Sporadic and Familial Pheochromocytomas Are Associated with Loss of at Least Two Discrete Intervals on Chromosome 1P

[CANCER RESEARCH 60, 7048–7051, December 15, 2000] Sporadic and Familial Pheochromocytomas Are Associated with Loss of at Least Two Discrete Intervals on Chromosome 1p

Diana E. Benn, Trisha Dwight, Anne Louise Richardson, Leigh Delbridge, Christopher P. Bambach, Michael Stowasser, Richard D. Gordon, Deborah J. Marsh,1 and Bruce G. Robinson Cancer Genetics, Kolling Institute of Medical Research [D. E. B., T. D., A. L. R., D. J. M., B. G. R.] and Department of Surgery [L. D., C. P. B.], Royal North Shore Hospital, St. Leonards, New South Wales 2065; Departments of Medicine [D. E. B., T. D., D. J. M., B. G. R.] and Surgery [L. D.], University of Sydney, New South Wales 2006; and Hypertension Unit, University Department of Medicine, Greenslopes Hospital, Brisbane, Queensland 4120 [M. S., R. D. G.], Australia

ABSTRACT reported loss being between 29 and 45% in sporadic pheochromocytomas (4–6) and 100% in pheochromocytomas from MEN 2 patients Pheochromocytomas are tumors of the adrenal medulla originating in at this locus (5). the chromaffin cells derived from the neural crest. Ten % of these tumors There is also evidence from LOH studies for the involvement of a are associated with the familial cancer syndromes multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and rarely, neurofi- putative tumor suppressor locus at chromosome 1p in the develop- bromatosis type 1, in which germ-line mutations have been identified in ment of other endocrine tumors such as medullary thyroid carcinoma, RET, VHL, and NF1, respectively. In both the sporadic and familial forms the primary component tumor of MEN 2 (4, 5, 7, 8). In parathyroid of pheochromocytoma, allelic loss at 1p, 3p, 17p, and 22q has been adenomas, a SRO has been defined by a 4-cM region at 1p35–p36 reported, yet the molecular pathogenesis of these tumors is largely un- flanked by the markers D1S228 and D1S507 (9). Furthermore, a known. Allelic loss at chromosome 1p has also been reported in other common region of loss from D1S214 to D1S228 was defined in endocrine tumors, such as medullary thyroid cancer and tumors of the neuroblastomas (10), and the combination of this result with those of parathyroid gland, as well as in tumors of neural crest origin including three previous studies (11–13) determined a 7-cM consensus region of neuroblastoma and malignant melanoma. In this study, we performed fine loss from D1S214 to D1S244 (10). Another SRO has been identified structure mapping of deletions at chromosome 1p in familial and sporadic in neuroblastomas and named the NB3 locus flanked by D1Z2 and p73 pheochromocytomas to identify discrete regions likely housing tumor suppressor genes involved in the development of these tumors. Ten mic- and including the p73 gene itself (14). rosatellite markers spanning a region of ϳ70 cM (1pter to 1p34.3) were To generate a fine map of the regions of allelic loss present in both used to screen 20 pheochromocytomas from 19 unrelated patients for loss familial and sporadic pheochromocytomas, we have performed LOH of heterozygosity (LOH). LOH was detected at five or more loci in 8 of 13 studies using 10 microsatellite markers spanning a region of ϳ70 cM (61%) sporadic samples and at five or more loci in four of five (80%) at 1pter to 1p34.3. Furthermore, we have shown overlap of these tumor samples from patients with multiple endocrine neoplasia type 2. No regions with regions of LOH identified previously in other endocrine- LOH at 1p was detected in pheochromocytomas from two VHL patients. and neural crest-derived tumors. Analysis of the combined sporadic and familial tumor data suggested three possible regions of common somatic loss, designated as PC1 (D1S243 to D1S244), PC2 (D1S228 to D1S507), and PC3 (D1S507 toward the PATIENTS AND METHODS centromere). We propose that chromosome 1p may be the site of at least three putative tumor suppressor loci involved in the tumorigenesis of Patients. The specimens used in this analysis were from a patient cohort of pheochromocytomas. At least one of these loci, PC2 spanning an interval 13 sporadic pheochromocytomas (Table 1) including 5 males (mean age at of <3.8 cM, is likely to have a broader role in the development of surgery, 57.2 Ϯ 12.2 years) and 8 females (mean age, 47.1 Ϯ 16.1 years), as endocrine malignancies. well as 6 familial cases (Table 2), including a 40-year-old male and 5 females (mean age, 39.6 Ϯ 16.5 years). Of the five female patients presenting with familial disease (Table 2), three were diagnosed with MEN 2A (P14, P15, and INTRODUCTION P16) and one with MEN 2B (P17). Two patients, one male and one female, were diagnosed with VHL (P18 and P19). Pheochromocytomas are tumors of the adrenal medulla, originating Tissue and Blood Samples. Twenty fresh pheochromocytoma samples in the chromaffin cells derived from the neural crest. Pheochromocy- from 19 patients were obtained and immediately frozen in liquid nitrogen tomas most often occur sporadically (90%) but may also present as a before being transferred to Ϫ70°C for storage. Corresponding peripheral blood component of three autosomal dominantly inherited cancer syn- samples were also collected into EDTA tubes and frozen at Ϫ70°C. Pheochro- dromes, commonly in MEN 2,2 in 10–14% of VHL patients and mocytoma from both left and right adrenal glands (removed at the same rarely in NF1 (1). These familial forms of pheochromocytoma have surgery) of one of the MEN 2A patients (P16) were collected. Tumor and been associated with germ-line mutations in RET, VHL, and NF1, constitutional DNA were extracted using a standard protocol (15). respectively, and a small subset of sporadic tumors have been shown RET Mutation Analysis. For the MEN 2 patients, RET mutation analysis to have somatic RET or VHL mutations (2, 3). Allelic loss at chro- of genomic DNA had been performed prior to this study for exons 10, 11, 13, 14, 15, and 16 according to protocols described previously (16–19). All MEN mosomes 1p, 3p, 17p, and 22q has also been reported in both sporadic 2 patients had been shown to harbor a germ-line RET mutation prior to this and familial forms of pheochromocytomas (4). The region of allelic study (Table 2). loss at chromosome 1p includes 1p34–p36, with the frequency of LOH Analysis. LOH analysis was undertaken using DNA from 20 pheochromocytoma/blood paired samples and 10 microsatellite markers linked to Received 6/12/00; accepted 10/18/00. chromosome 1p, from 1pter to 1p34.3. The markers are ordered as The costs of publication of this article were defrayed in part by the payment of page follows from the most telomeric to the most centromeric, D1S243-D1S468- charges. This article must therefore be hereby marked advertisement in accordance with D1S244-D1S2667-D1S228-D1S2728-D1S507-D1S478-D1S513-MYCL1 (20– 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed, at Cancer Genetics Unit, Kolling 24). Genomic and tumor DNA (50 ng) were amplified by PCR in a total Institute of Medical Research, Royal North Shore Hospital, St. Leonards, New South volume of 10 ␮l containing 50–200 ␮M each deoxynucleotide triphosphate Wales 2065, Australia. Phone: 61-2-9926-7176; Fax: 61-2-9926-8523; E-mail: (Boehringer Mannheim); 0.5 ␮M each primer, the forward primer end labeled [email protected]. with 1.5 ␮Ci/reaction [␥-33P]dATP (DuPont NEN, Boston, MA); 10 mM 2 The abbreviations used are: MEN 2, multiple endocrine neoplasia type 2; VHL, von Hippel-Lindau disease; NF1, neurofibromatosis type 1; LOH, loss of heterozygosity; Tris-HCl (pH 8.3); 50 mM KCl; 1–1.5 M MgCl2, and 0.5 unit of Taq DNA SRO, shortest region of overlap. polymerase (Perkin-Elmer, Norwalk, CT). The following PCR conditions were 7048

Table 1 Patient information on sporadic pheochromocytomas indicating the sex of the adrenal glands of a patient with MEN 2A and the RET germ-line patient and patient age at the time of surgery mutation C634R (P16) showed different patterns of LOH at 1p (Figs. Age 1B and 2). The tumor from the left adrenal showed retention of Patient code Sex (yr) heterozygosity, whereas the right adrenal tumor showed loss at five of P1 F 62 eight informative loci with retention of heterozygosity observed at the P2 F 27 P3 F 63 markers D1S243, D1S244, and D1S228. P4 F 40 Thus, in familial pheochromocytoma, two distinct regions of LOH P5 F 23 Ͻ P6 F 44 were identified: SRO1-f, corresponding to a 22.9 cM interval P7 M 46 flanked by D1S243 and D1S244; and SRO2-f, a Ͼ39 cM interval P8 M 61 flanked by D1S228 and extending toward the centromere (Fig. 1B). P9 M 56 P10 M 47 Analysis of the combined sporadic and familial results suggested P11 F 60 three regions of common loss: PC1 identical to SRO1-f (D1S243 to P12 F 58 D1S244); PC2 identical to SRO2-s (D1S228 to D1S507); and PC3 P13 M 76 identical to SRO3-s, a Ͼ35.3 cM interval flanked by D1S507 and extending toward the centromere. Table 2 Patient information on familial pheochromocytomas indicating the sex, age at time of surgery, and diagnosis for each patient including the results of RET testing on genomic samples for the MEN 2 patients Patient code Sex Age (yr) Diagnosis RET mutation analysis P14 F 63 MEN 2A C634Y P15 F 43 MEN 2A C634S P16-bilateral F 21 MEN 2A C634R P17 F 44 MEN 2B M918T P18 F 27 VHL P19 M 40 VHL used: a denaturation step of 94°C for 4 min, followed by 25 cycles of denaturation at 94°C for 30 s, annealing at 60°C for 15 s (for all markers except D1S507 and D1S513, where a 64°C annealing temperature was used), and extension at 72°C for 30 s. Electrophoresis was used to resolve the denatured samples (2 ␮l of each) for 3–4 h, followed by drying and overnight exposure to a Molecular Dynamics PhosphorImager screen (Phosphorimager SP; Mo- lecular Dynamics, Sunnyvale, CA). LOH was indicated if there was loss or clear reduction in the intensity of one of the allelic bands in the tumor sample, and this was confirmed by scanning densitometry (4). The residual density of the deleted band in the tumor DNA was normalized against the density of the retained band, and the band in the genomic DNA corresponding to the deleted band of tumor DNA was normalized against the corresponding retained band. The ratio of the normalized tumor band density to the normalized corresponding genomic band was calculated, and a ratio of Ͻ0.5 was defined as repre- senting LOH (4).

RESULTS LOH Analysis. Using microsatellite markers located at 1pter to 1p34.3, analysis of DNA from 20 blood/pheochromocytoma paired samples showed LOH in 8 of 13 (61%) sporadic samples (Fig. 1A). Of the 8 sporadic tumors exhibiting LOH, 4 (P3, P5, P6, and P9) showed LOH at each informative marker, and in the remaining 4 sporadic tumors, LOH was detected at each informative loci with the exception of D1S228 (P2 and P11) and D1S507 (P10, P11, and P13), which showed retention of heterozygosity. For the five sporadic tumors with retention of heterozygosity, 84% of loci were informative for the markers tested. Thus, in sporadic pheochromocytomas, three distinct intervals of LOH were determined: SRO1-s from 1pter up to D1S228 spanning a genetic distance of Ͻ32.4 cM; SRO2-s, an interval of Ͻ3.8 cM flanked by D1S228 and D1S507; and SRO3-s, flanked by D1S507 toward the centromere and spanning a region Ͼ35.3 cM (Fig. 1A). With regard to the familial tumors, LOH was detected at each informative locus in two of seven samples, P14 (MEN 2A) and P17 (MEN 2B; Fig. 1B). Patient 15 (MEN 2A) showed LOH at each Fig. 1. LOH analysis of 10 microsatellite markers at chromosome 1pter to 1p34.3 in pheochromocytoma. F, loss of heterozygosity; O, noninformative (homozygosity); E, reten- informative locus with the exception of retention of heterozygosity at tion of heterozygosity; ‚, indeterminate case. A, analysis of 13 sporadic pheochromocytomas D1S228. LOH at chromosome 1p was not detected in pheochromo- at this interval. B, analysis of seven familial pheochromocytomas consisting of three cases of MEN 2A (P16 with both left and right adrenals analyzed), one case of MEN 2B, and two cases PC1, PC2, and PC3 indicate the SROs from combining data from SROs of ,ء .cytomas from two VHL patients. of VHL Of interest, pheochromocytomas originating in both left and right sporadic (SRO-s) and familial (SRO-f) pheochromocytomas. 7049

DISCUSSION In this study of LOH in pheochromocytoma at 1pter to 1p34.3, we have identified three putative tumor suppressor loci likely to be involved in the pathogenesis of this tumor. Specifically, these regions are PC1 (D1S243 to D1S244), PC2 (D1S228 to D1S507), and PC3 (D1S507 toward the centromere). This fine structure mapping of 1p involvement in pheochromocytoma refines previously reported gross loss (4, 6–8) with a SRO defined previously as bounded proximally by D1S15 (1pter–p22) and distally by D1Z2 (1p36.3; Ref. 5). In our study, allelic loss at distal 1p was found in 8 of 13 (61%) sporadic pheochromocytomas compared with previous reports of loss at that region in the range of 28–54% (4, 5, 6, 8). Possible reasons for the differences in frequency of loss observed between these reports include the size of the cohorts studied and the range of markers used. Allelic loss at distal 1p was also observed in four of seven familial pheochromocytomas, including MEN 2 and VHL patients. Of con- siderable interest, two of the familial tumors that did not exhibit LOH Fig. 3. SRO for pheochromocytomas from the current LOH study of chromosome 1p at this locus were pheochromocytomas from VHL patients. This is in using 10 microsatellite markers, compared with SROs for other tumor types. SRO for contrast to another report that identified 1p loss in one of two VHL pheochromocytoma were identified, i.e., PC1 (D1S243 to D1S244), PC2 (D1S228 to D1S507), and PC3 (D1S507 toward the centromere). These regions are compared with pheochromocytomas studied (5). regions reported previously for neuroblastoma (NB), parathyroid (PT), and pheochromo- An additional familial tumor exhibiting retention of heterozygosity cytoma (PC). A common SRO for neuroblastoma, called NBL (D1S214 to D1S244), has at 1p34–36 for all informative markers was the left adrenal gland of been suggested (10) based on four studies (10–13). A SRO for parathyroid tumors has been described previously (9), as has a region for pheochromocytomas flanked distally by a MEN 2A patient with the corresponding right adrenal gland showing D1Z2 and proximally by D1S15 (5). LOH at D1S468 and loss flanked by D1S228 toward the centromere. This patient had undergone bilateral adrenalectomy, and pheochromocytoma was present in both glands. Although anecdotal, this raises neuroblastoma, another tumor of neural crest-derived tissue, with the the interesting possibility that somatic mutation of different genes, in regions identified in our study on pheochromocytomas (Fig. 3). In combination with a germ-line mutation in the RET proto-oncogene, neuroblastomas, a compilation of results from four studies (10–13) may lead to the formation of bilateral pheochromocytomas in MEN defined a common 7-cM region of loss from D1S214 to D1S244. This 2A patients along different genetic pathways. region falls within our defined PC1 region, which contains several We did not find any significant differences in the frequency of 1p potential candidate genes likely to function as tumor suppressors and LOH in sporadic versus familial (MEN and VHL) pheochromocyto- be active in endocrine or neural crest cell-derived tissues. Such mas (61 and 57%, respectively), an observation that is in agreement candidate genes include TNFRSF12 (DR3; Ref. 25), PIK3CD (26), with previous reports (4, 8). By excluding the VHL samples from the and p73 (27). In addition, our PC3 region partly overlaps a region of familial analysis, the frequency of 1p LOH for MEN 2 pheochromo- LOH described previously (12) in neuroblastoma and harbors poten- cytomas was 80%. Interestingly, a previous study had reported 1p tial suppressor genes such as CDC42 (28), E2F2 (29), HEIR 1 (30), LOH in 100% of MEN 2 pheochromocytomas (nine of nine), not and RAPIA (31). dissimilar to the findings reported in the current study (5). However, In the current study, we have identified the Ͻ3.8-cM region flanked this same study reported only 29% (two of seven) 1p loss in sporadic by D1S228 and D1S507 and designated it PC2. This region has been pheochromocytomas. Whether this discrepancy of the frequency of 1p reported previously as a SRO in parathyroid adenomas and addition- loss in sporadic pheochromocytomas is a true finding or rather reflects ally as part of a gross region of loss in pituitary adenomas (9) and the limited sample size of each study remains to be clarified by neuroblastomas (12). Thus, PC2 has been shown to be deleted in a analysis of a larger number of samples. However, our data do support range of endocrine tumors, including familial and sporadic pheochro- the possibility of chromosomal loci in addition to RET and 1p having mocytoma, and parathyroid tumors, as well as tumors of neural a role in the pathogenesis of both familial and sporadic pheochromo- crest-derived tissue including neuroblastoma. Possible candidate cytomas. genes in the PC2 region are caspase 9 (32), ZNF151 (33), and CD30 It is interesting to compare common regions of loss in 1p in (34). Therefore, it is likely that a putative tumor suppressor(s) at PC2 has a broad role in the pathogenesis of both endocrine and neural crest cell-derived tumors. It is also possible that the regions PC1 and PC3 may be additional sites of possible tumor suppressor genes involved in the pathogenesis of tumors of neural crest origin.

ACKNOWLEDGMENTS

We thank the following clinicians for providing tumor samples, Drs. Peter Campbell and Duncan Topliss.

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Diana E. Benn, Trisha Dwight, Anne Louise Richardson, et al.

Cancer Res 2000;60:7048-7051.

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