Gene Chromosome Cancer, 21, 101
–
107.
10.1002/(SICI)1098-2264(199802)21:2<101::AID-GCC4>3.0.CO;2-4 CAS PubMed Web of Science® Google Scholar
- Zhu, Y.M., Das-Gupta, E.P. & Russell, N.H. (1999) Microsatellite instability and p53 mutations are associated with abnormal expression of the MSH2 gene in adult acute leukemia. Blood, 94, 733 – 740.
Citing Literature
