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Journal of Neuropathology and Experimental Neurology Copyright q 2004 by the American Association of Neuropathologists Vol. 63, No. 10 October, 2004 pp. 1072 1079 Loss of Heterozygosity at 6q Is Frequent and Concurrent with 3p Loss in Sporadic and Familial Capillary Hemangioblastomas SEBSEBE LEMETA, MD, LEA PYLKKÄNEN, PHD, MARKKU SAINIO, MD, PHD, MIKA NIEMELÄ, MD, PHD, SIRKKU SAARIKOSKI, PHD, KIRSTI HUSGAFVEL-PURSIAINEN, PHD, AND TOM BÖHLING, MD, PHD Abstract. Capillary hemangioblastoma is a benign tumor, occurring sporadically or as a manifestation of von Hippel-Lindau (VHL) disease. Inactivation of the VHL gene at 3p25–26 has been demonstrated in all VHL-associated hemangioblastomas. However, the VHL gene has been found to be inactivated in only 20% to 50% of sporadic tumors. So far, no other gene has been reported to be involved in the development of hemangioblastomas. DNA losses at 6q are frequent alterations in hemangioblastomas, as shown by comparative genomic hybridization. We therefore analyzed 15 hemangioblastomas for loss of heterozygosity (LOH) on chromosome 3p and 6q to reveal the frequency of allelic losses and to determine minimal deleted areas. We detected LOH at 6q for one or more markers in 11 (73%) out of 15 cases (in 9 of 11 sporadic and in 2 of 4 VHLassociated tumors). The analyses revealed a minimal 3-megabase (Mb) deleted region at 6q23–24, where 9 of 11 (82%) informative cases showed LOH. LOH at 3p was seen in 14 out of 15 tumors. LOH occurred concurrently at 6q and 3p in 67% of cases. Our data strongly suggests that a tumor suppressor gene located at 6q23–24 is involved in tumorigenesis of hemangioblastomas, in addition to the VHL gene. Key Words: 6q loss; Chromosomal aberration; Hemangioblastoma; Loss of heterozygosity (LOH); Tumor suppressor gene. INTRODUCTION Capillary hemangioblastomas are solid or cystic benign tumors that are highly vascular, grow slowly, and account for less than 2% of all central nervous system tumors (1). They can occur in any part of the CNS, but the sites of predilection are the posterior fossa and the spinal cord. Regardless of their location, hemangioblastomas have the same histologic characteristics (2, 3). Hemangioblastomas occur either as a manifestation of von Hippel-Lindau (VHL) disease or as solitary sporadic lesions. VHL is a dominantly inherited disorder characterized by tumors or tumor-like lesions developing in several organs, including retinal hemangioblastomas, clear cell renal carcinomas (RCC), pheochromocytomas, pancreatic islet cell tumors, as well as renal, pancreatic and epididymal cysts; hemangioblastomas of the central nervous system are nevertheless the most common manifestation (4, 5). In VHL patients, hemangioblastomas are frequently multiple and occur at an earlier age as compared to sporadic tumors. The proportion of VHL-associated tumors is 10% to 40% of all hemangioblastomas From Department of Pathology, University of Helsinki, and Helsinki University Central Hospital (SL, TB), Helsinki, Finland; Departments of Industrial Hygiene and Toxicology (S L, LP, SS, KH-P) and Occupational Medicine (MS), Finnish Institute of Occupational Health; and Department of Neurosurgery (MN), Helsinki University Central Hospital, Helsinki, Finland. Correspondence to: Tom Böhling, MD, PhD, Department of Pathology, Haartman Institute, University of Helsinki, P.O. Box 21, (Haartmaninkatu 3), FIN-00014, Helsinki, Finland. E-mail tom.bohling@ helsinki.fi Supported by grants from the Finnish Cancer Foundation, Finska Läkaresällskapet, K.A. Johansson Foundation and Helsinki University Central Hospital (EVO). (6). Germ-line mutations of the VHL tumor suppressor gene, located at 3p25–26 (7), have been reported in all VHL families (8). A two-hit inactivation of the VHL gene has been shown in both VHL-associated and sporadic hemangioblastomas (9). However, studies on sporadic hemangioblastomas, including somatic mutation analyses, LOH, and hypermethylation studies have revealed loss or inactivation of the VHL gene area only in approximately 20% to 50% of the cases (10–14). Thus, the genetic mechanisms underlying the tumorigenesis of sporadic hemangioblastomas are still unclear. We and others have recently shown by comparative genomic hybridization (CGH) DNA losses on chromosomal arm 6q, in addition to those on 3p (15, 16). Losses of 6q were seen in 23% and 50% of the tumors, and they were the most or second most frequent DNA copy number changes after 3p loss (15, 16). With this background, we investigated the frequency of LOH at 6q in both sporadic and VHL-associated hemangioblastomas, in order to determine allele losses not observable by CGH. We sought to reveal the minimal deleted area to uncover the location of putative tumor suppressor genes important in hemangioblastoma tumorigenesis. In addition to prevalent 3p loss, we found LOH of 6q in 73% of the cases. To our knowledge, this is the first report documenting LOH in hemangioblastomas on the long arm of 6, with the minimal deleted region discovered at 6q23–24. MATERIALS AND METHODS Paraffin-embedded tumor tissue from 15 surgically removed hemangioblastomas, fixed in 4% phosphate-buffered formaldehyde was collected from the files of the Department of Pathology, University of Helsinki. The set included 11 sporadic 1072 1073 LOH AT 6q IN CAPILLARY HEMANGIOBLASTOMAS TABLE 1 Clinical Characteristics of Cases with Capillary Hemangioblastomas with a Summary of CGH and LOH Findings Sample No. Sex Location Age at surgery VHL-associateda T2 T5 T14 T15 M M M F Medulla Medulla Cerebellum Medulla 32 21 34 48 Sporadic T1 T3 T4 T6 T7 T8 T9 T10 T11 T12 T13 M M M M M M F F F M M Cerebellum Cerebellum Cerebellum Cerebellum Cerebellum Cerebellum Cerebellum Cerebellum Cerebellum Cerebellum Cerebellum 39 32 37 79 46 55 69 27 48 45 25 Loss in CGHb LOH at 6qc LOH at 3pc — — n.a. n.a. 1 2 2 1 2 1 1 1 — 3p, 6q n.a. 3p, 6q 6q 6q — — n.a. n.a. n.a. 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 See Materials and Methods. Reference 15. c This study. n.a., Not analyzed. 1, LOH detected. 2, No LOH or DNA loss detected. a b and 4 VHL-associated (VHL characterization described elsewhere [6]). The clinical characteristics of the patients are presented in Table 1. Nine of the 15 tumors were part of both CGH and LOH studies. DNA was extracted from histologically well-characterized paraffin sections of hemangioblastomas, from which adjacent normal tissues were carefully removed, and from corresponding peripheral blood samples by standard methods using proteinase-K digestion and phenol/chloroform purification followed by ethanol precipitation. Tumor and non-tumor DNA was amplified by the polymerase chain reaction (PCR), and LOH analysis was performed with 22 microsatellite markers (Research Genetics, Inc, Huntsville, AL) covering chromosome 6q and 16 spanning 3p. The markers (Figs. 1, 2) were selected to ensure a comprehensive representation of 6q and 3p. The names and the localization of the markers are based on the unified database (UDB) (http://bioinformatics. weizmann.ac.il/udb). PCR was carried out in the following conditions: 13 PCR buffer (10 mM Tris-HCl, 1.5 mM MgCl2, 50 mM KCl, 0.1% Triton X-100); 200 mM dGTP, dATP and dTTP; 2 mM dCTP; 0.7 mCi of [33 P] dCTP (3,000 Ci/mmol); 10 ng of each primer; 100 ng of genomic DNA template; and 0.5 units of Dynazyme II polymerase (Finnzymes, Espoo, Finland) in a volume of 10 ml. PCR amplification started with 5 min at 958C, then 35 cycles for 1 min at 958C, 1 min at 52– 558C, 1 min at 728C, followed by elongation for 8 min at 728C. The amplified samples were cooled down quickly and stored at 48C. Heat-denatured PCR products were subjected to electrophoresis in 6% polyacrylamide gel containing 7.7 M urea. After electrophoresis, the gels were dried and exposed by autoradiography to X-ray film. All PCR amplifications with unclear results were repeated. LOH was scored when an allelic band was absent or clearly reduced in density compared to the corresponding band in normal DNA in repeated experiments. All of the 15 cases were informative for more than 1 marker studied (a marker was considered non-informative when the normal tissue of the patient was homozygous with respect to this marker). RESULTS Altogether, 15 cases of hemangioblastomas were investigated for LOH at 6q and 3p regions with a comprehensive set of microsatellite markers. LOH was observed with at least 1 marker in all 15 cases (Figs. 1, 2; Table 1). The detection of allele loss for both 6q and 3p in 2 cases is illustrated in Figure 3. Allelic losses of 6q were detected in 11 (73%) of the 15 tumors (Fig. 1). Nine of these 11 cases were sporadic tumors, and 2 were VHL-associated. In the sporadic tumors, the prevalence of 6q LOH was thus 83%. In the VHL-associated tumors, 6q LOH was seen in 2 (50%) out of the 4 tumors included in the study. Four tumors (T3, T6, T7, and T8) showed DNA loss on the long arm of chromosome 6 in the previous CGH study (15) and for 3 of those, 6q LOH was also detected (Fig. 1). The results allowed us to define a minimal deleted region between markers D6S250 and D6S1705. Nine (82%) of the informative cases showed LOH with at least one of the markers (D6S250, D6S1703, or D6S1705). These markers span a 3-Mb region on 6q23–24 (Fig. 1). J Neuropathol Exp Neurol, Vol 63, October, 2004 1074 J Neuropathol Exp Neurol, Vol 63, October, 2004 LEMETA ET AL LOH AT 6q IN CAPILLARY HEMANGIOBLASTOMAS 1075 Fig. 2. Loss of heterozygosity (LOH) on the short arm of chromosome 3 in capillary hemangioblastoma. The delineated schematic chromosome arm indicates the approximate locations of the microsatellite markers used. The horizontal bar shows the VHL regional at 3p 25–26. Symbols used: m LOH; M No LOH; V Not informative; — No result. a The order of the markers, their distance from the telomere of the short arm of the chromosome (pter) in megabases (Mb) and the chromosomal location are based on the database (http://bioinformatics.weizmann.ac.il/udb). For the markers D3S1255 and D3S1481 no distance in Mb was indicated. b Tumors 3 and 6 with CGH 3p loss. With microsatellite markers for 3p, LOH was found in 14 (93%) of the 15 cases. The only case in which 3p LOH could not be detected was an VHL-associated tumor in which LOH on 6q was demonstrated with several markers. Allelic losses on 3p were detected in several different regions (Fig. 2). LOH on 3p was also detected in both tumors (T3 and T6) in which 3p and 6q loss had previously been shown by CGH. In total, all 5 tumors negative in the CGH analysis were positive in the LOH analysis. Moreover, 2 tumors negative in the CGH analysis (T9 and T10) displayed LOH concomitantly at 6q and 3p (Table 1). Four tumors (2 VHL-associated and 2 sporadic) showed LOH only at 3p and 1 VHL-associated tumor at 6q only. Concomitant LOH of 6q and 3p was detected on 10 (67%) of the 15 cases. These 10 cases with ← Fig. 1. Loss of heterozygosity (LOH) on the long arm of chromosome 6 in capillary hemangioblastoma. The delineated schematic chromosome arm indicates the approximate locations of the microsatellite markers used. The minimal deleted region discovered at 6q23–24 is indicated by the shaded areas. Symbols used: m LOH; M No LOH; V Not informative; —No result. a The order of the markers, their distance from the telomere of the short arm of the chromosome (pter) in megabases (Mb), and the chromosomal location are based on the database (http://bioinformatics.weizmann.ac.il/udb). For the marker Col9A, no distance in Mb was indicated. b Tumors 3, 6, 7, and 8 with CGH 6q loss. J Neuropathol Exp Neurol, Vol 63, October, 2004 1076 LEMETA ET AL Fig. 3. Illustration of LOH detected with the microsatellite markers D6S1698, D3S1038 in 2 tumors (T) as compared to (B) peripheral blood or normal. The horizontal lines indicate the alleles, and the arrows show the location of the missing alleles. LOH detected on both sites included 9 sporadic and 1 VHL-associated tumor. A summary of the results is given in Table 2. DISCUSSION Various sporadic tumors are characterized by somatic inactivation of the same genes responsible for hereditary tumor syndromes. Hemangioblastoma is a highly vascular benign tumor of the central nervous system and one of the major manifestations of VHL disease. The molecular basis for the development of sporadic hemangioblastoma is partially unclear. However, after discovery of a high frequency (23%–50%) of 6q DNA loss in this benign tumor by us and others (15, 16), we decided to perform a detailed mapping of allelic losses on 6q using LOH analysis. LOH for the long arm of chromosome 6 was found to be a frequent event occurring in 11 (73%) of the 15 hemangioblastomas. The minimal common region of allelic deletion was located at 6q23–24 (D6S250D6S1705). Losses at 6q have previously been described by CGH and LOH in several different types of tumors, including melanoma, ovarian carcinoma, neuroectodermal tumors, and small cell lung cancer (17, 18, 19, 20). Loss of 6q is also exhibited in several central nervous system tumors, including both sporadic and neurofibromatosis 2associated meningiomas (21, 22), glioblastomas (23), and oligodendroglial tumors (24). Interestingly, in addition to hemangioblastomas, loss of 6q has also been observed in most other tumor types occurring in VHL, including sporadic and VHL-associated renal cell carcinomas (RRC) J Neuropathol Exp Neurol, Vol 63, October, 2004 (25–28), pheochromocytomas (29), and endocrine pancreatic tumors (30). Previously, 6q loss has been associated with more aggressive growth or metastatic potential in certain tumor types (30). Hemangioblastomas are benign (2), and no differences in clinical behavior could be associated with LOH on 6q in our series. Interestingly, 3 of the 4 VHLassociated tumors were located in the medulla, and LOH of 6q was detected in one of these, showing that allelic losses at 6q is not specific to cerebellar hemangioblastomas. Several experimental studies have provided strong evidence on the importance of 6q in the process of tumorigenicity. The transfer of a normal chromosome 6 into breast and ovarian carcinoma cell lines suppressed their tumorigenic potential (31, 32). Interestingly, the authors analyzed the cell lines for the occurrence of LOH, and they indicated the region 6q23–25 as the area for a putative tumor suppressor gene. Other studies also support the view that this chromosome area harbors a tumor suppressor gene. Foulkes et al reported 6q allelic loss in 55% of ovarian carcinomas and indicated that 6q24 harbors a putative tumor suppressor gene (33). A number of other studies on ovarian carcinomas (34–36), melanoma (37), and prostate cancer (38) have also indicated that this region of 6q may contain a tumor suppressor gene. Acevedo et al found LOH on 6q in 48% of adenocarcinomas of the uterine cervix by using the marker D6S250, which is also included in the minimal deleted area discovered in hemangioblastoma in the present study (39). Together, these data suggest that this region may harbor a gene 1077 LOH AT 6q IN CAPILLARY HEMANGIOBLASTOMAS TABLE 2 Summary of 6q and 3p LOH Results in Capillary Hemangioblastomas 6q LOH 3p LOH Case Present Absent Total Present Absent Total Sporadic VHL-related 9 2 2 2 11 4 11 3 0 1 11 4 associated with the development or progression of a wide variety of tumor types. Several putative tumor suppressor genes are located in the vicinity of 6q23–24, including the newly described THW (human transmembrane protein) gene. THW has been shown to be expressed in brain, kidney, liver, pancreas, adrenal glands, uterus, and prostate (40). It is located between 6q16–23, and LOH of the THW gene has been detected in melanoma, pancreas, breast, prostate, cervical, and colon cancer cell lines (41, 42). Another tumor suppressor gene located at 6q24–25 is LATS1 (large tumor suppressor 1), which suppresses tumorigenesis by regulating cell proliferation and modulating cell survival (43). Xia et al demonstrated that transduction of recombinant LATS1 adenovirus to the MCF-7 human breast cancer cell line inhibited cell proliferation and suppressed colony-forming ability in soft agar as well as tumor development in nude mice (44). Therefore, the human LATS1 gene may also play an important role in suppressing tumor formation in humans (43, 44). A third interesting tumor suppressor gene located at 6q24–25 is ZAC (zinc finger C2 protein), also named LOT1 (45). It encodes a zinc finger protein, which displays antiproliferative properties through pathways central to the activity of p53, and inhibits tumor cell growth through induction of apoptotic cell death and G1 arrest (45, 46). ZAC is expressed in human pituitary gland, kidney, adrenal gland, liver, whole brain, and spinal cord, as well as in mouse in brainstem and cerebellum. Reduced ZAC expression has been shown in breast cancer cell lines and primary tumors (47). The possible role of these tumor suppressor genes in hemangioblastomas remains to be clarified, but since our results indicate 6q losses (shown by both LOH and CGH) to be so frequent, it is tempting to speculate that the loss of function of one or more of these suppressor genes is of importance in the tumorigenesis of hemangioblastomas. On chromosome 3p, we observed LOH with several markers spanning large regions of the chromosomal arm. The results are similar to those obtained previously on RCCs (27). Our combined LOH and CGH data indicate that 3p, in addition to 6q, is a characteristic site of allele loss in hemangioblastomas In this study, concomitant LOH on 6q and 3p was observed in a majority (67%) of the tumors. This observation was even more common in sporadic tumors, as 82% of the sporadic tumors had LOH on both 3p and 6q. This suggests that tumorigenesis in most hemangioblastomas—and perhaps in sporadic ones in particular—may be dependent on the inactivation of genes located in both 6q and 3p. These results are in concordance with the recent findings of Gijtenbeek et al, who suggested that the molecular mechanisms underlying sporadic and familial hemangioblastomas may be different (48). However, in the present study, 3p loss was more common in sporadic hemangioblastomas than previously reported, thus suggesting its role in the tumorigenesis of sporadic tumors also. In conclusion, this study is the first to report frequent LOH on 6q in hemangioblastomas with a minimal 3-Mb deleted region detected at 6q23–24. This region most likely contains one or more tumor suppressor gene(s), which may have relevance in the development and progression of a wide variety of tumor types. As all major tumor types occurring in VHL patients (renal cell carcinomas, pheochromocytomas, and endocrine pancreatic tumors) frequently exhibit 3p and 6q losses, this may indicate a common tumorigenic pathway for all VHLassociated tumors. ACKNOWLEDGMENTS We thank Ms. Satu-Marja Snellman, MSc, for secretarial assistance, and Ms. Tuula Suitiala, chief technician, Finnish Institute of Occupational Health, for skillful technical assistance. REFERENCES 1. Richard S, Campello C, Taillandier L, Parker F, Resche F. Haemangioblastoma of the central nervous system in von Hippel-Lindau disease. French VHL study group. J Intern Med 1998;243: 547–53 2. 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J Neurosurg 2002;97:977–82 Received October 20, 2003 Revision received April 19, 2004 Accepted July 2, 2004 J Neuropathol Exp Neurol, Vol 63, October, 2004