Neurosurg Focus 10 (3):Article 6, 2001, Click here to return to Table of Contents Identification of isochromosome 1q as a recurring chromosome aberration in skull base chordomas: a new marker for aggressive tumors? JEFFREY R. SAWYER, PH.D., MUHAMMAD HUSAIN, M.D., AND OSSAMA AL-MEFTY, M.D. Departments of Pathology and Neurosurgery, University of Arkansas for Medical Sciences; and Cytogenetics Laboratory, Arkansas Children's Hospital, Little Rock, Arkansas Object. The authors conducted a study of 22 skull base chordomas. Methods. A series of 22 skull base chordomas was analyzed with G banding. Subsequently, metaphase cells ob- tained from three tumors were reexamined using multicolor spectral karyotyping. Clonal chromosome aberrations were identified in 11 cases, all of which were recurrent tumors. Three tumors showed a remarkable similarity in cyto- genetic features, and these features appear to characterize a recurring combination of nonrandom chromosome aberra- tions, including isochromosome 1q, gain of chromosome 7, and monosomy for chromosomes 3, 4, 10,13, and 18. Isochromosome 1q was identified as the sole recurring structural chromosome rearrangement in these tumors. The pat- tern of chromosome loss reported in the progression of lumbosacral chordoma also appears to be true of skull base chordomas with the additional findings of isochromosome 1q, gain of chromosome 7, and loss of chromosome 18. Conclusions. Skull base chordomas characterized by isochromosome 1q and monosomy 13 provide support for the concept of the loss of putative tumor suppressor loci on 1p and 13q and aggressive tumor behavior. KEY WORDS • chordoma • chromosome aberration • isochromosome 1q • spectral karyotyping • cytogenetics Chordomas are locally invasive bone tumors that ap- 9,13,18,21 In most cases either normal karyotypes or hypo- pear in adulthood and are thought to originate from the diploidy with complex structural aberrations have been remnants of the notochord. Because chordomas have a shown. The hypodiploidy has most often included loss of predilection for the ends of the spinal column, most le- chromosomes 3, 4, 10, and 13.18 To date, no consistent sions are found in the sacrococcygeal region and the base structural chromosome aberrations have been reported. of the skull.7,16,17 Approximately 35% of chordomas arise In the present study, a series of 22 skull base chordomas at the base of the skull, approximately 50% arise in the was analyzed by classic G banding. In addition, meta- sacrococcygeal region, and the remaining 15% are found phase cells obtained from three tumors were analyzed in the vertebral bodies.14 Skull based chordomas are slow- with SKY, which is a molecular cytogenetic technique that growing tumors and, in many cases, are associated with a allows the simultaneous display of each chromosome in significant amount of bone and soft-tissue destruction. a different color.27 This technique makes possible the Metastasis can occur but usually in the late stages of tu- identification of chromosomal bands of unknown origin, mor progression. Because of their location, cranial chor- including translocations, insertions, complex rearrange- domas are difficult to manage and gross-total resection is ments, and small marker chromosomes. We report the not always possible; therefore the recurrence rate is high.14 largest cytogenetic study of skull base chordomas and, to Unfortunately, the prognosis for patients with intracranial our knowledge, the identification of isochromosome 1q as tumors is poor, as the progression of the tumor causes the first recurring structural chromosome aberration in death in most patients.12 these tumors. Cytogenetic studies of chordomas are limited. The great majority of cases reported are lumbosacral chordomas, which have shown diverse chromosome aberrations.2,3,6,8, MATERIALS AND METHODS Patient Population Abbreviations used in this paper: DAIP = 4,6-diamidino-2- There were 11 patients (four females and seven males) phenylidole; LOH = loss of heterozygosity; RB = retinoblastoma; who ranged in age from 15 to 69 years. Table 1 provides SKY = spectral karyotyping. a summary of clinical and histological data. Neurosurg. Focus / Volume 10 / March, 2001 1 Unauthenticated | Downloaded 09/28/21 02:26 AM UTC J. R. Sawyer, M. Husain, and O. Al-Mefty TABLE 1 Clinical and histological findings obtained in 11 patients with chordomas Tumor Characteristics Case Age (yrs), No. Sex Location Recurrent Histology No. of Ops (yr) Radiotherapy 1 57, F clival yes chondroid 1 (1992) yes 2 25, M clival yes chondroid 1 (1991) no 3 34, M clival yes conventional 1 (1992) no 4 58, F clival yes conventional 1 (1994) yes 5 41, M clival yes conventional 1 (1989) yes 6 33, M cervical yes conventional 2 (1993 & 1995) yes 7 65, M cervical yes conventional 1 (1987) yes 8 15, F clival yes conventional 2 (1998 & 1998) yes 9 52, M clival yes conventional 2 (1997 & 1999) yes 10 69, M clival yes conventional 1 (1996) yes 11 47, F clival yes conventional 1 (1998) yes Cytogenetic Analysis somes 3, 4, 13, and 18 (Cases 1, 5, 6, and 11), followed by Cytogenetic analysis was performed by standard in situ the loss of chromosome 10 (Cases 5, 6, and 11) in three of culture techniques and G banding, as described else- the four tumors (Table 2). The most common chromosome where.25 Chromosome aberrations have been described by gains included all or part of chromosome 1q (in Cases 1, the Cancer Cytogenetic Guidelines and Nomenclature of 5, 6, and 11) and chromosome 7 (Cases 2 and 5–7). Three the International System for Human Cytogenetic No- tumors shared chromosome aberrations of isochromo- menclature.20 In cases in which routine analysis of 20 col- some 1q, -3,-4,+7,-10,del13/-13, -18 (Cases 5, 6, and 11) onies obtained from at least three independent primary (Fig. 1). culture slides indicated chromosome instability, addition- al metaphase spreads were analyzed. Results of SKY Spectral karyotyping was used in three cases, resulting Spectral Karyotyping Methods in either confirmation or refinement of aberrations previ- We used prepared SKY probe mixture and hybridiza- ously identified by G banding. In the tumor obtained in tion reagents (Applied Spectral Imaging, Carlsbad, CA). the patient in Case 6 SKY refined the designation of an Slides for SKY were treated according to the manufactur- add(6)(q23) to an unbalanced translocation der(6)t(6;13) er's protocol: the probe cocktail was hybridized to the (q23;q21). This finding identified a deleted region in chro- slides for 2 days at 37°C. Image acquisition was per- mosome 13 including bands 13pter~13q14, indicating the formed using a Spectracube (SD200; Applied Spectral loss of the RB region (Fig. 2). In the tumor obtained in the Imaging, Inc.) mounted on a Zeiss Axiomat II microscope patient in Case 9 SKY refined the designation of an fitted with a custom-designed optical filter (SKY-1; add(9)(q34) to a der(9)t(9;11)(q34;?q23), and an add(19q) Chroma Technology, Brattleboro, VT) that allows for si- and del(20q) to a t(19;20)(q13;q11.2). The technique also multaneous excitation of all dyes and measurement of confirmed a questionable t(8;18)(q21.2;q12) in this case. their emission spectra. The DAPI banding images were In the tumor obtained in the patient in Case 10 SKY con- acquired as part of the image-acquisition process and were firmed the complex translocations demonstrated by G analyzed using a DAPI-specific optical filter. The DAPI banding including t(3;5)(p23;p11),t(3;10)(q21;q24),t(4;6) images were used in conjunction with spectral classifica- (q31.1;p11.2), and t(4;16)(q25;p11.2). tions and G banding for the identification of chromosome aberrations, as previously described.26 DISCUSSION RESULTS Cytogenetic studies of skull base chordomas are rare. To our knowledge, only two recent studies have been Twenty-four tumors were cultured and harvested. Two reported.3,8 Four tumors were analyzed by Buonamici, et specimens could not be evaluated due to the absence of al.,3 three of which showed a normal karyotype, whereas growth or low mitotic index. Eleven tumors showed no one tumor showed a t(6;11)(q12;q23) as the sole aber- clonal chromosome aberrations, nine were new primary ration. Dalpra, et al.,8 reported a clonal dicentric (1;9) tumors, and two were recurrent. Clonal chromosome aber- (p36.1;p21) cell line and involvement of 1p in unbalanced rations were found in 11 cases, all of which were recurrent translocations that led to variable loss of 1p. This finding tumors (Table 2). Five of these tumors showed multiple has more recently led to the localization of a putative tu- clones (Table 2). mor suppressor locus in familial and sporadic chordomas being mapped to 1p36.19 In addition to this locus, the RB Results of G Banding tumor suppressor gene (13q14) has also been implicated Clonal chromosome losses were identified in six tumors in the pathogenesis of chordomas. In a screening for LOH (obtained from Cases 1–3, 5, 6, and 11) (Table 2). In four for the RB gene, Eisenberg, et al.,10 identified two of seven of these, losses included the deletion or loss of chromo- chordomas in which LOH for the RB gene was demon- 2 Neurosurg. Focus / Volume 10 / March, 2001 Unauthenticated | Downloaded 09/28/21 02:26 AM UTC Cytogenetics of skull based chordomas TABLE 2 Cytogenetic findings in tumors with abnormal karyotypes Case No. Findings 1 46,XX,inv(1)(q23q42),t(1;10)(q32;p11),t(3;14)(p21;q13),inv(4)(p14q31),add(12)(q22),del(14)(q32)[5] 46~48,XX,add(1)(q?32),del(3)(p25),del(5)(q31),del(6)(q15),add(11)(p13),+del(12)(q22),-13,add(16)(p11),add(16)(q24),+17,der(18)t(1;18)