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(American Journal of Pathology. 2000;156:651-659.)
© 2000 American Society for Investigative Pathology

Regular Articles

Comparative Genomic Hybridization Reveals Frequent Losses of Chromosomes 1p and 3q in Pheochromocytomas and Abdominal Paragangliomas, Suggesting a Common Genetic Etiology

Elisabeth Edström^*, Eija Mahlamäki, Brita Nord, Magnus Kjellman^*, Ritva Karhu, Anders Höög^§, Nikolai Goncharov^¶, Bin Tean Teh, Martin Bäckdahl^* and Catharina Larsson

From the Departments of Surgery,^*
Molecular Medicine,
and Clinical Pathology,^§
Karolinska Hospital, Stockholm, Sweden; the Laboratory for Cancer Genetics,
Institute of Medical Technology, University of Tampere, Tampere, Finland; and the Institute for Endocrinological Research,^¶
Russian Medical Academy, Moscow, Russia

	Abstract

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Pheochromocytomas and abdominal paragangliomas are rare, catecholamine-producing tumors that arise from the chromaffin cells derived from the neural crest. We used comparative genomic hybridization (CGH) to screen for copy number changes in 23 pheochromocytomas and 11 abdominal paragangliomas. The pattern of copy number changes was similar between pheochromocytomas and paragangliomas, with the most consistent finding being loss of 1cen-p31, which was detected in 28/34 tumors (82%). Losses were also found on 3q22–25 (41%), 11p (26%), 3p13–14 (24%), 4q (21%), 2q (15%), and 11q22–23 (15%), and gains were detected on 19p (26%), 19q (24%), 17q24-qter (21%), 11cen-q13 (15%), and 16p (15%). Losses of 1p and 3q were detected in the majority of tumors, whereas gains of 19p and q, 17q, and 16p were seen only in tumors with six or more CGH alterations. This progression of genetic events did not correspond with the conversion to a malignant phenotype. CGH alterations involving chromosome 11 were more frequent in the malignant tumors, compared with the benign tumors (9/12 versus 3/16). In summary, we propose that pheochromocytomas and abdominal paragangliomas, which share many clinical features, also have a common genetic origin and that the loss of 1cen-p31 represents an early and important event in tumor development.

	Introduction

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Pheochromocytomas occur either sporadically or, in approximately 10% of the cases, as a part of familial-cancer syndromes, such as multiple endocrine neoplasia type 2 (MEN-2), von Hippel-Lindau’s disease (VHL), or neurofibromatosis type 1 (NF1). Pheochromocytomas have also been reported in multiple endocrine neoplasia type 1 (MEN-1) patients.^3,4,5,6 Recently, loss of the wild-type alleles was demonstrated in two MEN-1–related pheochromocytomas, supporting the underlying role of the MEN-1 gene in their tumorigenesis.⁷ Although the hereditary forms of pheochromocytoma are fairly well characterized, the genetic background of sporadic pheochromocytomas is still poorly understood. In a minority of sporadic cases, somatic mutations have been found in genes that are involved in the familial forms of the disease, ie, RET in 10q11, VHL in 3p25, and NF1 in 17q11.^8,9 However, the involvement of the MEN-1 gene is yet to be determined. Studies of somatic genetic alterations in primarily benign pheochromocytomas have shown loss of heterozygosity (LOH) in 1p, 3p, 3q, 11p, 17p, and 22q, suggesting the existence of tumor suppressor gene loci in these locations.^10-21

Most of the patients with head and neck paragangliomas have a familial background related to the PGL1 and PGL2 loci, which have been mapped to 11q23 and 11q13, respectively, and are both subjected to maternal genomic imprinting.^22-24 Based on the frequent and specific LOH of the 11q23 region in the sporadic and familial forms of these tumors, the PGL1 gene is anticipated to have a tumor suppressor gene function. Abdominal paragangliomas are most frequently sporadic, although familial forms have also been reported, suggesting that this disease may occur as a distinct genetic entity.²⁵ Available genetic data on abdominal paragangliomas have been limited and mainly include analysis of single cases or studies of candidate regions in a few selected cases.²⁶

We have used comparative genomic hybridization (CGH) to screen a panel of benign and malignant pheochromocytomas and abdominal paragangliomas for DNA sequence copy number alterations. Furthermore, the involvement of the MEN-1 gene was determined by mutation analysis.

	Materials and Methods

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Clinical Cases

The study includes 34 tumors from 33 patients with pheochromocytoma or abdominal paraganglioma. Twenty-eight of the patients were operated on between 1985 and 1997 and then clinically monitored at the Endocrine Surgical Unit at the Karolinska Hospital. Six patients were operated on at the Russian Center for Endocrinology, Moscow, Russia, in 1995, but have not been available for follow-up. The study was approved by the local ethics committee at the Karolinska Hospital.

The clinical data for the 23 pheochromocytomas and 11 abdominal paragangliomas are summarized in Table 1 . From one patient with a malignant paraganglioma, both the primary tumor and the liver metastasis were analyzed (Table 1 , cases 29 and 34). In the pheochromocytoma group, there were four cases of sporadic malignant tumors, 13 sporadic cases without evidence of malignancy, and five MEN-2A–associated cases and one related to NF1. In the paraganglioma group, there were eight sporadic-malignant cases and three sporadic-benign cases. Of the 34 tumors analyzed, 32 were primary tumors (Table 1 , cases 1–32). Two of the malignant paragangliomas were metastases. In one of those cases (Table 1 , case 34), DNA from the corresponding primary tumor (Table 1 , case 29) was also analyzed; in the other case (Table 1 , case 33), only metastatic DNA was available. Tumors were classified as malignant, based on histopathological criteria and the presence of metastasis. Because no World Health Organization classifications covering these tumors have been published, we have adapted the criteria for malignancy published by the Armed Forces Institute of Pathology, ie, extensive local invasion and/or the presence of metastasis.² Of the 12 tumors classified as malignant, 9 had developed metastasis (Table 1) .

CGH

All 34 tumors were analyzed by CGH, essentially as described.²⁷ Tumor DNA labeled with fluorescein isothiocyanate-deoxyuridine triphosphate (400 ng; DuPont, Boston, MA) and 400 ng of sex-matched reference DNA labeled with Texas Red-deoxyuridine triphosphate (DuPont) were hybridized together with 10 µg of unlabeled Cot-1–blocking DNA (Boehringer Mannheim, Mannheim, Germany) on normal metaphase preparations (Vysis Inc., Downers Grove, IL). After 48 hours of incubation, the slides were washed and counterstained with 4',6-diamidino-2-phenylindole (Boehringer Mannheim) in an antifade solution. Normal male DNA and female DNA were hybridized together to normal metaphase preparations as a negative control, and, as a positive control, a previously characterized breast cancer cell line (MCF-7) was used.

The ratios of green-to-red fluorescence intensities, representing tumor to normal copy number, were analyzed along each autosome and the X chromosome in a digital image analysis system. In a CGH analysis system, an Olympus BX50 fluorescence microscope (Olympus, Tokyo, Japan) and a Photometrics Image-Point b/w CCD camera (Photometrics Ltd., Tuscon, AZ) equipped with IPLab software (Signal Analytics Corp., Frederick) were used. Images were further analyzed with the Quips CGH (Vysis) software package. A chromosomal region was considered to be over-represented if the average green-to-red fluorescence ratio exceeded the 1.15 cutoff line (a gain), as amplified if the ratio exceeded the 1.5 cutoff line, and as under-represented if the ratio was below the 0.85 line (a loss).

Mutation Analysis of the MEN-1 Gene

Mutation analysis was performed in 30/34 tumors, using single-stranded conformation analysis (SSCA) and direct sequencing, essentially as previously described.²⁸ The coding exons 2–10 and the untranslated exon 1 of the MEN-1 gene were amplified using 15 different fragmentsof 200–300 bp each. Except for primers within exons 2, 3, and 10, the primers originated from the flanking intronic sequences. Genomic DNA (50 ng) was amplified in 15-µl polymerase chain reaction (PCR) reactions containing 50 mmol/L KCl; 10 mmol/L Tris-HCl, pH 9.0; 1.5 mmol/L MgCl₂ (Promega, Madison, WI); 0.2 mmol/L each of deoxyribosylthymine triphosphate, deoxyadenosine triphosphate, and deoxyguanosine triphosphate; 0.05 mmol/L deoxycytidine triphosphate; -³²P-labeled deoxycytidine triphosphate (Amersham Pharmacia Biotech, Stockholm, Sweden) at 1 mCi/reaction, 0.2 mmol/L of each oligonucleotide primer, and 2 U of DNA polymerase (Dynazyme, Finnzyme Oy, Finland). Thermocycling conditions consisted of denaturing at 94°C for 5 minutes and 30 cycles of 1 minute at 94°C, 1 minute at 60°C, and 1 minute at 72°C, followed by a final extension step for 2 minutes at 72°C. For exons 2.2 and 10.2, the following PCR conditions were used: denaturing at 96°C for 2 minutes and 30 cycles of 96°C for 45 seconds, 62°C for 30 seconds, and 72°C for 30 seconds, followed by a final extension step for 2 minutes at 72°C. The PCR products were then electrophoresed in 25% mutation detection enhancement gels (FMC BioProducts, Rockland, ME) at room temperature for 12 hours at 6–8 W, followed by autoradiography. When an SSCA-shifted band was detected, it was excised from the gel and sequenced on a 377 automated fluorescent sequencer (Applied BioSystems, The Perkin Elmer Corp., Foster City, CA).

Statistical Analysis

A correlation between CGH aberrations and clinical features was analyzed using the Mann-Whitney U test and Fisher’s exact test with the StatView 4.5 software. The six pheochromocytoma cases that were not available for follow-up were excluded from the comparisons between malignant and benign tumors.

	Results

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CGH Alterations in Pheochromocytomas and Paragangliomas

Chromosomal imbalances were detected in 32/34 tumors (Figure 1 and Table 2 ). Losses were twice as common as gains. In pheochromocytomas, the most frequent losses were found on chromosome arms 1p (83%), 3q (39%), 11p (17%), 3p (17%), 4q (17%), and 11q (13%). Gains were seen predominantly on 19p (26%), 19q (26%), 17q (17%), and 16p (9%), and in one tumor 20q was amplified. The 6 hereditary and 13 sporadic benign tumors showed similar patterns of CGH alterations. In paragangliomas, the most frequent losses were found on chromosome arms 1p (82%), 3q (45%), 11p (45%), 3p (36%), 4q (27%), and 11q (18%). Gains were seen predominantly on chromosome arms 19p (55%), 11q (36%), 16p (27%), 17q (27%), and 19q (18%). When the results were compared, the gain of 11cen-q13 was found to be sig-nificantly more frequent in paragangliomas than in pheochromocytomas (P < 0.05, Fischer’s exact test). No other major differences in the patterns of copy number changes nor in the minimal regions of involvement between pheochromocytomas and paragangliomas were seen (Figure 1) . The minimal regions involved in the most commonly detected losses and gains are listed in Table 3 .

View larger version (33K): [in this window] [in a new window]   Figure 1. Summary of DNA copy number alterations detected by CGH in 23 pheochromocytomas and 11 abdominal paragangliomas. Each line represents one alteration detected in one tumor with losses illustrated to the left and gains to the right of the ideograms.

CGH Alterations in Benign and Malignant Tumors

The distribution of losses and gains on the different chromosome arms in the benign contra malignant tumors is shown in Figure 2 . The main difference was that chromosome 11 was partly lost and/or gained in 9/12 malignant cases versus 3/16 benign tumors. Of the nine cases that had developed metastasis, eight showed involvement of chromosome 11 (Table 3) . Loss of 11q22–23 was significantly more common in malignant tumors than in benign ones (P < 0.05, Fischer’s exact test). The mean and median values of the total number of genetic aberrations (P = 0.06, Mann-Whitney U test) were higher in the malignant tumors (mean 4, median 5.7) than in the benign ones (mean 2.5, median 6), but with a wide range in all groups as illustrated in Table 2 and Figure 2 . No specific aberration that correlated to a poor prognosis was identified in the five patients who died from the disease. There was no significant difference in the pattern of CGH alterations between malignant pheochromocytomas and malignant paragangliomas.

View larger version (36K): [in this window] [in a new window]   Figure 2. The number of gains (white bars) and losses (filled bars) on each chromosome arm in the benign (top), and the malignant (bottom) tumors. A dotted line representing two CGH alterations is added to more easily visualize the most frequent gains and losses. The frequency of recurrent alterations is listed in Table 3 .

Mutation analysis of the MEN-1 gene was performed on 30 of the tumors (Table 1) and did not reveal any mutations, although polymorphisms were readily identified. Twenty SSCA shifts were detected, and by sequencing they were all shown to represent polymorphisms: 17 cases of D418D (57%) and 3 cases of R171Q (10%). Furthermore, the detected frequencies of these polymorphisms were in agreement with those previously reported. ²⁹

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
This study represents the first genome-wide screening for copy number changes by CGH in pheochromocytomas and abdominal paragangliomas. CGH changes were detected in 32/34 tumors, which shows that alterations affecting genetic copy number are common in these tumor types. The most striking observation was the loss of all or parts of chromosome arm 1p, which was detected in 28/34 cases (82%). In previous studies, LOH on 1p has been reported in approximately one half of pheochromocytomas, but no clear, minimal common region has been identified.^{10,11,13-15,26} Some LOH studies have focused on the distal part of 1p, because 1p36 deletions correlate with a poor prognosis in neuroblastomas, a childhood tumor with the same embryonic origin as pheochromocytomas and paragangliomas.³⁰ 1p36 was later found to harbor the p73 tumor suppressor gene.³¹ In this study, the minimal region involved was 1cen-p31, which makes p73 unlikely as a candidate gene (Figure 1) . However, the proximal loss of 1p detected by CGH does not exclude additional deletions affecting the p73 locus or other genes in distal 1p. Results from CGH and LOH studies are not always comparable. For example, deletion of one chromosomal region accompanied by duplication of the remaining allele would give the appearance of no loss by CGH, but would be detected by LOH. Nevertheless, the combined results of the present and previous studies suggest the involvement of one or several genes, located within or proximal to 1p31, in the development of pheochromocytomas and abdominal paragangliomas.

Moley et al found LOH on 1p in 9/9 pheochromocytomas from patients with MEN-2, but in only 2/7 sporadic cases, and these authors speculated that 1p could harbor genes that are specifically involved in the tumorigenesis of MEN-2–related tumors.¹⁴ We did not find any significant differences in copy number changes between hereditary and sporadic pheochromocytomas that could confirm this hypothesis.

Losses were more common than gains, indicating that the inactivation of tumor suppressor genes plays a critical role in tumorigenesis. Apart from the loss of 1p, previous LOH studies have reported frequent allele losses on 3p, 3q, and 11p and on 17p and 22q. Mulligan et al allelotyped 16 sporadic and 13 familial pheochromocytomas and found significant LOH on 1p (60%), 3p (55%), 3q (60%), 11p (16%), 13q (10%), 17p (15%) and 22q (40%).¹¹ Khosla et al tested 34 sporadic and 7 familial cases of pheochromocytomas for LOH near a variety of potentially important genetic loci and reported significant allele losses on chromosomes 1p (42%), 3p (16%; VHL locus), 17p (24%; p53 and NF1 loci), and 22q (31%), but not on 10q (MEN-2 locus).¹⁰ In a study of 22 pheochromocytomas, 55% of the tumors showed LOH on 1p and 40% on 22q, and the two alterations co-occurred significantly within the same tumors.¹⁵ In the present study, losses of 3q22–25 and 3p13–14 were frequently detected (in 41% and 24%, respectively) in both pheochromocytomas and paragangliomas. The minimal common region on 3p, though, is located proximal to the VHL locus. In contrast to previous LOH data, we could not detect copy number changes of 22q in more than two cases. Losses and gains of 17p were detected only in a minority of cases.

With CGH we could not detect any major differences in the pattern of copy number changes between pheochromocytomas and abdominal paragangliomas (Figure 1) . The only exception was that a gain of 11cen-q13 was more common in paragangliomas than in pheochromocytomas. This may reflect the higher frequency of malignant tumors in the paraganglioma group, because this chromosomal region is commonly gained in malignant tumors, or it may point toward an involvement of the PGL2 locus. The general pattern of copy number changes in chromaffin paragangliomas, with the high frequency of 1cen-p13 losses, is quite different from available LOH data on non-chromaffin paragangliomas with specific losses on 11q23.³² Although involvement of the PGL1 and PGL2 loci cannot be excluded in the tumorigenesis of chromaffin paragangliomas, it seems likely that alternative molecular pathways are involved in chromaffin and nonchromaffin paragangliomas. Our findings suggest that pheochromocytomas and catecholamine-secreting paragangliomas not only share many clinical features, but also have a similar genetic background.

No mutations in the MEN-1 gene were detected in any of the tumors, which suggests, despite the sensitivity of our mutation detection strategy (ie, SSCP), that the MEN-1 gene is rarely involved in the tumorigenesis of sporadic pheochromocytomas and abdominal paragangliomas. This may explain the very low frequency of these tumors in MEN-1 patients.

The distribution of genetic alterations on the most frequently involved chromosome arms (Table 2) suggests that there may be a progression of genetic events in the development of these tumor types. Because loss of 1cen-p13 was detected in the large majority of tumors, regardless of subtype and degree of malignancy, it is likely that inactivation of a gene located in this region is an important early event. On the other hand, the most common gains detected with CGH were seen predominantly in tumors with a high total number of aberrations. Taken together, losses of 1cen-p13 and 3q22–25 seem to precede gains of 19p and q, 16p, and 17q23–24. However, this genetic progression cannot be directly translated into a clinical progression, which indicates that these are not key events in the development of malignant tumors.

The malignant tumors showed generally a higher number of genetic aberrations than the benign cases, which is a sign of genetic instability. However, as shown in Table 2 , the individual variations in the number of detected alterations fell within a wide range, and, in addition, three benign tumors displayed a large number of alterations. The major difference between benign and malignant tumors (Figure 2) was involvement of chromosome 11, which was partly lost and/or gained in the majority of malignant cases. Loss of 11q22–23 (including the PGL1 locus) was particularly common in malignant tumors. However, there was no single, minimal region of involvement, which makes these results difficult to interpret.

In conclusion, the results from our study with CGH in pheochromocytomas and abdominal paragangliomas indicate that inactivation of a gene located on the proximal part of 1p is an important and early event in the development of these tumor types and that there may be a progression of genetic events that involves chromosomes 3, 11, 17, and 19. Conversion to a malignant phenotype may be associated with changes on chromosome 11. We further conclude that intra- and extra-adrenal paragangliomas of the sympathoadrenal system share common progression pathways.

	Acknowledgements

 
We thank Lisa Ånfalk and Ann Svensson for helpful technical assistance and Professor Lars Grimelius for valuable discussions.

	Footnotes

 
Address reprint requests to Dr. Elisabeth Edström, Department of Surgery, Karolinska Hospital, SE-171 76 Stockholm, Sweden. E-mail: keem{at}kir.ks.se

Supported by grants from the Swedish Medical Research Council (02330), the Cancer Society of Stockholm (97:148), the Swedish Cancer Foundation, the Torsten and Ragnar Söderberg Foundations, and the Medical Research Fund of Tampere University Hospital.

Accepted for publication October 8, 1999.

	References

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