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First cytogenetic study of a recurrent familial chordoma of the clivus

1999; Wiley; Volume: 81; Issue: 1 Linguagem: Inglês

10.1002/(sici)1097-0215(19990331)81

1097-0215

L. Dalpr�, Roberta Malgara, Monica Miozzo, Paola Riva, Marinella Volont�, Lidia Larizza, A. Conti,

Oral and Maxillofacial Pathology

International Journal of CancerVolume 81, Issue 1 p. 24-30 Human CancerFree Access First cytogenetic study of a recurrent familial chordoma of the clivus Leda Dalprà, Corresponding Author Leda Dalprà Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalyDipartimento di Biologia e Genetica per le Scienze Mediche, via Viotti 3/5, 20133 Milano, Italy. Fax: (39)2–70602472.Search for more papers by this authorRoberta Malgara, Roberta Malgara Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalySearch for more papers by this authorMonica Miozzo, Monica Miozzo Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalySearch for more papers by this authorPaola Riva, Paola Riva Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalySearch for more papers by this authorMarinella Volonté, Marinella Volonté Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalySearch for more papers by this authorLidia Larizza, Lidia Larizza Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalySearch for more papers by this authorAnna M. Fuhrman Conti, Anna M. Fuhrman Conti Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalySearch for more papers by this author Leda Dalprà, Corresponding Author Leda Dalprà Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalyDipartimento di Biologia e Genetica per le Scienze Mediche, via Viotti 3/5, 20133 Milano, Italy. Fax: (39)2–70602472.Search for more papers by this authorRoberta Malgara, Roberta Malgara Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalySearch for more papers by this authorMonica Miozzo, Monica Miozzo Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalySearch for more papers by this authorPaola Riva, Paola Riva Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalySearch for more papers by this authorMarinella Volonté, Marinella Volonté Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalySearch for more papers by this authorLidia Larizza, Lidia Larizza Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalySearch for more papers by this authorAnna M. Fuhrman Conti, Anna M. Fuhrman Conti Department of Biology and Genetics, Medical Faculty, University of Milan, Milan, ItalySearch for more papers by this author First published: 08 November 1999 https://doi.org/10.1002/(SICI)1097-0215(19990331)81:1 3.0.CO;2-OCitations: 51AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Two recurrences of a familial clivus chordoma, arisen from a patient who developed the primary tumor at age of 8 years, were investigated by cytogenetic and the fluorescence in situ hybridization (FISH) approach. Of the patient's 3 daughters, 2 developed, respectively, a clivus chordoma and an astrocytoma in infancy, a familial aggregation highly suggestive of a genetic background. After a 31-year hiatus, 2 tumor recurrences, developed over 17 months, were removed surgically. Both were hypo- or nearly diploid, and had a pronounced karyotypic heterogeneity with clonal and non-clonal rearrangements affecting several chromosomes. The same rearrangement, a dic(1;9)(p36.1;p21), was shared in both tumor specimens and, in 90% of the cells, chromosome 1p appeared to be involved in unbalanced translocations with different chromosomes, leading to variable losses of 1p. Previous cytogenetic data concerning chordoma are limited to 10 sporadic tumors with an abnormal karyotype; although no tumor-specific rearrangements have been identified, chromosome 1p appears to be involved frequently. Int. J. Cancer 81:24–30, 1999. © 1999 Wiley-Liss, Inc. Chordoma is a malignant bone tumor, thought to be due the persistence of notochordal cells into the postnatal life. The most frequently involved sites are the sacrococcygeal and sphenooccipital regions, as well as the vertebral bodies. Chordoma, which accounts for 1–4% of all primary malignant bone tumors, is locally invasive and may metastasize in about 30% of cases. The cytogenetic data concerning chordoma are limited to 18 sporadic tumors (Butler et al., 1995; Mertens et al.,1994). A wide variety of chromosome anomalies have been observed in all studies, with clonal changes being found in 8 tumors only (Bridge et al., 1994; De Boer et al., 1992; Gibas et al., 1992; Mertens et al.,1994; Persons et al., 1991). Although most chordomas are sporadic, 5 families with chordoma occurrence have been reported (Chetty et al., 1991; Foote et al., 1958; Kerr et al., 1975; Korczak et al., 1997; Stepanek et al., 1998), the tumors being not investigated cytogenetically. We report here the results of a cytogenetic study of the first and second recurrence of a clivus chordoma in a patient (aged 39 and 40) who first developed this tumor in infancy. He had 3 children, 2 of whom, respectively, expressed an astrocytoma and chordoma when they were young. The identification of the chromosome regions involved clonally in hereditary chordoma might be a useful guide for further molecular studies aimed at pinpointing the region where the gene responsible for susceptibility to chordoma is localized. CASE REPORT The patient developed a chordoma of the clivus at the age of 8 years, and underwent radiotherapy. When he was 39 years old, a local recurrence infiltrating the paranasal sinuses was found and removed surgically by transpalatal excision (tumor A); 17 months later, the tumor relapsed and the patient underwent a second surgical resection (tumor B). Conventional histo-pathological examination of the tumor A revealed a typical pattern (Fig. 1). Figure 1Open in figure viewerPowerPoint Histology of tumor A showing typical chordoma features mainly consisting of physaliferous cells with mucinous intercellular substance (hematoxylin and eosin). Scale bar: 70 μm. The patient has 3 children: the eldest (aged 17 years) is apparently healthy, but the second (aged 14 years) and the youngest (aged 11 years), respectively developed an astrocytoma and a clivus chordoma at ages 11 and 5 years. No history of tumors was recorded in the patient's maternal or paternal ancestors and relatives. MATERIAL AND METHODS Cell cultures Peripheral blood lymphocyte (PBL) cultures were set up using both standard and modified RPMI (Irvine Scientific, Santa Ana, CA) plus 10% fetal calf serum (FCS; GIBCO, Gaithersburg, MD). In order to obtain high resolution chromosomal spreads (> 550 bands), 10−3M methotrexate (MTX, Lederle, Cynamid, Catania, Italy) were added to 72 hr PBL cultures in RPMI for 17 hr 30 min, and replaced after washing with 1.2 × 10−4M thymidine (Sigma, St. Louis, MO) for an additional 4 hr. Colcemid (Boehringer Mannheim, Germany) at a final concentration of 0.1 μg/ml was added for the last 10 min or 2 h to the cultures with or without MTX. The tumor specimens removed at surgery were incubated in Hank's with collagenase (Merck, Darmstadt, Germany) (200 U/ml) overnight, washed off and resuspended in RPMI plus 10% FCS and maintained in short-term culture (2–5 days). Colcemid was added for the last 5 hr (1 μg/ml). Chromosome spreads from the PBL cultures were prepared using standard methods. The tumor specimens were processed by means of the standard in situ and suspension methods. Constitutional and tumor karyotypes were reconstructed using QFQ-banded chromosome spreads and defined according to the ISCN (1995). At least 100 metaphases from the PBL cultures were scored for the presence of fragile sites. All metaphases in the processed tumor cultures were karyotyped. Fluorescence in situ hybridization (FISH) The digoxigenin-labeled libraries from chromosomes 9 and 10 (WCP 9 and WCP 10), and the biotinylated-labeled libraries from chromosomes 1 and 6 (WCP 1 and WCP 6,), were purchased from Oncor (Gaithersburg, MD). The conditions for the in situ hybridization and detection of the dig- and bio-labeled libraries were as recommended by the supplier. The chromosomes were counterstained with either propidium iodide (Sigma) (1 μg/ml) in antifade solution (p-phenylenediamine) (Sigma) or 4,6-diamidine 2-phenylindole (DAPI, Sigma, 1 μg/ml). FISH was performed on cell suspension chromosome preparations. The metaphases were visualized using a Leitz DM-RB microscope equipped for DAPI and fluorescein isothiocyanate (FITC)/TRITC epifluorescence optics. Filter I3–51 3683 was used for single color, and a double pass filter G/R 513803 for dual color FISH. DAPI counterstaining was visualized using an A 513678 filter. The photographs were taken on Kodak Gold 400 color film. RESULTS High-resolution cytogenetic analysis (> 550 bands) of the PBL karyotype of the patient and his tumor-bearing daughters did not reveal any subtle structural chromosomal change. No fragile sites were found across the whole karyotype. The cytogenetic analysis of 37 and 58 metaphases from the first (tumor A) and the second chordoma recurrence (tumor B) showed a hypodiploid mode in both tumors, with a hyperdiploid set in only 4 cells from tumor A and 9 cells from tumor B (Fig. 2). All 37 metaphases from tumor A had an abnormal karyotype, with a great variety of structural changes affecting all chromosomes except 2, 4, 5, 10, 14, 16, 19 and 22. The clonal rearrangements are listed in Table I and a representative karyotype in shown in Figure 3. A major clonal abnormality was the translocation leading to a dic(1;9)(p36.1;p21), which was found in 80% of the cells. In particular, chromosome 1p appears to be involved in translocations with various chromosomes (including chromosome 10) in the vast majority (90%) of the metaphases. These translocations are probably unbalanced, as they give rise to visible losses of 1p. Table I. RECURRENT STRUCTURAL REARRANGEMENTS OF TUMORS A AND B Chromosomal Tumors rearrangements A B t(1;9)(p36.1;p21) 80% 32% t(1;10)(p36.1;q24) 7% t(1;6)(p11;q25) 10% 6% add(1)(p12) 27% add(1)(q21) 14% del(2)(p12pter) 18% del(3)(p21pter) 5% del(3)(q21qter) 11% add(9)(q34) 6% add(10)(q26) 16% Figure 2Open in figure viewerPowerPoint Distribution of chromosome number per metaphase: the open bars indicate the metaphases of tumor A (number 37) and the black bars those of tumor B (number 58). Karyotypes with 46 chromosomes were structurally rearranged. Figure 3Open in figure viewerPowerPoint Complete karyotype of a cell from tumor A: 39, XY, dic(1;9)(p36.1;p21), add(1)(p12), del(3)(p13), -4, -4, der(6)t(1;6;14)(6pter→6q27::1p36→1p13::14pter→14qter), -7, -8, -8, -11, -17, -17, -18, -18, -19, -20, -20, -22, -22, +8mar. A number of structural rearrangements, including marker chromosomes m1, m4 and m5, (Fig. 3) recurred in the different metaphases but could not be defined. As far as numerical changes are concerned the nullisomy of chromosomes 18 and 22 and monosomy of chromosomes 1, 4, 7, 8, 9, 10, 11, 16, 17 and 19 were found to be clonal. Chromosome gain was only observed as trisomy of a single chromosome in single cells. Unlike in tumor A, 18 of the 51 metaphases from tumor B had an apparently normal karyotype. Table II shows the aberrant karyotypes of the remaining 33 metaphases. As can be seen, trisomies were found only sporadically (tris 21 in metaphase no. 11, tris 20 plus tris 22 in metaphase no. 7 and tris 10 in metaphase no. 29), whereas monosomies recurred for all of the chromosomes except chromosomes 1, 3, 5, 9, 10 and X. The clonal structural rearrangements are listed in Table I, from which their relative percentages can be compared with those recorded for tumor A. Abnormalities affecting chromosome 1p were observed in 72% of the metaphases from tumor B, including its apparent loss in 65% of them. Table II. KARYOTYPES OF TUMOR B 1 46,XY [18] 2 40,XY,del(2)(p12pter),del(3)(q21qter),−3,−6,−9,del(12)(q21qter), −13,−13,−15,−19,−19, −20,+mar1,+mar2,+mar3 3 45,X,−Y,add(6)(p25) 4 46,XY,del(7)(q32qter) 5 47,XY,+mar1 6 48,XY,+r1,+r2,(ace and dmin) 7 44,X,−Y,−2,del(2)(q31qter),t(2;Y)(p25;q11.2),add(10)(q26),−13,−14, −15,del(15)(q15qter), +20,+22,+mar1 8 45,XY,−4,add(10)(q26) 9 46,XY,del(6)(q21qter),add(D)(q?) 10 46,XY,add(6)(q27),add(10)(q26) 11 44,XY,−D,−16,−17,−18,+21,+mar1 12 45,XY,inv(1)(p21;q32–44),−4,−20,+mar 13 46,XY,add(1)(q21),add(10)(q26) 14 48,XY,del(3)(q21qter),−7,add(9)(q34),t(9;10)(q11;p15)+add(20)(q13.3) 15 43,XY,del(2)(p12pter),−6,add(10)(p15),−11,−13,−16,+mar1 16 46,XY,del(2)(p12pter),add(11)(q14 o q22) 17 46,XY,−2,−7,t(15;15)(p?;p?),−19,+mar1,+mar2,+mar3 18 46,XY,−4,+add(10)(q26),del(12)(q22qter) 19 45,Y,−X,add(1)(p12),−20,+mar 20 45,XY,del(6)(q25qter),del(10)(q23–24qter),−12, der(16)t(12;16)(q12–13;q23–24) 21 46,XY,del(3)(q21qter),add(9)(q34) 22 44,XY,add(1)(p?),del(2)(p12pter),−6,−8,−11,−18,+mar1,+mar2 23 46,XY,−2,add(11)(p?),−12,+iso(12p),+mar1 24 43,XY,−2,add(3)(p23),−4,−21 25 46,XY,−6,+mar1 26 45,XY,del(3)(p21),−16,+mar1 27 43,XY,del(1)(q11qter),add(1)(p12 → p13)[¥2],−15,−17,−20 28 46,XY,add(6)(q27),del(4)(q21.3qter) or t(4;6)(q21.3;q27) 29 44,XY,del(4)(p12),−5,t(5;11)(q12;p15),−7,−8,+10 30 46,XY,add(10)(q26) [2] 31 46,XY,+mar1 32 46,XY,del(2)(p12pter),add(16)(p12–p13) 33 47,XY,t(1;10)(p36;q24) Figure 4 shows the structural clonal rearrangements of tumor B that were also observed in tumor A. FISH experiments aimed at confirming the chromosomal rearrangements revealed by Q-banding analysis or identifying new ones could be performed only for tumor B, from which abundant chromosome spreads sampled by different fragments were obtained. Painting libraries of chromosomes 1, 4, 6, 9, 10 and 17 were used in single and dual color FISH. Figure 4Open in figure viewerPowerPoint Partial metaphases from tumor B with structural rearrangements also observed in tumor A: dic(1;9) (solid arrows), chromosome 6 derivative due to a t(1;6) (open arrows), an unidentified mar 4 chromosome (arrow head). The clonal dic(1;9), which was frequently identified in both tumors by QFQ banding (Table I), was not revealed in the 37 metaphases simultaneously hybridized with the chromosome libraries. By contrast, an add (1p) marker, showing the loss of the distal region of 1p undetected by QFQ banding was found in 30 of 37 metaphases hybridized with WCP 1 and WCP 9 (Fig. 5a). The same marker was probably detected in 19 of the 49 cells processed by means of dual FISH with WCP 1 and WCP 10 (Fig. 5b), which failed to reveal the clonal t(1p;10q) identified by QFQ banding (Table II, metaphase 33). The analysis of 79 cells using WCP 10 allowed the reciprocal translocation t(1p;10q) to be identified in 2 cells (Fig. 6a), but additional chromosome 10 rearrangements were also detected: a derivative 10q+ marker (Fig. 6b) in two cells and del(10q) and del(10p) in 4 and 2 cells, respectively. The use of WCP 6 made it possible identify different chromosome 6 rearrangements in a total of 60 metaphases, involving either unknown (Fig. 7a) or known partners, such as the t(2;6) in a single metaphase (Fig. 7b) and a del(6q) in 5 cells. Figure 5Open in figure viewerPowerPoint (a, b) Metaphase spreads from tumor B stained with 4,6-diamidine 2-phenylindole (DAPI, left) and hybridized with WCP 1 (fluorescein isothiocyanate, FITC) and WCP 9 (rhodamine) (a, right); and hybridized with WCP 1 (FITC) and WCP10 (rhodamine) (b, right). Arrowheads show the add(1p). Figure 6Open in figure viewerPowerPoint Three metaphases from tumor B hybridized with WCP 10. The arrows point to the t(1;10) (a) and the add(10q) (b). Figure 7Open in figure viewerPowerPoint Two metaphases from tumor B hybridized with WCP 6. Arrows indicate unidentified markers (a) and the t(2;6) (b). Dual color FISH using WCP 4 and WCP 17 was also applied in order to check 2 chromosomes known to be rearranged in chordoma (Bridge et al., 1994; Mertens et al.,1994), even though we could appreciate only numerical changes for these chromosomes in tumor A and B by conventional cytogenetics. No aberrations of chromosomes 4 and 17 were identified in the 30 scored metaphases. DISCUSSION Chordoma is a rare malignant tumor. Only 18 cases of sacral chordoma have been studied cytogenetically and, of these, abnormal karyotypes were present in 10 cases (Bridge et al., 1994; De Boer et al., 1992; Gibas et al., 1992; Mertens et al.,1994; Persons et al., 1991). No common tumor-specific rearrangements were found in these investigations, and so chordoma can be considered heterogeneous. In some cases (Mertens et al., 1994), recurrences and/or metastases, arising after radiation therapy have been studied, making it difficult to interpret the cytogenetic findings and to compare one case with another. Conversely, clear indications exist concerning the number of chromosomes per metaphase, as most of the abnormal chordomas were found to be hypo- or near-diploid. Furthermore, only numerical changes recurred among the tumors with karyotypic deviations (Mertens et al., 1994). We observed clones with different cytogenetic aberrations in both of the chordoma recurrences analyzed in this study. In particular, classical cytogenetics revealed that an apparently same unbalanced clonal dic(1p;9p) was shared by tumors A and B, but this finding could not be confirmed when dual color FISH using chromosomes 1 and 9 was applied to tumor B. A probable explanation for this discrepancy is that the 2 methods were carried out on different fragments from the same tumor specimen. Intra-sample heterogeneity (i.e., the presence of several related or unrelated clones within a tumor sample), and inter-sample heterogeneity, (previously reported in a few tumors) (Örndal et al., 1994) may account for this result. Moreover, the pronounced karyotypic heterogeneity could be linked with the radiation therapy received when the patient manifested the primary tumor. Despite this, band 1p36 was found to be involved in unbalanced translocations with a number of chromosome partners (chromosomes 6, 9 and 10). Different chromosome 1 derivatives showing losses of variable portions of telomeric 1p were observed in the majority of the metaphases (Figs. 3 and 5, Table I and II). Assuming that chordoma is a monoclonal tumor, it is reasonable to propose that the 1p36 deletion may have been an early event in chordoma genesis in the case described. Visible chromosome 1 rearrangements were not observed in a small number of metaphases from both recurrences, as they were probably masked by ever-present marker chromosomes. The complex karyotypic pattern may be due to the progression of the tumor cells, which may acquire additional aberrations in different tumor areas. In 4 of 8 abnormal chordomas reported previously, either non-random 1p anomalies involving 1p11 (Mertens et al., 1994), 1p22 (Gibas et al., 1992), 1p34 (Persons et al., 1991), 1p36 (Mertens et al., 1994) or the complete loss of chromosome 1 (Butler et al., 1995) have been described. Taken together, these observations are consistent with the hypothesis that chromosome 1p plays a primary role in chordoma development. Among the genes mapped to this region, PAX7 is of particular interest as its expression is modulated by signals coming from the notochord during spinal cord embryogenesis (Wehr and Gruss, 1996), and it is rearranged in alveolar rhabdomyosarcoma (Davis et al., 1994). The evidence that 1p36 deletion is an early event in childhood astrocytoma (Wernicke et al., 1997), coupled with the fact that one of the daughters of our patient presented an astrocytoma, pinpoint chromosome 1 as the major candidate to investigate. No cytogenetic studies of the astrocytoma and chordoma developed by the patient's daughters could be performed. Thus, the question of a common region, marked by a cytogenetic change, that is shared in this cancer family, and making it possible to map the genetic predisposition, can only be answered by using other approaches. The only rearrangement of chromosome 1p shared by tumors A and B is the same dic(1;9) affecting the 9p21 breakpoint. The multiple tumor suppressor gene MTS1 is mapped to the 9p21 breakpoint and is known to be involved in hereditary melanoma, as well as in predisposition to other cancers and sporadic tumors (Borg et al., 1996). Clonal alterations of chromosome 9p have been reported in 3 chordomas and may thus be a non-random change. The heterozygous loss of loci on chromosome 10q has been reported in different malignant tumors, including medulloblastoma and multiform glioblastoma (GBM), a tumor arising from astrocytic cell (Albarosa et al., 1996; Mollenhauer et al., 1997). The loss of genetic material on chromosome 10 (also indicated by cytogenetics) appears to play a crucial role in GBM development (Magnani et al., 1994). Two different clonal rearrangements of chromosome 10 involving region q24–26 were observed in tumor B (Table I), thus suggesting that this region may play a role in chordoma development as well. In conclusion, our results indicate that 1p deletions, including those in the 1p36 region, found in the vast majority of metaphases from tumors A and B, and the 9p21 and 10q24–26 regions, are clonally involved in chordoma. Some genes mapped to these regions play a role in embryogenic tumors or familial tumors (Borg et al., 1996; Davis et al., 1994; Lahti et al., 1994). Further investigations should thus concentrate on these candidate regions when studying chordoma pathogenesis. ACKNOWLEDGEMENT The authors thank Dr. A. Mazzoni (Ospedali Riuniti, Bergamo, Italy) for providing the tumor samples. REFERENCES Albarosa, R., Colombo, B.M., Roz, L., Magnani, I., Pollo, B., Cirenei, N., Giani, C., Fuhrman Conti, A.M, Di Donato, S., and Finocchiaro, G., Deletion mapping of gliomas suggests the presence of two small regions for candidate tumor-suppressor genes in a 17-cM interval on chromosome 10q. Amer. J. hum. Genet, 58, 1260– 1267 (1996). Medline Bridge, J.A., Pickering, D., and Neff, J.R., Cytogenetic and molecular cytogenetic analysis of sacral chordoma. Cancer Genet. Cytogenet, 75, 23– 25 (1994). Medline Borg, A., Johannsson, U., Johannsson, O., Hakansson, S., Westerdahl, J., Masback, A., Olson, H., and Ingvar, C., Novel germline p16 mutation in familial malignant melanoma in Southern Sweden. Cancer Res, 56, 2497– 2500 (1996). Medline Butler, M.G., Dahir, G.A., Hedges, L.K., Juliao, S.F., Sciadini, M.F., and Schwartz, H.S., Cytogenetic, telomere, and telomerase studies in five surgically managed lumbosacral chordomas. Cancer Genet. Cytogenet, 85, 51– 57 (1995). Medline Chetty, R., Levin, C.V., and Kalan, M.R., Chordoma: a 20-year clinicopathologic review of the experience at Groote Schuur Hospital, Cape Town. J. surg. Oncol., 46, 261– 264 (1991). Medline Davis, R.J., D'Cruz, C.M., Lovell, M.A., Biegel, J.A., and Barr, F.G., Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res, 54, 2869– 2872 (1994). Medline De Boer, J.M., Neff, J.R., and Bridge, J.A., Cytogenetics of sacral chordoma. Cancer Genet. Cytogenet, 64, 95– 96 (1992). Medline Foote, R.F., Ablin, G., and Hall, W., Chordoma in siblings. Calif. Med, 88, 383– 386 (1958). Gibas, Z., Miettinen, M., and Sandberg, A.A., Chromosomal abnormalities in two chordomas. Cancer Genet. Cytogenet, 58, 169– 173 (1992). Medline Kerr, W.A., Haynes, D.R., and Sellars, S.L., Familial nasopharyngeal chordoma. S. Afr. Med.. J., 49, 1584 (1975). Medline Korczak, J.F., Kelley, M.J., Allikian, K.A., Shah, A.A., Goldstein, A.M., and Parry, D.M., Genomic screening for linkage in a family with autosomal dominant chordoma. Amer. J. hum. Genet, 61, A400 (1997). ISCN, F. Mitelman, (ed.) An International System for Human Cytogenetic Nomenclature. Karger, Basel, Switzerland (1995). Lahti, J.M., Valentine, M., Xiang, J., Jones, B., Amann, J., Grenet, J., Richmond, G., Look, A.T., and Kidd, V.J., Alterations in the PITSLRE protein kinase gene complex on chromosome 10p36 in childhood neuroblastoma. Nature (Genet.), 7, 370– 375 (1994). Medline Magnani, I., Guerneri, S., Pollo, B., Cirenei, N., Colombo, B.M., Broggi, G., Galli, C., Bugiani, O., Di Donato, S., Finocchiaro, G., and Fuhrman Conti, A.M., Increasing complexity of the karyotype in 50 human gliomas. Progressive evolution and de novo occurrence of cytogenetic alterations. Cancer Genet. Cytogenet, 75, 77– 89 (1994). Medline Mertens, F., Kreicber, G.S., Rydholm, A, Willen, H., Carlen, B., Mitelman, F. and Mandahl, N., Clonal chromosome aberrations in three sacral chordomas. Cancer Genet. Cytogenet, 73, 147– 151 (1994). Medline Mollenhauer, J., Wiemann, S., Scheurlen, W., Korn, B., Hayashi, Y., Wilgenbus, K.K, Von Deimling, A., and Poustka, A., DMBT1, a new member of the SRCR superfamily, on chromosome 10q25.3–26.1 is deleted in malignant brain tumours. Nature (Genet.), 17, 32– 39 (1997). Medline Örndal, C., Rydholm, A., Willén, H., Mitelman, F., and Mandahl N., Cytogenetic intra-tumor heterogeneity in soft tissue tumors. Cancer Genet. Cytogenet, 78, 127– 137 (1994). Medline Persons, D.L., Bridge, J.A., and Neff, J.R., Cytogenetic analysis of two sacral chordomas. Cancer Genet. Cytogenet, 56, 197– 201 (1991). Medline Stepanek, J., Cataldo, S.A., Ebersold, M.J., Lindor, N.M., Jenkins, R.B., Unni, K., Weinshenker, B.G., and Rubenstein, R.L., Familial chordoma with probable autosomal dominant inheritance. Amer. J. med. Genet, 75, 335– 336 (1998). Medline Wehr, R., and Gruss, P., Pax and vertebrate development. Int. J. Develop. Biol, 40, 369– 377 (1996). Medline Wernicke, C., Thiel, G., Lozanova, T., Vogel, S., and Witkowski, R., Numerical aberration of chromosomes 1, 2, and 7 in astrocytoma studied by interphase cytogenetic. Genes Chromosomes Cancer, 19, 6– 13 (1997). Medline Citing Literature Volume81, Issue131 March 1999Pages 24-30 FiguresReferencesRelatedInformation