Genomic Annotation of the Meningioma Tumor Suppressor Locus on Chromosome 1P34

Genomic annotation of the meningioma tumor suppressor locus on chromosome 1p34

Erik P Sulman1,2, Peter S White2,3 and Garrett M Brodeur*,2,3

1The Fels Institute for Molecular Biology and Cancer Research, Temple University School of Medicine, Philadelphia, PA 19140, USA; 2Division of Oncology, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA; 3Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

Meningioma is a frequently occurring tumor of the 13–20% of adult brain tumors, with an overall incidence meninges surrounding the central nervous system. Loss of approximately 7–8/100 000 per year, including of the short arm of chromosome 1 (1p) is the second most asymptomatic cases discovered at autopsy (Nakasu frequent chromosomal abnormality observed in these et al., 1987; Bondy and Ligon, 1996). Although usually tumors. Previously,we identified a 3.7 megabase (Mb) benign, 5–10% of tumors are malignant and invasive region of consistent deletion on 1p33–p34 in a panel of 157 and 20–40% of patients suffer from recurrent disease tumors. Loss of this region was associated with advanced (Zu¨ lch, 1979; Mathiesen et al., 1996). Meningiomas are disease and predictive for tumor relapse. In this report,a also associated with Neurofibromatosis type 2, occur- high-resolution integrated map of the region was con- ring nearly as frequently in that disease as vestibular structed (CompView) to identify all markers in the schwannomas (Evans et al., 1992). smallest region of overlapping deletion (SRO). A regional Molecular studies of meningiomas have identified somatic cell hybrid panel was used to more precisely frequent deletion of the long arm of chromosome 22 localize those markers identified in CompView as within (22q) in 60–70% of tumors (Dumanski et al., 1987, or overlapping the region. Additional deletion mapping 1990; Rempel et al., 1993; Ruttledge et al., 1994b). using microsatellites localized to the region narrowed the Inactivation of the NF2 tumor suppressor gene has been SRO to approximately 2.8 Mb. The 88 markers remain- demonstrated in approximately 60% of cases (Ruttledge ing in the SRO were used to screen genomic databases to et al., 1994a; Wellenreuther et al., 1995). Several other identify large-insert clones. Clones were assembled into a genomic regions have been proposed to undergo physical map of the region by PCR-based,sequence- alteration in meningiomas. Cytogenetic studies have tagged site (STS) content mapping. A sequence from shown that allelic loss of the short arm of chromosome 1 clones was used to validate STS content by electronic (1p) is the second most common karyotypic abnormality PCR and to identify transcripts. A minimal tiling path of observed in these tumors (Jime´ nez-Lara et al., 1992). 43 clones was constructed across the SRO. Sequence data Loss of heterozygosity (LOH) of 1p has been suggested from the most current sequence assembly were used for to play a role in tumor progression (Simon et al., 1995; further validation. A total of 59 genes were ordered within Sulman et al., 1998; Leone et al., 1999; Muller et al., the SRO. In all,17 of these were selected as likely 1999; Lamszus et al., 2000). candidates based on annotation using Gene Ontology In order to systematically identify the frequency and Consortium terms,including the MUTYH, PRDX1, extent of 1p LOH in meningioma, we previously FOXD2, FOXE3, PTCH2,and RAD54L genes. This examined a panel of 157 matched normal and tumor annotation of a putative tumor suppressor locus provides a DNAs and characterized a region of consistent deletion resource for further analysis of meningioma candidate within 1p33–p34 (Sulman et al., 1998). This smallest genes. region of overlapping deletion (SRO), flanked distally Oncogene (2004) 23, 1014–1020. doi:10.1038/sj.onc.1206623 by microsatellite marker D1S271 and proximally by ONCOGENOMICS D1S2134, spans approximately 1.5 centiMorgans (cM) Keywords: meningioma; tumor suppressor gene; chro- or 3.7 megabases (Mb). Allelic loss of this region mosome 1 correlated significantly with 22q deletion and NF2 inactivation and was associated with advanced disease (WHO grade III). Moreover, 1p LOH was predictive for tumor recurrence, suggesting that a putative tumor Meningioma is a tumor of the arachnoid meninges suppressor gene in this region may serve as a molecular surrounding the central nervous system. It accounts for marker for advanced disease. Several additional tumor types exhibit characteristic deletions of this region on *Correspondence:GM Brodeur, Division of Oncology, Children’s 1p, including breast carcinoma and oligodendroglioma Hospital of Philadelphia, Room 902 – Abramson Research Center, (Bieche et al., 1993; Bello et al., 1995a, b). In addition to 3516 Civic Center Blvd., Philadelphia, PA 19104-4318, USA; E-mail:[email protected] neoplasia, several genetic disorders demonstrate linkage Received 10 July 2001; revised 21 March 2003; accepted 17 March 2003 to within a 2 cM region overlapping this region, Annotation of the meningioma suppressor locus on 1p34 EP Sulman et al 1015 including paroxysmal choreoathetosis, one form of hereditary congenital ptosis, and muscle–eye–brain disease, which was recently shown to involve mutation of the POMGNT1, located within the SRO (Auburger et al., 1996; Engle et al., 1997; Cormand et al., 1999; Yoshida et al., 2001). In the current study, we have endeavored to fully characterize this tumor suppressor locus by conducting additional deletion mapping in the region and by precisely identifying and localizing transcripts to this region. These candidate genes can then be assessed for their role in tumorigenesis. To identify all expressed genes in the SRO as well as additional polymorphic loci for deletion mapping, we first constructed a high-resolution map (CompView) of the region integrating all publicly available radiation hybrid (RH), genetic linkage (GL), and cytogenetic data for chromosome 1 (White et al., 1999b). According to the CompView map, the SRO spans 57.7 centirays (cR) and approximately 3.7 Mb of physical distance. Analysis of the defined region yielded 114 unique loci within or overlapping the SRO, including 76 transcripts, 33 polymorphisms, and five anonymous markers. Another 14 genes were identified as mapping to 1p32–p34 by Figure 1 LOH somatic cell hybrid mapping of the meningioma SRO. Patient sample collection preparation PCR amplification Medline queries (White et al., 1999a; Schutte et al., methodologies have been described previously (Sulman et al., 2001). For all markers, unique sequence-tagged sites 1998). PCR was performed in the presence (for LOH analysis) or (STSs) were selected or constructed for STS content absence (for somatic cell hybrid analysis) of a [g32P]dATP end- mapping. labeled primer. Somatic cell hybrid DNAs were the generous gift of Dr John K Cowell (Roberts, 1996). Microsatellite markers used for Since many of the 128 markers identified could not be LOH analysis were analysed as described (Sulman et al., 1998). precisely ordered within the SRO, a somatic cell hybrid Products from STSs used for somatic cell hybrid mapping were panel containing a series of 1p deletions and transloca- separated by gel electrophoresis (Visigel; Stratagene, La Jolla, CA, tions was screened to identify clones which could be USA). All data generated were stored and analysed in a custom used for marker localization (Roberts, 1991). Two relational database developed using 4th Dimension (4D, Inc., San Jose, CA, USA). Shown at left is an ideogram of chromosome 1p. hybrids containing 1p chromosomal breakpoints were Adjacent to the ideogram is a portion of the genetic linkage map of identified (Figure 1) that together roughly approximate chromosome 1, corresponding to bands p33–34 (Vance et al., the SRO:WAG8, which contains a (1;X) translocation, 1997). Centimorgan (cM) positions are shown for the markers on and 1108, which contains a 1p deletion. The breakpoint the genetic map. Microsatellites located between D1S2713 and D1S2824 have been ordered based on the CompView map and/or of the WAG8 1p translocation lies just distal to the physical map (Figure 2). LOH results for the three tumors D1S2713 and the distal breakpoint of the 1108 deletion whose allelic deletions define the meningioma SRO are shown. An lies just proximal to D1S2824. Using this panel, 24 open circle indicates retention of heterozygosity, a filled circle markers could be localized outside of the SRO, 13 indicates loss of heterozygosity, and a dash indicates constitutional distally and 11 proximally. homozygosity. A large bracket to the right of the LOH data identifies the meningioma SRO, spanning from D1S421 distally to Of the remaining 29 polymorphic markers still D1S2134 proximally. Shown to the right of the LOH results are the mapping within the SRO following somatic cell hybrid somatic cell hybrids. The retention patterns of the hybrids are analysis, seven had sufficient ordering information in indicated by gray bars. WAG8 contains a (1;X) translocation with CompView to be useful for LOH analysis. Three a proximal 1p breakpoint between D1S2713 and D1S1586. 1108 contains a deletion of distal 1p with a breakpoint between D1S2824 tumors, #79, #96, and #106, whose deletions were and D1S2661. At far right are ethidium bromide-stained gels previously used to define the SRO, were subjected to demonstrating the retention pattern of the somatic cell hybrids for further LOH analysis (Figure 1). The distal boundary of specific marker LOH for tumor #79 was further refined to proximal of D1S421, reducing the SRO by approximately 0.9– 2.8 Mb. No further reduction was possible proximally. fingerprint data both from the Sanger Institute and the By moving the distal boundary of the SRO to D1S421, Washington University Genome Sequencing Center an additional 16 markers, including 12 genes, were were screened to identify additional clones (Pruitt, excluded from the region. 1997). Approximately 118 clones were identified in this The 88 markers still localized to the SRO as well as manner and obtained for STS content mapping. some flanking markers were used to screen the Sanger Initially, six contigs were assembled within the region. Institute’s chromosome 1 physical mapping database to As the clone sequence became available, conventional identify candidate P1- and bacterial-artificial chromo- PCR-based STS content mapping was confirmed by somes (PACs and BACs, respectively) in the region a DNA sequence-based in silico STS identification (Gazetteer 1998; Lander et al., 2001). In addition, clone algorithm (e-PCR, modified from Schuler, 1997). The

Oncogene Annotation of the meningioma suppressor locus on 1p34 EP Sulman et al 1016 combination of e-PCR-based content mapping and tutional and tumor DNAs from patients with nevoid clone sequence comparisons using BLAST (Altschul basal cell carcinoma syndrome (NBCCS). NBCCS is a et al., 1990) permitted the closure of all the five gaps in developmental defect and tumor predisposition syn- the physical map. The resultant physical map consists of drome in which patients develop medulloblastomas and a single PAC and BAC clone contig containing a total of basal cell carcinomas (BCCs) as well as other tumors, 106 clones. A minimal tiling path of this contig, including meningiomas (Hahn et al., 1996). Analysis of represented by 43 clones, is shown in Figure 2. Draft PTCH2 in medulloblastomas and BCCs identified rare sequence for 30 and finished sequence for 45 of the 106 mutations of the gene (Smyth et al., 1999). Mutational clones on the physical map is presently available. analysis in neuroblastoma failed to find evidence of The physical map was confirmed by comparison to PTCH2 mutations in the 14 tumors analysed (Jogi et al., the build 31 sequence assembly of the human genome 2000). Nevertheless, no mutational studies of the gene from the National Center for Biotechnology Informa- have been conducted to date in meningioma. tion (NCBI) (www.ncbi.nlm.nih.gov/genome/guide/hu- There are several other plausible candidate genes in man/), using version 17 of the Human Genome Browser the region. The PRDX1 gene has been shown to be from the University of California, Santa Cruz (UCSC upregulated during cell proliferation (Prosperi et al., Genome Browser) (Kent et al., 2002). An additional 15 1993, 1998). The RAD54L gene is a member of a family genes, including 10 previously characterized, were of helicases (Rasio et al., 1997). Genes with helicase identified within or just flanking the SRO by direct activity have been implicated in a number of cancer sequence analysis or by comparison to genome assem- predisposition syndromes (Bello et al., 2000). However, blies. In total, 59 genes have been localized to the SRO mutational analysis of RAD54L in 25 oligodendroglio- (Table 1), including 32 genes previously characterized mas and 18 meningiomas failed to identify any deletions with respect to function. Of the remaining 27 genes, 11 or inactivating mutations of the gene (Mendiola et al., represent putative full-length transcripts. The remaining 1999; Bello et al., 2000). Specific variants in the 16 genes consist of clusters of expressed sequences or a MUTYH gene, involved in base excision repair, may single expressed sequence tag, the majority of which play a role in cancer predisposition; however, somatic support gene predictions shown in the sequence mutations of the gene have not been demonstrated in assembly. The build 31 assembly consists of two tumors (Al-Tassan et al., 2002). In addition, micro- sequence contigs reported by the NCBI as nonoverlap- satellite instability, as is seen in the defective mismatch ping (Genbank Accession numbers NT_004852 and repair of hereditary nonpolyposis colorectal cancer, is NT_032977), but which in fact overlap significantly an infrequent finding in meningiomas (Pykett et al., according to the analysis presented here (see Figure 2). 1994; Simon et al., 1996; Sulman et al., 1998). The To further identify likely candidates, the European FOXD2 and FOXE3 genes belong to a family of genes Bioinformatics Institute’s (EBI) annotation of the with homology to Drosophila forkhead (Ernstsson et al., human proteome (Brooksbank et al., 2003; Pruess 1997; Blixt et al., 2000). Members of the forkhead et al., 2003) was screened using the genes in the SRO. protein family have been shown to play a role in The EBI annotation relies on terms defined by the Gene embryonic development and tumorigenesis (Galili et al., Ontology (GO) Consortium that describe gene function 1993; Li and Vogt, 1993; Shapiro et al., 1993; Downing and localization (Gene Ontology Consortium, 2001). et al., 1995). To specifically identify tumor suppressor genes, two Several proposed 1p candidate meningioma suppres- GO terms were queried against the entire EBI annota- sor genes have been mapped outside the SRO based tions (dated January 23, 2003 and available at www. on the work presented here. Santarius et al. (2000) geneontology.org):‘tumor suppressor’ (GO:0008181) conducted mutational analysis of the CDKN2C and ‘negative regulation of cell proliferation’ (GO: (p18INK4C) gene (located proximal to the SRO) in a 0008285). A total of 236 genes (‘the suppressor set’) panel of 40 meningiomas, identifying a single silent were identified in this manner. The set of molecular mutation in one tumor. Similarly, the alkaline phospha- function and biological process GO terms for this set of tase gene (ALPL) has been proposed as a candidate genes as used to query the set of GO terms belonging to suppressor gene but maps quite distal to the SRO all the genes in the SRO. Of the 32 known genes in (Niedermayer et al., 1997). the SRO, 30 had GO annotations in the EBI dataset. This annotation of the meningioma consensus dele- Of these, 17 had annotations in common with tion region will permit a focused interrogation of the suppressor set. We propose this set of 17 genes as localized transcripts. While the large-scale efforts of the most likely candidates. the Human Genome Project will soon provide a finished Several of the genes within the SRO identified via the sequence of the genome, focused analysis and validation GO analysis are particularly compelling candidate of disease gene loci will still be necessary (Lander et al., tumor suppressors. The PTCH2 gene is a homolog to 2001; McPherson et al., 2001; Venter, 2001). In this the Drosophila patched gene, whose product is involved report we provide a comprehensive ordering and in signaling with hedgehog in the establishment of identification of transcripts in the meningioma SRO, segment polarity and anterior–posterior orientation which is an important step towards the eventual (Smyth et al., 1999; Zaphiropoulos et al., 1999). elucidation of the meningioma 1p tumor suppressor Mutations of the human PTCH gene, the first patched gene. A complete evaluation of all candidate suppressor homolog identified, have been demonstrated in consti- genes within the SRO will require a systematic

Oncogene noaino h eigoasprso ou n1p34 on locus Sulman suppressor EP meningioma the of Annotation

Figure 2 Physical map of the meningioma SRO. STS content mapping for the construction of PAC and BAC contigs was accomplished initially by PCR amplification of clone DNAs using STSs tal et in the region and then later confirmed using a program written in 4th Dimension (4D, Inc., San Jose, CA, USA) based on the e-PCR algorithm (Schuler, 1997). Clones were prepared either in 5 or 500 ml cultures using the Qiagen Plasmid Midi Kit (Qiagen, Valencia, CA, USA) with modifications indicated by the manufacturer. To facilitate map closure, several STSs (those beginning with MG1P) were designed from an overlap sequence between clones by first screening the overlapping sequence using RepeatMasker (ftp.genome.washington.edu/cgi-bin/RepeatMasker) and then designing primers to the masked sequence using Primer3 (www-genome.wi.mit.edu/cgi-bin/primer/primer3_www.cgi). A linear order for all markers is shown from telomere (left) to centromere (right) at the top of the figure. The position of the meningioma SRO is indicated by a black bar. Underlined markers are microsatellites. Markers indicated with a w are anonymous STSs. All other markers are expressed transcripts. Markers with an * correspond to framework radiation hybrid markers on the CompView map (genome.chop.edu) whose linear order was predicted with high statistical probability. Below the marker list is a minimal tiling path of large-insert clones that span the region. Clone sizes are determined by the extent of STS content and do not reflect actual physical distance. Below the contig are the approximate positions of the NCBI sequence assemblies (build 31) for this region. Assemblies NT_004852 and NT_032977 overlap based on e-PCR results Oncogene 1017 Annotation of the meningioma suppressor locus on 1p34 EP Sulman et al 1018 Table 1 Candidate meningioma tumor suppressor genes shown in map order Gene symbol/marker name Description Database identifiera

CNKb Cytokine-inducible kinase 1263 PTCH2b Homolog 2 of Drosophila Patched 8643 EIF2B3 Eukaryotic translation initiation factor 2B, subunit 3g 8891 AK095730 Putative full-length transcript Hs.376217 FLJ21156b Putative full-length transcript 79654 UROD Uroporphyrinogen decarboxylase 7389 KIAA1511 Putative full-length transcript 57643 TIGR-A004V29 Novel gene UniSTS:72524 WI-21196 Cluster of expressed sequence tags of putative novel gene Hs.167405 MUTYHb Homolog of E.coli MutY mismatch repair gene 4595 BC006119 Putative full-length transcript Hs.334348 MGC15668 Putative full-length transcript 84842 TESK2b Testis-speciﬁc kinase 2 10420 DKFZP564I122 Putative full-length transcript 25974 PRDX1b Peroxiredoxin 1 5052 AKR1A1 Aldo-keto reductase family 1, member A1 10327 FLJ33084 Putative full-length transcript 149483 NASP Nuclear autoantigenic sperm protein, histone binding 4678 SP192 Putative full-length transcript 60313 stSG16256 Novel gene UniSTS:32867 WI-13726 Cluster of expressed sequence tags of putative novel gene UniSTS:8584 LOC51249 Putative full-length transcript 51249 IPP Intercisternal A particle-promoted polypeptide 3652 RH69362 Cluster of expressed sequence tags of putative novel gene UniSTS:39476 MAST205b Microtubule-associated,testis-speciﬁc,serine/threonine protein kinase 23139 PIK3R3 Phosphoinositide-3-kinase, regulatory subunit, polypeptide 3 8503 TIGR-A008Z33 Cluster of expressed sequence tags of putative novel gene UniSTS:15800 TSPAN-1b Tetraspan-1 10103 POMGNT1 O-linked mannose b-1,2-N-acetylglucosaminyltransferase 55624 RAD54Lb Homolog to S.cerevisiae Rad54 DNA repair gene 8438 MUF1 Elongin BC-interacting leucine-rich repeat protein 10489 UQCRH Ubiquinol-cytochrome c reductase hinge protein 7388 BC016907 Cluster of expressed sequence tags of putative novel gene Hs.375757 FAAH Fatty acid amide hydrolase 2166 stSG24251 Novel gene with weak homology to FAAH 386104 LOC148932 Putative full-length transcript 148932 OTX3b Homolog to Drosophila orthodenticle transcription factor 127343 AK05673 Putative full-length transcript Hs.350764 MKNK1b MAP kinase-interacting serine/threonine kinase 1 8569 ATPAF1 Assembly factor for mitochondrial F1 complex assembly factor 64756 KIAA0494 Putative full-length transcript 9813 stSG12794 Cluster of expressed sequence tags of putative novel gene UniSTS:47409 stSG15244 Expressed sequence tag of putative novel gene UniSTS:1036 CYP4X1 Cytochrome P450, subfamily IVX, polypeptide 1 260293 CYP4B1 Cytochrome P450, subfamily IVB, polypeptide 1 1580 RH17479 Cluster of expressed sequence tags with weak homology to CYP4A11 Hs.176588 AK097373 Putative full-length transcript Hs.404984 CYP4A11 Cytochrome P450, subfamily IVA, polypeptide 11 1579 stSG8063 Novel gene with weak homology to CYP4A11 UniSTS:82953 DD96b Membrane associated protein 17 upregulated in carcinoma 10158 TAL1b T-cell acute lymphocytic leukemia 1 6886 AI766054 Cluster of expressed sequence tags of putative novel gene Hs.315562 SILb TAL1 (SCL) interrupting locus 6491 UMP-CMPKb UMP-CMP kinase 51727 AI393217 Cluster of expressed sequence tags of putative novel gene Hs.159718 FOXE3b Forkhead box E3 2301 FOXD2b Forkhead box D2 2306 SHGC-155201 Novel gene UniSTS:182064 FLJ00388 Putative full-length transcript Hs.61504 RH68723 Cluster of expressed sequence tags of putative novel gene UniSTS:9790

aA unique identifier has been given for querying Internet-based databases. Identifiers beginning ‘Hs.’ can be used to query UniGene (www.ncbi.nlm.nih.gov/UniGene/). Those beginning ‘UniSTS’ can be used to search the UniSTS database (www.ncbi.nlm.nih.gov/genome/sts/). All others can be used to query LocusLink (www.ncbi.nlm.nih.gov/LocusLink). bGenes identified by GO analysis (in bold).

Oncogene Annotation of the meningioma suppressor locus on 1p34 EP Sulman et al 1019 approach, including mutational analysis, transcriptional (GMB) and MH-60240 (PSW), and the Audrey E. Evans proﬁling, and functional demonstration of suppression. Endowed Chair (GMB). We also thank Dr John Maris and Dr Michael Hogarty for their helpful advice, Dr Jan Dumanski Acknowledgements for providing meningioma specimens, Dr John Cowell for the This work was supported by grants from the National Cancer somatic cell hybrid DNAs, and Tamar Marensky and Bing Center (EPS), the National Institutes of Health CA-39771 Kung for their technical assistance.

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