Clustering of deletions on chromosome 13 in benign and low-malignant lipomatous tumors
Article first published online: 6 DEC 2002
Copyright © 2002 Wiley-Liss, Inc.
International Journal of Cancer
Volume 103, Issue 5, pages 616–623, 20 February 2003
How to Cite
Dahlén, A., Debiec-Rychter, M., Pedeutour, F., Domanski, H. A., Höglund, M., Bauer, H. C. F., Rydholm, A., Sciot, R., Mandahl, N. and Mertens, F. (2003), Clustering of deletions on chromosome 13 in benign and low-malignant lipomatous tumors. Int. J. Cancer, 103: 616–623. doi: 10.1002/ijc.10864
- Issue published online: 18 DEC 2002
- Article first published online: 6 DEC 2002
- Manuscript Accepted: 25 SEP 2002
- Manuscript Revised: 27 AUG 2002
- Manuscript Received: 23 JUL 2002
- Swedish Cancer Society, l'Association pour la Recherche contre le Cancer. Grant Number: ARC 5955
- Belgian Programme on Interuniversity Poles of Attraction, Belgian State, Prime Minister's Office, Science Policy Programming
- European Co-operation in the Field of Science and Technical Research (COST). Grant Number: Action B19
- chromosome 13;
- fluorescence in situ hybridization;
Deletions and structural rearrangements of the long arm of chromosome 13 are frequently observed in benign and low-malignant lipomatous tumors, but nothing is known about their molecular genetic consequences. We assessed the karyotypes of 40 new and 22 previously published cases (35 ordinary lipomas, 15 spindle cell/pleomorphic lipomas, 2 myxolipomas, 1 angiomyxolipoma and 9 atypical lipomatous tumors) with chromosome 13-abnormalities, and found bands 13q12–22 to be frequently affected. Twenty-seven cases with structural abnormalities within this region were selected for breakpoint and deletion mapping by metaphase fluorescence in situ hybridization (FISH), using a set of 20 probes. Deletions were found in 23 of 27 cases. The remaining 4 cases had seemingly balanced rearrangements. The breakpoints were scattered but clustered to band 13q14, and in all cases with unbalanced abnormalities, a limited region within band 13q14 was partially or completely deleted. A deletion within band 13q14 was found together with a breakpoint on the other homologue in 5 cases, 4 of which could be tested further with regard to the status of the retinoblastoma (RB1)-gene. In all 4 cases, only 1 copy of the gene was deleted. In addition to the breaks and deletions in the vicinity of the RB1-locus, several other regions of 13q were recurrently affected, e.g., in the vicinity of the hereditary breast cancer (BRCA2; 13q12)- and lipoma HMGIC fusion partner (LHFP; 13q13)- genes. Our findings strongly indicate that deletion of a limited region (∼2.5 Mbp) within 13q14, distal to the RB1-locus, is of importance in the development of a subset of lipomatous tumors. © 2002 Wiley-Liss, Inc.
Adipocytic tumors constitute the largest subgroup of soft tissue tumors. Several histopathologic subtypes, associated with different clinical features, have been recognized.1 Cytogenetic analysis of adipose tissue tumors has shown that the various histopathologic subtypes are characterized by distinctive clonal chromosomal abnormalities.1, 2 Ordinary lipomas typically harbor abnormalities involving 12q13–15, 6p or 13q,3, 4 hibernomas exhibit 11q13 abnormalities,5 lipoblastomas are characterized by 8q11–13 abnormalities6 and spindle cell and pleomorphic lipomas typically display complete or partial loss of 13q and chromosome 16.7 Among the malignant adipose tissue tumors, the presence of giant chromosome markers and ring chromosomes, most often containing amplified chromosome 12-material, signifies atypical lipomatous tumors,8 and the translocation t(12;16)(q13;p11) is pathognomonic for myxoid/round cell liposarcoma.9 For most of these abnormalities, the molecular genetic consequences have been disclosed, revealing that the cytogenetic aberrations result in fusion or amplification of specific genes.
One of the more frequent abnormalities among benign and low-malignant adipose tissue tumors, i.e., rearrangement of 13q, has not yet been investigated at the molecular level. A survey of all published karyotypes from lipomatous tumors2 revealed that rearrangement of, or monosomy for, chromosome 13 had been detected in 72 of 463 cases (16%). Among the different histotypes, the frequency of chromosome 13-abnormalities varies greatly, ranging from 0% in lipoblastoma and hibernoma to 67% in spindle cell and pleomorphic lipomas (Table I). An assessment of the breakpoints involved in structural rearrangements shows 3 bands to be more frequently affected, i.e., 13q12, 13q14 and 13q22, and the region spanning 13q12–22 to be most frequently deleted (Fig. 1). The aim of the present study was to delineate, by fluorescence in situ hybridization (FISH), the localization of breakpoints and the extent of deletions on chromosome 13 among benign and low-grade malignant lipomatous tumors.
|Lipomatous tumor||Number of cases||Number of cases with chromosome 13 aberrations2 (%)|
|Spindle cell- and pleomorphic lipoma||9||6 (67)|
|Atypical lipomatous tumors4||98||12 (12)|
|Myxoid/round-cell liposarcoma5||87||4 (5)|
|Pleomorphic- and dedifferentiated liposarcoma||17||9 (53)|
MATERIAL AND METHODS
The material consisted of 62 benign and low-malignant lipomatous tumors that had been cytogenetically analyzed at the Department of Clinical Genetics in Lund, Sweden, at the Center for Human Genetics in Leuven, Belgium or at the Laboratoire de Génétique in Nice, France. All cases included in the study were selected on the basis of their showing clonal loss and/or structural rearrangement of chromosome 13. Of the 62 tumors, 53 were diagnosed as benign lipomas (35 ordinary lipomas, 15 spindle cell/pleomorphic lipomas, 2 myxolipomas and 1 angiomyxolipoma) and 9 as atypical lipomatous tumors. Four of the samples were from local recurrences, whereas the remaining 58 were from primary tumors.
Cell culture and cytogenetic analysis
Probes for FISH
Yeast artificial chromosome (YAC) probes were selected from the Whitehead Institute for Biomedical Research, Cambridge (http://www-genome.wi.mit.edu/; October 2000) and provided by le Centre d′Etudes du Polymorphisme Humain (CEPH), (http://www.cephb.fr/infoclone.html), Paris. Bacterial artificial chromosome (BAC) probes were selected from the human RP11-BAC library based on the status presented by NCBI Map Viewer (http://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/map_search; October 2001) and provided by the BAC-PAC resources at the Roswell Park Institute, New York (http://genomics.roswellpark.org/human/overview.html). The choice of probes was based on the findings from the preceding cytogenetic analysis of the samples and the relative positions of known sequence tagged sites (STS). The positions of the YAC and BAC clones in relation to each other and to known genes in 13q12–21 are presented in Figure 2. Whole-chromosome painting probes (AppligeneOncor, Illrich, France and Vysis, Downers Grove, USA) were used to distinguish unequivocally chromosome 13-material and other chromosomes when necessary.
BAC DNA was extracted using standard protocols. Total yeast DNA was extracted from YAC yeast clones, and human sequences were specifically amplified by using the primers ILA3′ and ILA5′, as described by Höglund et al.18 The PCR-amplified YAC DNA and the BAC DNA were subsequently labeled by random hexamer priming (Megaprime DNA labeling system, Amersham, Buckinghamshire, UK), either indirectly with biotin-16-deoxyuridinetriphosphate (dUTP) (Roche, Mannheim, Germany), digoxigenin-11-dUTP (Boehringer Mannheim, Mannheim, Germany) or estradiol-15-dUTP (Roche), or else directly with Cy3-conjugated deoxycytosinetriphosphate (dCTP) (Amersham). The labeled DNA was passed through a sepharose column and 2 μg of labeled probe were precipitated with carrier DNA (12 μg Human Cot DNA, 56 μg salmon sperm DNA), 0.5 of the volume ammonium acetate (7.5 M) and 2.5 volumes absolute ethanol before being dissolved in 50% formamide/2× saline sodium citrate (SSC) hybridization solution to a final concentration of 20 ng/μl. The probes were denatured at 72°C and then prehybridized at 37°C for 45 min. The probe combinations were made immediately before application to the slides.
The metaphase spreads were aged over-night at 60°C, washed in 2× SSC for 2 hr at 60°C and finally air-dried. The preparations were washed in 1× phosphate-buffered saline (PBS) for 5 min and then enzymatically digested with pepsin (10 mg/ml in 0.01 M HCl), followed by a wash in 1× PBS for 5 min. The slides were postfixed in 1% formaldehyde for 5–10 min, washed once in 1× PBS for 5 min and finally dehydrated in an ethanol series (70%, 85% and 100%). Denaturation of the chromosomes was done in 70% formamide/2× SSC for 40 sec to 2.5 min at 74°C, followed by dehydration in an ethanol series. Labeled and denatured probes (100 ng/probe) were added to each slide and the spread was covered with an 18 × 24-mm coverslip and sealed with rubber glue. Alternatively, the chromosomes were denaturated by adding the labeled and denaturated probe solution (see above) directly to the slide, which was then sealed with coverslip and rubber glue and finally heated at 74°C for 3–4 min. Hybridization was done over-night in a humid chamber at 37°C. Posthybridization washes were done in 0.4 × SSC for 2 min at 70°C, followed by a 3 min rinse in 4T (4 × SSC, 0.05% TWEEN-20, Sigma Chemical Co., St. Louis, MO) for ordinary preparations, and TNT (0.1 M Tris-HCl pH=7.5, 0.15 M NaCl, 0.05% TWEEN-20, Sigma Chemical Co.) for in situ preparations.
Unspecific binding of antibodies was prevented by treatment with a blocking solution [4 M (5% fat-free dry milk in 4 × SSC) for ordinary preparations, TNB (Boehringer Mannheim) for in situ preparations] for 15–30 min at room temperature, followed by a rinse in 4T/TNT for 3 min. Biotin-labeled probes were detected with avidin-conjugated Cy3, Cy5 (Amersham) or fluorescein-isothiocyanate (FITC) (Sigma Chemical Co.). Digoxigenin-labeled probes were detected with sheep-anti-digoxigenin antibodies conjugated to FITC (Sigma Chemical Co.). The slides were treated with the appropriate mixture of antibodies for 30 min at room temperature, followed by 3× 5 min rinses in 4T/TNT and a final dehydration in an ethanol series. For the detection of estradiol-labeled probes, the slides were first treated with rabbit-anti-estradiol immunoglobulin G (IgG) (Roche) for 30 min, followed by a rinse in 4T for 3 min. In a second step, the slides were treated for 30 min with goat-anti-rabbit IgG coupled to Cy5 (Amersham), in combination with additional antibodies needed for the detection of other probes. After a final 3 × 5 min rinsing in 4T, the slides were dehydrated in an ethanol series. Slides hybridized only with directly labeled probes were dehydrated in an ethanol series immediately after the posthybridization wash. For detection of nuclei and evaluation of probes, the spreads were counterstained with 0.5 mg/ml 4,6,diamidino-2-phenylindole (DAPI, Boehringer Mannheim) and mounted in a 2% 1,4-diazabicyclo-[2,2,2]-octane (DABCO, Sigma Chemical Co.) solution. The slides were examined in an Axioskop microscope (Zeiss) coupled to a CytoVision Ultra system (Applied Imaging), with a cooled charge-coupled device camera. A minimum of 10, typically 20–30, well-spread metaphase cells were evaluated on each slide.
All 62 cases included in the present study had abnormal karytopes with loss and/or structural rearrangement of chromosome 13. In Table II, the complete karyotypes of 40 new cases as well as 7 of the 22 previously published cases4, 7, 12, 13, 14, 15, 16, 17 that were used for FISH analysis are presented. The structural changes could be dichotomized into balanced and unbalanced rearrangements. In 14 cases, a seemingly balanced exchange was disclosed, and in 5 of them the exchange was present as the sole abnormality. In 1 other tumor,12 a clone with a balanced t(13;17) was found together with a clone with del(13). Unbalanced structural rearrangements were due to translocations (11 cases) and/or interstitial (11 cases) or terminal (12 cases) deletions. In 1 other tumor (case 35), the rearrangement resulted in loss of 13q12–13 as well as gain of 13q14-qter. In 9 of the cases, the unbalanced structural rearrangement of chromosome 13 was the only change seen. In 12 cases, the entire chromosome 13 was lost, always together with other numerical or structural abnormalities.
|76||F/42||Upper arm/S||6||46,XX,t(4;15)(p15;q15),t(5;9)(q22;q32),ins(8;13)(q24;q34q14),add(16) (q13),der(20)t(16;20)(q13;q12)|
|15||M/63||Lower arm/S||3||46,XY,del(1)(p13),der(2)t(1;2)(p32;q3?7),?del(4)(q31),−5,add(6)(p23), ?add(8)(q1?),+9,add(10)(q24),der(10)t(5;10)(q15;q24),add(11)(p11), ?der(13)t(8;13)(q13;q14),add(21)(q22)|
|30||M/59||Trunk wall/S||5||58,XXY,+X,−1,−2,−3,−6,−9,−10,−11,−13,−13,−14,−15,−16,+19, −22|
|Spindle cell lipoma|
|Atypical lipomatous tumor|
|46||M/58||Lower leg/D||9||45,XY,der(12)add(12)(p11)add(12)(q13),?del(13)(q14),der(13) t(12;13)(q15;q14),−21|
In 28 cases, the structural abnormalities of chromosome 13 were accompanied by another abnormality typically associated with lipomatous tumors, i. e., rearrangement of 12q13–15 (7 cases) or 6p21-pter (6 cases), loss of chromosome 16 material (9 cases) or the presence of ring chromosomes (6 cases).
Material for metaphase FISH was available from 27 of the 50 cases with structural chromosome 13-rearrangements (Table II). Among these 27 cases, the karyotypes indicated that all bands on chromosome arm 13q were involved at least once, with a clustering of breaks to 13q12–q22 (Fig. 1). Hence, a series of FISH-probes for this region was used to delineate the distribution of breakpoints (Fig. 2).
Breakpoints and deletions.
In 4 tumors (cases 4, 5, 7 and 28 clone B), FISH analysis could not reveal any gain or loss of chromosome 13-material, which was in agreement with the karyotypic data. Three of them had balanced translocations (cases 4, 5 and 28 clone B) and 1 had an insertion (case 7). In 2 of the tumors, (cases 5 and 28 clone B), the breakpoints were found in the same region (Fig. 3).
In the other 23 cases, unbalanced rearrangements with loss of 13q-material were detected by FISH analysis (Fig. 3). These included all cases that at chromosome banding analysis were interpreted to have deletions or unbalanced translocations, as well as 5 of the 9 cases that were interpreted to have balanced rearrangements. In 7 cases, terminal deletions were seen and in 17 cases the structural changes resulted in interstitial loss of material. The breakpoints were widely distributed, and in 18 cases, more than 1 break was seen (Fig. 2). Nine cases had breaks in the large region flanked by 876F2 and 911D4/935G10, 13 cases had breaks in the region covered by RP11-189B4 to RP11-550E22 (hereafter referred to as breakpoint region I), 6 cases had breaks between 833A2 and RP11-189B4 and 5 cases had breaks in the region covered by probes 931F4 and 746G10. Deletions varied considerably in size, ranging from loss of all analyzed sequences in the 13q12–21 region to loss of a single locus. The frequencies with which deletions were detected increased from the centromeric side towards the telomere, until a maximum (21 cases) was reached for probe RP11-103J18. The sequences recognized by probes RP11-278A16, RP11-103J18 and RP11-550E22 (hereafter referred to as deletion region I) were deleted in at least 20 cases. In 5 of 6 cases with a breakpoint between 900G6 and RP11-278A16, the corresponding region on the other chromosome 13 was deleted. To evaluate the status of the RB1-gene in these cases, a probe for the RB1-locus (RP11-305D15) was used in cases 2, 17, 42 and 43 (no material was available for case 45). In all of them, 1 copy of the genes was retained (data not shown).
Complex structural rearrangements.
FISH analysis revealed complex structural rearrangements in 6 of the cases. In cases 2 and 42, the rearrangement appeared to be an ins(13;13) rather than a t(13;13). In case 42, the inverted ins(13;13) was accompanied by loss of material from 1 of the 2 homologues (Fig. 4a). In case 2, the exact nature of the multiple rearrangements of the 2 chromosomes 13 could not be elucidated in spite of extensive analysis. Most likely, at least 7 breakpoints were involved in insertions and interstitial deletions, resulting in net loss of material from both homologues (Fig. 4b).
Case 45 was at cytogenetic analysis thought to harbor an ins(13;17), with an interstitial deletion within the other chromosome 13-homologue. The FISH analysis showed that the inserted chromosome 17 segment contained an inserted fragment from chromosome 13. On the derivative chromosome 13, 2 regions in the vicinity of the inserted chromosome 17 segments were deleted (Fig. 4c). The other chromosome 13 homologue had an interstitial deletion.
Cases 33 and 17 were from the cytogenetic results expected to contain an interstitial deletion in combination with a normal homologue. In case 33, 1 homologue seemed normal but the other exhibited small interstitial deletions, but also a complex translocation that involved chromosomes 6 and 19 (Fig. 4d). In case 17, none of the 2 homologues was normal. The interstitial deletion observed at cytogenetic analysis was confirmed but part of the deleted segment was inserted into the “normal” homologue (Fig. 4e). Furthermore, the breakpoint on this second homologue was associated with a small deletion.
In case 20, which at cytogenetic analysis was interpreted to have a terminal deletion, an ins(13;13) as well as a translocation to an unknown chromosome was found. At least 3 breaks within 1 of the homologues led to deletion of 2 parts and translocation and insertion of the 2 other segments (Fig. 4f).
The 27 cases that could be analyzed by FISH included 14 ordinary lipomas, 7 spindle cell lipomas, 4 atypical lipomatous tumors, 1 myxolipoma and 1 angiomyxolipoma (Table II). The number of cases in each histopathologic subgroup being small, no attempt to correlate breakpoint distribution with morphology was made. However, it could be noted that all spindle cell lipomas carried rather simple chromosome 13-changes and that all of them displayed fairly large deletions of 13q, the minimal region of overlap being flanked by probes RP11-278A16 and 876F2 (Fig. 2). Furthermore, in 3 of 4 atypical lipomatous tumors, both homologues of chromosome 13 were involved in rearrangements. All 4 cases with balanced rearrangements were diagnosed as ordinary lipomas, only 1 of which possibly displayed another lipoma-associated aberration [?inv(12)(q14q21) in case 5].
Previous cytogenetic studies have shown that a substantial subset of adipose tissue tumors displays rearrangement or loss of chromosome 13.1, 2 In the present study, 62 cytogenetically analyzed cases of benign or low-malignant adipose tissue tumors, all harboring structural rearrangements and/or loss of chromosome 13, were collected (Table II and previously published karyotypes7, 12, 14, 15). In approximately 1/4 of the cases, only 1 or no additional rearrangement could be detected, supporting the view that rearrangements of 13q constitute a separate, primary change in adipose tissue tumors. A survey of the karyotypic data on these and all previously published cases confirmed the nonrandom pattern of chromosome 13-rearrangements, with a clustering of breakpoints and deletions to the 13q12–q22 region (Fig. 1). We also assessed the correlation between karyotype and patient sex and age in 362 benign and low-malignant lipomatous tumors, including cases presented here and cases previously included in the Mitelman Database of Chromosome Aberrations in Cancer2 (Table III). For ordinary lipomas, no difference was seen between cases with and without chromosome 13-rearrangements. For atypical lipomatous tumors, a tendency for cases with chromosome 13-rearrangements to be more common in men and at younger age was seen, but these associations did not reach statistical significance (Fisher's exact test).
|Tumor type2||Sex||Age (years)|
|Male (%)||Female (%)||<30 (%)||30–59 (%)||>59 (%)|
|L without 13q-abnormalities||94 (52)||86 (48)||4 (3)||86 (63)||46 (34)|
|L with 13q-abnormalities||33 (52)||30 (48)||–||34 (67)||17 (33)|
|SL/PL without 13q-abnormalities||1 (33)||2 (67)||–||2 (67)||1 (33)|
|SL/PL with 13q-abnormalities||15 (88)||2 (12)||–||7 (41)||10 (59)|
|ALT without 13q-abnormalities||42 (51)||40 (49)||–||23 (32)||50 (68)|
|ALT with 13q-abnormalities||12 (71)||5 (29)||–||6 (40)||9 (60)|
A non-random distribution of 13q-rearrangements was confirmed by FISH analysis of 27 of the 62 cases and, not unexpectedly, several abnormalities undetected by cytogenetic G-banding analysis were disclosed by FISH analysis (Fig. 4). In 23 cases, FISH analysis revealed unbalanced rearrangements, including most of the cases where cytogenetic analysis had indicated balanced changes. The breakpoints were scattered and the extension of the deleted regions varied from the entire analyzed region to a more limited segment within 1 chromosome band. Despite the variable breakpoint distribution, 13 of the 23 cases displayed 1 or more breakpoints within breakpoint region I in chromosome band 13q14, with an ensuing partial or complete loss of this same region. The deletion breakpoint was within or closely proximal to RP11-189B4 in 15 cases, within the sequence recognized by 900G6 in 3 cases and between the sequences recognized by 900G6 and RP11-278A16 in 5 cases. The status of the RB1-locus, flanked by 900G6 and RP11-278A16, was thus analyzed further in the 4 cases in which a breakpoint between the sequences recognized by 900G6 and RP11-278A16 was found concomitantly with deletion of the corresponding region on the other homologue. However, in all these cases, only 1 copy of the gene was deleted, a finding that, of course, does not exclude functional inactivation of RB1 through a point mutation or an aberrant methylation pattern, affecting the expression of the retained allele.19
Deletion of 13q is a recurrent karyotypic feature of several types of neoplasia, including solid tumors of epithelial, mesenchymal and neuronal origin as well as hematopoietic neoplasms.2 Furthermore, deletions of 13q have been frequently detected by molecular genetic or molecular cytogenetic approaches in, e.g., breast,20 head and neck,21 liver22 and prostate cancer,23 as well as in B-cell chronic lymphocytic leukemia24 and multiple myeloma.25 The molecular studies have revealed that loss of heterozygosity (LOH) is particularly common in 2 regions close to, but outside, the RB1-locus: 1 on the centromeric side and 1 on the telomeric side. The conclusion that the RB1-gene is not the main target for the deletions is supported by the lack of correlation between LOH at the RB1-locus and reduced RB1-expression in breast, prostate and head and neck tumors,21, 26, 27 although contrasting reports have been reported for some breast28 and liver cancers.29 Interestingly, an association between a constitutional RB1-mutation and the development of lipoma has been suggested from an epidemiological study of 556 patients with hereditary retinoblastoma.30 Although inactivation of the RB1-gene could not be excluded in the present study, the clustering of breaks and deletions opens the possibility for the presence and involvement of other target genes, which are located close to RB1. Deletion region I, which was lost in a minimum of 20 cases, harbors the genes RFP2/LEU5 (Ret Finger Protein 2), BCMS/LEU1 (B-Cell neoplasia associated gene with Multiple Splicing) and BCMSUN/LEU2 (BCMS-Upstream Neighbour). These genes, localized 1–2 Mbp distal to RB1,31 have all been implicated in B-cell chronic lymphocytic leukemia. So far, however, there are no convincing data that indicate that they are involved in the pathogenesis of leukemias,32 let alone solid tumors.
In 5 cases with unbalanced rearrangements, deletion breakpoints were seen within, or closely distal to, 931F4 in chromosome band 13q12, and in 7 cases, this probe was deleted. Probe 931F4 contains the marker D13S260, which maps to the BRCA2-gene.33 As with the RB1-locus, the involvement of the BRCA2-gene cannot be excluded unless molecular genetic studies are performed, but it could be noted that no increase in lipoma incidence among BRCA2-mutation carriers has been reported. Four tumors shared a breakpoint in the distal part of band 13q13. A possible target for these rearrangements is the Lipoma HGMIC Fusion Partner (LHFP)-gene, associated with the marker WI-7467,34 which is located between probes 791F5 and 853G8 according to the Whitehead Institute. One of them displayed an exchange with band 12q15, but no material was available for FISH analysis of the HMGA2 (a.k.a. HMGIC)-gene in this case.
The number of cases that could be subjected to FISH analysis was too small to identify any significant differences among the various histopathologic subsets of lipomatous tumors. However, with regard to 13q-abnormalities, it seems as if homozygous deletions that involve band 13q14 may be more common in ALTs, that balanced translocations are characteristic for benign lipomas and that spindle cell lipomas display relatively large 13q-deletions (Fig. 2). Thus, it cannot be excluded that subtype-specific genetic mechanisms are operative, in spite of the fact that they all exhibit a clustering of abnormalities to the same limited chromosome segment.
Taken together, the results of this FISH study, which is the first attempt to delineate chromosome 13-rearrangements in adipose tissue tumors, show that chromosome 13 is involved in a variety of rearrangements that are likely to have many different consequences at the DNA level. Most importantly, however, the results strongly indicate that deletions that cover a limited segment (∼2.5 Mbp) of chromosome band 13q14, distal to the RB1-gene, are of importance in the development of a subset of adipose tissue tumors. Whether these deletions point to the existence of 1 or more tumor suppressor genes of importance for adipose tissue tumorigenesis will have to be investigated by molecular genetic techniques. Bearing in mind the rapid progress in the mapping of the human genome, it should soon be possible to analyze the expression status of all genes within the critical region, which might be a necessary approach in order to unravel haplo-insufficiency as a pathogenetic mechanism.
- 2Mitelman Database of Chromosome Aberrations in Cancer. Mitelman F, Johansson B, Mertens F, eds. http://cgap.nci.nih.gov/Chromosomes/Mitelman.
- 10Methods in solid tumor cytogenetics. In: . Human cytogenetics: malignancy and acquired abnormalities, 3rd ed. New York: Oxford University Press, 2001. 165–203..
- 11MitelmanF, ed. ISCN an International System for Human Cytogenetic Nomenclature. Basel: S Karger, 1995.