Differential MSH2 Promoter Methylation in Blood Cells of Neurofibromatosis Type 1 (NF1) Patients

Overview

Journal Eur J Hum Genet

Specialty Genetics

Date 2009 Jul 30

PMID 19639020

Citations 12

Authors

Sabrina Titze

Hartmut Peters

Sandra Wahrisch

Thomas Harder

Katrin Guse

Annegret Buske

Sigrid Tinschert

Anja Harder

Affiliations

Soon will be listed here.

Abstract

Neurofibromatosis type 1 (NF1) is caused by NF1 gene mutations. The phenotype is highly variable, with 'modifiers' being discussed as potential determinants. Mismatch repair deficiency was shown to cause NF1 mutations, but constitutional mutation of mismatch repair genes was identified only once in a NF1 patient. We aimed to analyze whether DNA methylation of mismatch repair gene promoters, known to lead to transcriptional silencing, is associated with increased tumor load in NF1 defined by the number of cutaneous neurofibromas. Leukocyte DNA of 79 controls and 79 NF1 patients was investigated for methylation of mismatch repair genes MLH1, MSH2, MSH6, and PMS2 by methylation-specific PCR and pyrosequencing. MLH1, MSH6, and PMS2 promoters were not methylated. By contrast, we found promoter methylation of MSH2 with a higher rate of methylation in NF1 patients compared with controls. Furthermore, when comparing NF1 patients with a low vs those with a high number of cutaneous neurofibromas, MSH2 promoter methylation was significantly different. In patients with a high tumor burden, methylation of two (out of six) CpGs was enhanced. This finding was not confounded by age. In conclusion, enhanced methylation involving transcription start points of mismatch repair genes, such as MSH2 in NF1, has not been described so far. Methylation-induced variability of MSH2 gene expression may lead to variable mismatch repair capacity. Our results may point toward a role of MSH2 as a modifier for NF1, although the amount of DNA methylation and subsequent gene expression in other cell types of NF1 patients needs to be elucidated.

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References

Gutmann D, Aylsworth A, Carey J, Korf B, Marks J, Pyeritz R . The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997; 278(1):51-7. View

Szudek J, Joe H, Friedman J . Analysis of intrafamilial phenotypic variation in neurofibromatosis 1 (NF1). Genet Epidemiol. 2002; 23(2):150-64. DOI: 10.1002/gepi.1129. View

Kluwe L, Friedrich R, Mautner V . Loss of NF1 allele in Schwann cells but not in fibroblasts derived from an NF1-associated neurofibroma. Genes Chromosomes Cancer. 1999; 24(3):283-5. DOI: 10.1002/(sici)1098-2264(199903)24:3<283::aid-gcc15>3.0.co;2-k. View

Esteller M . Epigenetics in cancer. N Engl J Med. 2008; 358(11):1148-59. DOI: 10.1056/NEJMra072067. View

Shin K, Shin J, Kim J, Park J . Mutational analysis of promoters of mismatch repair genes hMSH2 and hMLH1 in hereditary nonpolyposis colorectal cancer and early onset colorectal cancer patients: identification of three novel germ-line mutations in promoter of the hMSH2 gene. Cancer Res. 2002; 62(1):38-42. View

Kruger S, Kinzel M, Walldorf C, Gottschling S, Bier A, Tinschert S . Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1. Eur J Hum Genet. 2007; 16(1):62-72. DOI: 10.1038/sj.ejhg.5201923. View

Wang Q, Montmain G, Ruano E, Upadhyaya M, Dudley S, Liskay R . Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. Hum Genet. 2003; 112(2):117-23. DOI: 10.1007/s00439-002-0858-4. View

Gutmann D, Winkeler E, Kabbarah O, Hedrick N, Dudley S, Goodfellow P . Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice. Oncogene. 2003; 22(29):4581-5. DOI: 10.1038/sj.onc.1206768. View

Fahsold R, Hoffmeyer S, Mischung C, Gille C, EHLERS C, Kucukceylan N . Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000; 66(3):790-818. PMC: 1288164. DOI: 10.1086/302809. View

10.

Upadhyaya M, Huson S, Davies M, Thomas N, Chuzhanova N, Giovannini S . An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2006; 80(1):140-51. PMC: 1785321. DOI: 10.1086/510781. View

11.

Wiest V, Eisenbarth I, Schmegner C, Krone W, Assum G . Somatic NF1 mutation spectra in a family with neurofibromatosis type 1: toward a theory of genetic modifiers. Hum Mutat. 2003; 22(6):423-7. DOI: 10.1002/humu.10272. View

12.

Goldberg M, Rummelt C, Foja S, Holbach L, Ballhausen W . Different genetic pathways in the development of periocular sebaceous gland carcinomas in presumptive Muir-Torre syndrome patients. Hum Mutat. 2006; 27(2):155-62. DOI: 10.1002/humu.20281. View

13.

Noda H, Kato Y, Yoshikawa H, Arai M, Togashi K, Nagai H . Microsatellite instability caused by hMLH1 promoter methylation increases with tumor progression in right-sided sporadic colorectal cancer. Oncology. 2005; 69(4):354-62. DOI: 10.1159/000089768. View

14.

Fang J, Lu R, Mikovits J, Cheng Z, Zhu H, Chen Y . Regulation of hMSH2 and hMLH1 expression in the human colon cancer cell line SW1116 by DNA methyltransferase 1. Cancer Lett. 2006; 233(1):124-30. DOI: 10.1016/j.canlet.2005.03.005. View

15.

Chan T, Yuen S, Kong C, Chan Y, Chan A, Ng W . Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat Genet. 2006; 38(10):1178-83. DOI: 10.1038/ng1866. View

16.

Fleisher A, Esteller M, Wang S, Tamura G, Suzuki H, Yin J . Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. Cancer Res. 1999; 59(5):1090-5. View

17.

Maertens O, Brems H, Vandesompele J, De Raedt T, Heyns I, Rosenbaum T . Comprehensive NF1 screening on cultured Schwann cells from neurofibromas. Hum Mutat. 2006; 27(10):1030-40. DOI: 10.1002/humu.20389. View

18.

Harder A, Rosche M, Reuss D, Holtkamp N, Uhlmann K, Friedrich R . Methylation analysis of the neurofibromatosis type 1 (NF1) promoter in peripheral nerve sheath tumours. Eur J Cancer. 2004; 40(18):2820-8. DOI: 10.1016/j.ejca.2004.07.021. View

19.

Truninger K, Menigatti M, Luz J, Russell A, Haider R, Gebbers J . Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology. 2005; 128(5):1160-71. DOI: 10.1053/j.gastro.2005.01.056. View

20.

Shannon K, OConnell P, Martin G, Paderanga D, Olson K, Dinndorf P . Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N Engl J Med. 1994; 330(9):597-601. DOI: 10.1056/NEJM199403033300903. View