title: Epigenetic silencing of the kinase tumor suppressor WNK2 is tumor-type and tumor-grade specific.
abstract: Both genetic and epigenetic mechanisms contribute to meningioma development by altering gene expression and protein function. To determine the relative contribution of each mechanism to meningioma development, we used an integrative approach measuring copy number and DNA methylation changes genomewide. We found that genetic alterations affected 1.9%, 7.4%, and 13.3% of the 691 loci studied, whereas epigenetic mechanisms affected 5.4%, 9.9%, and 10.3% of these loci in grade I, II, and III meningiomas, respectively. Genetic and epigenetic mechanisms rarely involved the same locus in any given tumor. The predilection for epigenetic rather than genetic silencing was exemplified at the 5' CpG island of WNK2, a serine-threonine kinase gene on chromosome 9q22.31. WNK2 is known to negatively regulate epidermal growth factor receptor signaling via inhibition of MEK1 (mitogen-activated protein kinase kinase 1), and point mutations have been reported in WNK1, WNK2, WNK3, and WNK4. In meningiomas, WNK2 was aberrantly methylated in 83% and 71% of grade II and III meningiomas, respectively, but rarely in a total of 209 tumors from 13 other tumor types. Aberrant methylation of the CpG island was associated with decreased expression in primary tumors. WNK2 could be reactivated with a methylation inhibitor in IOMM-Lee, a meningioma cell line with a densely methylated WNK2 CpG island and lack of WNK2 expression. Expression of exogenous WNK2 inhibited colony formation, implicating it as a potential cell growth suppressor. These findings indicate that epigenetic mechanisms are common across meningiomas of all grades and that for specific genes such as WNK2, epigenetic alteration may be the dominant, grade-specific mechanism of gene inactivation.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, Cancer Center, Room N225, 2340 Sutter St., San Francisco, CA 94143, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Jun
authors.forename: Chibo
authors.initials: C
authors.lastname: Hong
authors.forename: Anita
authors.initials: A
authors.lastname: Lal
authors.forename: Judith M
authors.initials: JM
authors.lastname: Wong
authors.forename: Michael W
authors.initials: MW
authors.lastname: McDermott
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Bollen
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: William A
authors.initials: WA
authors.lastname: Held
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Smiraglia
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Costello
mesh_terms: D015153:Blotting, Western; D003114:Colony-Forming Units Assay; D055028:Comparative Genomic Hybridization; D018899:CpG Islands; D019175:DNA Methylation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D008577:Meningeal Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008579:Meningioma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D015778:Minor Histocompatibility Antigens; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D008156:Luciferases; C523482:WNK2 protein, human; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C488586:WNK3 protein, human; D048369:MAP Kinase Kinase 1