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[CANCER RESEARCH54, 6321—6324, December 15, 1994] Advances in Brief CDKN2 (p16/MTS1) Gene Deletion or CDK4 Amplification Occurs in the Majority of Glioblastomast Esther E. Schmidt,2 institute for Oncology Stockholm, Sweden Koichi and Pathology, Ichimura,2 Division Guido Reifenberger, of Tumor Pathology, and V. Peter Collins3 and Ludwig institute for Abstract Forty-six gioblastomas, 16 anaplastic astrocytomas, and 8 astrocyto mas were studied for the loss of the CDKN2 (p16/MTSJ) gene on 9p. The CDKN2 locus was homozygously deleted in 19 of 46 glioblastomas (41%) and 1 allele was lost in an additional 13 cases (28%). The deleted regions were limited centromerically in some cases by the MTS2 locus and tab merically by the 1063.7 locus. CDKN2 was homozygously deleted in 3 of 16 anaplastic astrocytomas (19%) and 2 further cases showed loss of 1 allele. Amplification of the CDK4 gene was present in 7 of 14 (50%) glioblasto mas and 3 of 11 (27%) anaplastic astrocytomas Cancer Research, Stockholm Branch, Karolinska Hospital, S-171 76 In this study we have carried out an allelic assessment at the CDKN2, MTS2, and surrounding loci in a series of 70 human glioma tissue samples. The findings support a role for the CDKN2 gene as a tumor suppressor gene in glioblastomas and anaplastic astrocytomas; furthermore we have found that CDK4 gene amplification is a com mon abnormality in tumors not showing loss of CDKN2 gene alleles. It would appear that aberrations of the genes coding for components of this cell cycle-regulatory system occur in at least 85% of human glioblastomas and 50% of anaplastic astrocytomas. with no losses at the CDKN2 locus as well as in 2 of 32 (6%) glioblastomas with CDKN2 losses. Thus one or more of these two genes were shown to be aberrant in 85% of glioblastomas and 50% of anaplastic astrocytomas. None of the 8 astrocytomas showed abnormalities of these genes. Materials and Methods Tumor Material, 8 astrocytomas reported Cytogenetic and molecular genetic analyses of anaplastic astro cytomas and glioblastomas [WHO malignancy grades III and IV (1)] indicate consistent loss and amplification of genetic informa tion at several specific genomic locations (2—6).One region of loss found among anaplastic astrocytomas and glioblastomas involves portions of the short arm of chromosome 9. The common region of homozygous deletion has been defined as lying between the were included previously extraction, Introduction DNA Extraction, and Southern Blotting Analysis. A total of 70 tumors including 46 glioblastomas, 16 anaplastic astrocytomas, and in this study. Almost (constant case number) Southern blotting, hybridization, all of the cases have been in various studies (4, 6). DNA exposure on Storage Phosphor Screens, and analysis using a Phosphorlmager (Molecular Dynamics, Sunny vale, CA) and ImageQuant software were performed as described (4). For Southern blotting, TaqI was used as the restriction enzyme. DNA Probes. DNA probes were generatedby PCR amplificationusing the following primers CDKN2(MTSJ) (exon and normal human leukocyte DNA as template: 1) (2FU, CCCAGTCACGACGTfGTAAAACGACG GCCAGTGAAGAAAGAGGA0000CFG; 1108R, GCGCTACCFGAUC CAATFC); CDKN2(MTSJ)(exon 2)(42F, GGAAATFGGAAACTGGAAGC; 551RU, CCCAGTCACGACGrFGTAAAACGACGGCCArFCTGAGCrF TGGAAGCFCF); MTS2 (89F, TGAG1TFAACCFGAAGGTGG; 50R, GGG D9S171locusandtheIFNce/wgenecluster(4). Thisregionhas TGGGAAATTGGGTAAG);1063.7 (forward, CCG1TFCAGCTTCTCAT been reported to be deleted in various tumors suggesting that a CAC; reverse,CCGACFGTCCCAUGTGAU); cl.b (forward,AAGCITF tumor suppressor gene common to different malignancies is local CCCACAAACFGGC; ized in this limited area. Recently, the CDKN2 (p16/MTSJ) gene was identified in this area and shown to be deleted in a series of cell lines (7—9).The CDKN2 gene has been reported to be mutated in some families with inherited melanoma susceptibility (10, 11) and also in a high proportion of esophageal (12), pancreatic (13), and non-small cell lung carcinomas (14). p16 has been shown to specifically inhibit the binding of the CDK4 protein to cyclin Dl (9). Cyclin Dl and CDK4 form a complex which, among others, is capable of phosphorylating the Rbl protein and thus p16 is involved in inhibiting cells progressing from G1 into S phase. The MTS2 gene has recently been reported to code for a protein, p15Thl@(4B, which has a similar function (15). We have previously described amplification of the CDK4 gene in approximately 15% of anaplastic astrocytomas and glioblastomas, the MDM2 gene being frequently coamplified (6). 35 cycles of amplificationwere performed at 94°Cfor 1 min, 60°Cfor 1 mm, and 72°Cfor 1 min with (CDKN2/MTSJ and MTS2) or without (1063.7 and reverse, AATGC(TFGGCATAAGGGAC). Thirty to cl.b) 5% DMSO. The PCR products were separated on a 1.2% low-melting point agarose gel. The bands were excised and the PCR products were purified by Magic PCR kit (Promega, as described identical. Madison, WI) and used as probes. All primers are by Kamb et a!. (7), who showed These probes were initially MTSJ(CDKN2) hybridized several cell lines including T98G, U118MG, to TaqI-digested and p16 to be DNA from and normal human leukocyte DNA. Because of the high homology of exon 2 in CDKN2 and MTS2,both the CDKN2 (exon 2) probe and the MTS2 probe identified identical band pairs in normal DNA, 3.3 and 1.3 kilobases, respectively (data not shown). In T98G DNA, only the 1.3-kilobase band was detected while neither band was found in U118MG DNA. T98G has a homozygous deletion only at the CDKN2locus while U118MG has a much larger deletion including both the CDKN2 and MTS2 loci. Accordingly, the 3.3-kilobase band corresponds to CDKN2 exon 2 and the 1.3-kilobase band to MTS2,and the CDKN2 exon 2 probe was used to analyze both loci. The CDKN2 exon 1 probe gave a single 1.0-kilobase band (datanotshown). Received 9/26/94; accepted 11/3/94. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by grants from the Swedish Cancer Society and the Funds of the Karolinska Institute. 2 These authors contributed equally to this work. 3 To whom requests for reprints should be addressed, at Institute for Oncology and Pathology, Division of Tumor Pathology, Box 100, Karolinska Hospital, 5-171 76 Stockholm, Sweden. A probefor the cyclin Dl gene was generatedby reversetranscription-PCR using the primers TCCTGTGCTGCGAAGTGGAAAC GGGGCfCCFCAGGUC and cDNA from the A431 and AAGTFGTF cell line. A 655-base pair PCR fragment corresponding to bases 158 to 812 of the cyclin Dl cDNA sequence (EMBL Accession No. M64349) was subcboned into the pCRII vector using the TA-cloning kit (Invitrogen, San Diego, CA), and purified plasmid was used as a probe. The identity of the probe for cyclin Dl was confirmed by sequencing using the Sequenase Version 2.0 DNA Sequencing 6321 Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1994 American Association for Cancer Research. CDKN2 DELE11ONS AND CDK4 AMPLWICATIONS Kit (USB) (data not shown). The DNA probes for CDK4 and MDM2 have been described previously Densitometric Analysis. Densitometric and calculated as described signals were using measured formula GB23 GB14 GB29 AA49 AA18 (6). formed measured interest― (LOl) GB22 IN GUOMAS hybridization analysis of allele dosage was per previously the ImageQuant signals were at the control locus D2S44 (4). Briefly, software, normalized B hybridization and the “locusof against T B T 1063.7 the signals (CL) on the same blot according to the 1.8 No. of alleles = 2 X N X LOIm B T B T =@ B T B T 0.2 1.1 1.4 0.2 0.1 CDKN2 LOI(B) with @ CL(B@l) CL(B@2) — CL(T@l 0.6 1.0 0.2 0.6 1.2 1.2 2.0 0.2 0.2 1.8 1.0 MTS2 CL(T@2) 2 where T represents tumor, B blood, and A 1 and A2 larger and smaller alleles, ci .b respectively. For DNA extraction, tumor pieces containing a minimum of 70% tumor cells were used. On the basis of this principle, 0 to 0.6 as representing a homozygous we consider deletion, an allele value of 0.9 to 1.3 as representing a 1.2 hemizygous deletion, and values of 1.7 or more as representing retention of both alleles. significant Only an allele copy number of 5 or more was 1.6 considered amplification. Results In a previous study we found a common region of homozygous deletion in glioblastomas flanked by the D9S171 and JFNcrJw loci. Nine homozygous deletions involving one or the other or both of these loci were determined among the 47 glioblastomas studied (19%) (4). The incidence of homozygous deletions in this region more than doubled (41%) among the glioblastomas when 4 loci between the Fig. 1. I@oci [cI.b (centromcric), M1@2, CDKN2, 1%3.7 (telomeric)J studied by Southern blot analysis are shown for 4 glioblastoma cases (GB22, GB23, GB14, and GB29) and 2 anaplastic astrocytomas (AA49 and AA18). B, constitutional WBC DNA T, D9S171andtheIFNcvJw lociwereexamined. Nohomozygous dele tumor DNA. To assess loading of DNA, control hybridizations of the same Southern blots tions had been identified previously among the anaplastic astrocyto mas, yet one case which had previously shown loss of one allele at the IFNa/w locus and 2 cases in which no losses had been identified at either locus were found to have homozygous deletions located be tween but not involving the D9S171 or the IFNcrJw loci. The homozygous deletions in the glioblastomas are frequently large. The smallest region in a single case is found in GB22 and includes the MTS2 and CDKN2 loci (the status of the 1063. 7 locus could not be determined in this case) with breakpoints between the tumor DNA is given below the tumor lane (for estimation of allele values see “Materials and Methods―). GB22 showed the smallest region of homozygous deletion. The tissue cl.b and MTS2 loci centromerically and the CDKN2 and lFNctho loci telomerically (Figs. 1 and 2). The homozygous deletions in the ana plastic astrocytomas (AA12, 49, and 18; Fig. 2) all involve a more limited area with AA49 and AA18 (Figs. 1 and 2) limiting the loss of both alleles to the CDKN2 and MTS2 loci with breakpoints centro merically between MTS2 and cl.b and telomerically between CDKN2 and 1063. 7. A similar tebomeric breakpoint can be found in case GB23 (Figs. 1 and 2) which shows loss of one allele at the CDKN2 locus with retention of both alleles at the 1063. 7 locus. Case GB14 (Figs. 1 and 2) shows a complex pattern ofloss with the retention of one allele at the MTS2 locus and loss of both alleles at all surrounding loci suggesting that the MTS2 locus may not always be included in the common region of loss. This is further supported by the deletion mapping of the glioblastomas with losses of one allele. Cases GB25 and GB29 retain both alleles at the MTS2 locus and lose one at the CDKN2 locus and thus have centromeric breakpoints between these loci. Of the loci studied, the common region lost thus always includes only the CDKN2 locus. When the incidence of losses (of one or both alleles) at all loci are considered, alleles in the region between D9S171 and the lFNcrJo loci were lost in 32 of 46 glioblastomas (70%) with CDKN2 and adjacent at the highly informative D2S44 locus are shown. The allele value at each locus for the sample used was determined histologically to contain approximately 80% tumor cells. Note the loss of one allele at cl.b, loss of both alleles at MTS2 and CDKN2.The 1063.7 locus was not determinable but both alleles were retained at the iFNaJw locus (see Fig. 2). GB23 shows boss of one allele at the MTS2 and CDKN2 loci with the centromeric breakpoint between D9S126 (see Fig. 2) and MTS2 but with the tebomeric breakpoint between CDKN2 and 1063.7. GB14 retains one allele at the MTS2 locus despite losing both alleles at the surrounding loci, placing the MTS2 gene outside the region of common loss. GB29 shows retention of all centromeric alleles including the hflT2 gene and then shows loss of one allele at the CDKN2locus. Both alleles were determined to be retained at the iFNcsJw locus. AA49 and AA18 show retention of at beastone allele at the flanking loci cl.b and 1063.7 with loss of both alleles at the intervening MTS2 and CDKN2 lad. loci (MTS2 and 1063. 7) showing the highest incidence of loss. The anaplastic astrocytomas showed loss of genetic material from the same region in 10 of 16 cases (63%) but the highest incidence did not occur at the CDKN2 and adjacent loci (5 of 16). The genetic loss was more common at the D9S126 and IFNoJco loci, often with loss of one allele at both these loci, with retention ofboth alleles at all intervening loci (Fig. 2). When all tumors were studied for amplification of the CDK4 and MDM2 genes, CDK4 was found to be amplified in 20% of the glioblastomas and 19% of the anaplastic astrocytomas. MDM2 was coamplified in five of the glioblastomas and in two of the anaplastic astrocytomas (Fig. 2). Amplification occurred preferentially among the glioblastomas and the anaplastic astrocytomas which retain both alleles at all loci in the immediate region of the CDKN2 locus. Two glioblastomas, GB28 and GB7, show amplification of CDK4 and MDM2 in the presence of losses of alleles at the CDKN2 and sur rounding loci (Fig. 2). GB28 has a homozygous deletion which stretches centromerically from between the D9S126 and the cl.b loci, 6322 Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1994 American Association for Cancer Research. @ ‘@ e CDKN2 DELEtiONS A cen CD @ @ @ @ @ tel ‘- c*1 @; .@Cl) @2 @ @ @ @ @ 9p C@1 N. r'@ AND CDK4 AMPLIFICATIONS to a position telomerically between the 1063. 7 and the IFNcsJw loci. GB28 shows an allele copy number ofjust over 5 for the CDK4 gene. GB7, which shows loss of one allele at all loci between the cl.b and @B :@ c@ the 1063.7 loci has a high level of CDK4 and MDM2 amplification GB97 GB2I GB69 GBI4 — — — — — — — — — — GB32 GB2S GBI7 — — — — — — — — — — — : GBI6 GB45 — — — ——n— : :LIIII LIII GBI5O GBI5I GB2 GBIOI LIII GB4O GB4 GBI (Fig. 2). None of the three anaplastic astrocytomas with losses in the region of the CDKN2 gene showed evidence of amplification of CDK4 or MDM2. All of the low-grade astrocytomas were assessable at the CDKN2, MTS2, CDK4, and MDM2 loci and no evidence of any losses of alleles or amplification of genes was found. All 70 tumors were additionally screened for amplification of the cyclin Dl gene. However, no am plification was found in this series. — — ! LIII — : — ! LIII — : LIII LIII — — — — — — — — — — — — — — — — — — — — — — : LIII — LIII LIII — : 11111 L@J — : — LIII LIII : LII LIII Discussion LIII The results of this study implicate the CDKN2 gene to be involved in the development of anaplastic astrocytomas and glioblastomas. Homozygous deletion of the region encompassing the CDKN2 gene was found in a high percentage of glioblastomas (41%). In addition, we found the same region homozygously lost in 19% of the anaplastic m : — GB38 @ @ GB6 LIII GB22 — GB7 @ GB8 GB5 E@I ___ __ @LI __ ELI @ GB23 GB39 @ GB29 E@ ___ L@@II LIII @ GB9O @ GB142 GBI3 E@ @ @ @ @ ___ ___ __ ___ ___ :: ___ _____ : : LII LIII LII LII LIIIEli ___ __ LII : : :L@I L@J LIII: @II L@II : :@:@ :L@IIL@II LII :L@IILIII GBI2 GB15 GB27 GB44 AAI2 El E@I E1 : E@I LII LIII LII LII EIIILIIILII LII LII LII LIII — @J :LLI LIII :LII LIII : LII LII LII LII EII1 ———— AA49 AAI8 LIII : — AA2 AA13 ELIILII EEl LIII AA5O AA34 ELI LIII LIII LIII LII : : @ LIII LIII L@ LIII LIII LII @ @ AA45 AAI7 IIIII LIII LIII LIIILII : : . AA52 AA3 AA2O A LIII E@ LLI LII of one allele in the same region. Another area telomeric to the 1063.7 locus and including EIIII LIII Homozygousdeletion <5 .@...: s.is locus is frequently involved in inter occurs more frequently in cell lines than in tumors (16, 17), the band Retention olboth alleles 16.3O@@ the IFNaJw stitial deletions in GB1O, AA14, AASO, AA34, and AA19. These two interstitial deletions are commonly found in the same tumor. In the light of reports that suggest that mutation of the CDKN2 gene Hemlzygousdeletion am Retention ofatleast one allele B addition GB1O,AA14, AA5O,AA34, and AA4 show interstitial bosses LIIII LIII LIIIII LIII Partial homozygous and hemizygous deletion with aberrant @ study (4) inasmuch as they are restricted to a region located inbetween the loci examined formerly. The distance between the CDKN2 gene and its flanking loci, MTS2 and 1063. 7 has been estimated to be between 20 and 30 kilobases (7). In this study, breakpoints have been demonstrated within this rela tively short distance in a number of the tumors. Breakpoints occurred between the MTS2 locus and the CDKN2 locus in GB25, GB29, and GB14, and between CDKN2 and 1063. 7 in GB23, AA18, and AA49. The common region of loss, when data from both the homozygous deletions and losses of one allele are combined, is thus between the MTS2 locus centromerically and the 1063. 7 locus telomerically and encompasses a region, estimated to be 40—50kilobases, within which the CDKN2 gene lies. The finding that amplification of the CDK4 gene occurs in up to 50% of the glioblastomas which show no abnormalities in the region of the CDKN2 gene suggests that aberrations of the cell cycle control mechanism are critical for the development of this tumor form. Aberrations of this mechanism are not involved in the development of astrocytomas. They first appear among anaplastic astrocytomas and are most frequent among glioblastomas and thus may be involved in the progression of these tumors. When aberrations of these two genes, the proteins of which are involved in the control of the phosphoryl ation of Rbl are included, 85% of the glioblastomas in the series show abnormalities. Cyclin Dl, which is also part of this cell cycle-regu latory mechanism, was not found to be amplified in this series. Thus, amplification of cyclin Dl does not appear to be a factor involved in the progression of these tumors. Some of the findings suggest that CDKN2 may not be the only tumor suppressor gene of interest on 9p. The interstitial homozygous deletion in GB7 encompasses areas centromeric to the cl.b locus. In :@I LII : @j :LIIILIII AA4 AA16 @ astrocytomas. The latter deletions could not be detected in a previous :LII LII : : LIII LII ELIJ LII E@I LII LLI GB1O5 LIII AAI9 @ LII • IIJE::RRRRE:J@R AAI4 @ : LII GBIOO @ : LIII GB25 GBIO GB26 GB37 ___ @::i LIII ___ GB144 GB36 GB34 LIII @ @ — GB3O GB24 GB4I IN GLIOMAS present data document that the region containing the CDKN2 gene is >30 Fig. 2. A, summary of the status of alleles at all loci studied between D9S126 and IFNaJw in all glioblastomas and anaplastic astrocytomas of the series. The results at the CDKN2 locus represent a combination of the findings using both the CDKN2 exon 1 and exon 2 probes, which gave similar allele values. Loci for which no data are given are loci at which the case was not informative or where quantitative analysis gave intermediate values, not permitting a determination of the state of the alleles. B, summary of the status of amplification at the CDK4 and MDM2 loci. Copy numbers are indicated. 6323 Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1994 American Association for Cancer Research. CDKN2 DELETIONS AND CDK4 AMPLIFICATIONS definitely involved in the majority of glioblastomas and some ana plastic astrocytomas. It remains to be seen whether there are any other genes in this limited, commonly deleted region. Recently, MTS2 has been shown to code for another inhibitor of CDK4 and CDK6 (15). Although MTS2 is not included in our commonly deleted region, loss of this gene could also contribute to tumorigenesis, because MTS2 was found to be deleted in addition to CDKN2 in a high percentage of cases studied. Mutational analysis of the CDKN2 gene in the cases retaining one or both alleles is ongoing. Such studies and the effects of the expression of the wild type gene on the phenotype of tumor cells will confirm or exclude the CDKN2 gene as a tumor suppressor gene involved in the progression of gliomas. 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