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Dipartimento Ricerca BioMedica, Section for Molecular Medicine and Gene Therapy, University Campus Bio Medico, 00155 Rome, Italy [P. P.], and Department of Otolaryngology, Head & Neck Surgery, Division of Head and Neck Cancer Research [P. P., D. S.] and Wilmer Ophthalmological Institute, Department of Ophthalmology [S. L. M.], John Hopkins University School of Medicine, Baltimore, Maryland 21287
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Introduction |
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Uveal melanomas are believed to arise from the neuroectodermally derived melanocytes present in the choroid, ciliary body, or iris. Iris melanomas comprise less then 10% of uveal melanomas and are typically associated with a good prognosis (3) . In contrast, ciliary body or choroidal melanomas are associated with poor prognosis, with at least 30% of affected patients developing metastases within 10 years of successful local management of the primary tumor (4) . The average life expectancy after identification of metastases is only 7 months (5) .
Advances in molecular genetics have made possible the identification of genetic changes and particular mutant genes in human tumors. To date, many chromosomal loci have been implicated in the development of human cancer, and over a dozen genes have now been isolated that are specifically mutated in primary tumors of various types (6) . Studies have also shown that tumor induction and progression are characterized by the accumulation of multiple genetic alterations in the long and complex evolution of cells from a normal to a malignant phenotype (7) . The frequent loss of a specific chromosome in cancer is thought to represent one step in the inactivation of a tumor suppressor gene residing on the lost chromosome. Tumorigenesis can also result from the amplification or mutation of an oncogene.
Although current histopathological and cytogenetic methods can provide some prognostic information, relatively little is known about the molecular genetic alterations and their temporal relationship leading to the development of uveal melanoma. Many cytogenetic investigations of cultured uveal melanoma cells have revealed that the majority of choroidal and ciliary body melanomas are characterized by nonrandom alterations in chromosomes 3, 6, and 8 (8) .
These observations have been confirmed by CGH3 (9, 10, 11) and, for chromosome 3, by FISH analysis (12) . M3 (either true or functional) and trisomy 8, partial duplication of 8q, or isochromosome 8q are the most frequent karyotypic abnormalities present in approximately 50% of cases (8 , 13) . Abnormalities in chromosomes 3 and 8 often coexist in the same tumor, whereas chromosome 6 alterations are detected in about 40% of cases (8, 9, 10, 11) .
To further investigate the molecular genetic aberrations that underlie the development of uveal melanoma and to uncover areas of chromosomal loss that may contain tumor suppressor genes, we performed a comprehensive allelotype of 50 posterior uveal melanomas. Every autosomal arm and the X chromosome were screened with highly informative microsatellite markers for genetic alterations. The highest frequency of LOH was found on chromosome 3 (64%), followed by chromosomal arm 8q (60%). Chromosome 6p allelic imbalance was found in 28% of tumors. LOH at all informative loci on chromosome 3 (likely M3) and 6p alterations were almost mutually exclusive, suggesting the presence of two distinct pathways in the development of uveal melanoma.
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Materials and Methods |
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16 mm); and (c ) 10 large tumors (AH > 10 mm or BD > 16 mm; 14
). The BD ranged from 5–18 mm (mean, 12 ± 3 mm), and the AH ranged from 2–19 mm (mean, 7 ± 4 mm). Tumors were classified by the modified Callendar classification (15)
. Five tumors (10%) were classified as spindle cell tumors, 43 tumors (86%) were classified as mixed cell tumors, and 2 tumors (4%) were classified as epithelioid cell tumors. DNA from the 50 choroidal and ciliochoroidal tumors was extracted from paraffin-embedded tissue as described previously (16) . Briefly, unstained paraffin sections of each block were microdissected into tumor and normal tissue. The normal ocular tissue was used as the source of normal control DNA for each patient. Normal tissue and tumor tissue were digested with SDS-proteinase K for 24 h at 48°C, and samples were extracted with phenol/chloroform. Pigments, which coisolated with the DNA after the extraction, tended to inhibit the PCR. Therefore, DNA samples were additionally purified using Geneclean II according to the manufacturer’s instructions (Bio 101, Vista, CA).
For sample UM58, two distinct regions of the tumor, one pigmented and one unpigmented, were microdissected and processed separately as tumor samples A (unpigmented) and B (pigmented). Both regions were classified as mixed cell tumors composed predominantly of spindle B cells with some epithelioid cells. For the allelotype and all statistical calculations, the results for UM58A were used (see "Results").
Allelotyping.
DNA from normal and tumor tissue was analyzed for LOH by amplification of microsatellite markers using PCR and the conditions described below (17)
. Primer pairs designed to amplify microsatellite markers were obtained from Research Genetics (Huntsville, AL). As an initial screen, two markers per chromosomal arm were used: 1p, D1S214 and D1S219; 1q, D1S305 and D1S237; 2p, D2S162 and D2S358; 2q, D2S126 and D2S125; 3p, D3S1597 and D3S1284; 3q, D3S1292 and D3S1268; 4p, D4S394 and D4S404; 4q, D4S430 and D4S171; 5p, D5S417 and D5S455; 5q, D5S421 and D5S429; 6p, D6S470 and D6S265; 6q, D6S268 and D6S264; 7p, D7S481 and D7S507; 7q, D7S479 and D7S495; 8p, D8S262 and D8S261; 8q, D8S285 and D8S257; 9p, D9S171 and D9S104; 9q, D9S176 and D9S170; 10p, D10S249 and D10S191; 10q, D10S185 and D10S221; 11p, d11S907 and D11S929; 11q, INT2 and D11S873; 12p, D12S341 and D12S77; 12q, D12S329 and D12S86; 13q, D13S263 and D13S170; 14q, D14S283 and D14S67; 15q, D15S117 and D15S87; 16p, D16S404 and D16S412; 16q, D16S514 and D16S413; 17p, D17S796 and CHRNB1; 17q, D17S579 and D17S789; 18p, D18S52 and D18S453; 18q, D18S67 and D18S61; 19p, D19S424 and D19S177; 19q, D19S412 and D19S926; 20p, D20S95 and D20S104; 20q, D20S119 and D20S171; 21q, D21S11 and D21S262; 22q, D22S283 and IL2RB; Xp, DXS996 and DXS451; and Xq, DXS990 and DXS1192. Markers were chosen so that each member of a pair was widely separated on its chromosomal arm. The vast majority of chromosomal arms had at least 90% informativity for all tumors using only these two markers per chromosomal arm. An additional marker was used for the four chromosomal arms with less than 90% informativity, for those samples which were noninformative for both standard markers. The additional markers were D1S255 (1p), D1S158 (1q), D8S265 (8p), and D9S196 (9q).
Using T4 kinase (Life Technologies, Inc., Gaithersburg, MD), 500 ng of one primer from each pair were end-labeled with [32 P]ATP (20 mCi; Amersham, Piscataway, NJ) in a total volume of 20 µl (16) . Approximately 50 ng of DNA in 1x PCR buffer [16.6 mM ammonium sulfate, 67 mM Tris (pH 8.8), 6.7 mM magnesium chloride, 10 mM ß-mercaptoethanol, 1% DMSO, and 1.25 mM deoxynucleotide triphosphates) were amplified using 25 ng of end-labeled primer, 60 ng of each unlabeled primer, and 2 units of Taq DNA polymerase (New England Biolabs, Beverly, MA). PCR conditions were as follows: 35 cycles of 95°C for 1 min, 54°C for 1 min, and 72°C for 1 min, followed by a final 4-min extension at 72°C. About one-fourth of the PCR product was separated on an 8 M urea-formamide-polyacrylamide gel and exposed to film.
Cases were considered informative if two alleles were present in the normal sample. For informative cases, allelic loss was scored if the intensity of one allele was at least 30% reduced in tumor DNA as compared with the normal DNA, as determined visually by two independent observers (D. S. and S. L. M.).
Tumors with LOH of all informative markers on chromosome 3 and at least one informative marker per arm were considered to be M3. We did not perform cytogenetic studies or FISH analysis to distinguish cases of true M3 from cases of functional M3 (acquired isodisomy) (13) . Because both allelic loss and allelic amplification can be detected by microsatellite analysis, and because duplications of 6p and 8q have been observed in uveal melanoma by cytogenetic studies, we refer to apparent LOH on 6p and 8q only as allelic imbalance.
Statistical Analysis.
Statistical analyses were performed using SigmaStat program 1.02. The associations between the discrete variables were assessed using Fisher’s exact test. Mean values were compared using the two-tailed t test. Differences were considered statistically significant for P < 0.05.
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Results |
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For each chromosomal locus, the total number of informative cases and the number of cases with LOH are shown. All chromosomal arms had at least 90% informativity for all tumors, and the majority had greater than 95% informativity.
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). Forty-seven of the 50 tumors were informative for both arms of chromosome 3, and 3 tumors were noninformative at chromosome 3q (Table 1)
. Of the 47 informative tumors, 28 (59%) showed allelic loss of all informative markers, consistent with M3, and 15 (32%) showed retention of all informative markers. Of the remaining 4 tumors, two displayed only 3p LOH, and two displayed only 3q LOH.
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. Although 8p imbalance was found in 20 of 48 cases (42%), in 17 cases, a concomitant imbalance of 8q was present, suggesting that the vast majority of 8p alterations occur in association with changes in 8q. Seven other chromosomal arms had LOH of markers greater than or equal to 30%: (a) 1p (33%); (b) 1q (30%); (c) 4q (30%); (d) 11p (33%); (e) 11q (32%); (f) 17p (34%); and (g) 19p (37%; Fig. 1
). For chromosome 6, allelic imbalance was observed in 28% (6p) and 18% (6q) of cases.
For further analysis, the tumors were divided into two groups: (a) those with retention of markers from both arms of chromosome 3 (R3); and (b) those with LOH of all markers from both arms of chromosome 3 (M3). Table 2
compares the frequencies of allelic imbalance for these two groups. Only chromosomal arms for which the frequencies were not identical are shown (Table 2)
. Most striking was the relative absence of 6p alterations in tumors with M3. In fact, only 1 of 26 informative cases (4%) had both LOH of all chromosome 3 markers (M3) and allelic imbalance of markers on 6p, whereas 8 of 15 cases (53%) with retention of all chromosome 3 markers (R3) showed a 6p imbalance (P = 0.0005).
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). Of note, all tumors in the R3 group with 8q alterations also had an allelic imbalance of markers on 6p. In other words, we found no tumors with 8q alterations that did not have alterations in either chromosome 3 or 6p. This suggests that 8q alterations follow alterations of chromosome 3 or 6p during tumor progression.
Allelic imbalance of chromosome 3 or chromosome 6p was found in 43 of 50 tumors (86%), and in 28 of 41 tumors (2 tumors were noninformative for 8q), 8q alteration was also present (68%). In those few tumors without alterations in 3, 6p, or 8q, no alternative common regions of LOH were noted (data not shown). Every tumor had at least one marker that displayed LOH. Representative results for two tumors, UM3 and UM14, are shown in Fig. 2A
. Only 12 tumors showed microsatellite instability of at least one but no more than two microsatellite markers (data not shown).
We found no statistically significant difference in the frequency of chromosome 3 loss between those tumors with ciliary body involvement. M3 with associated alteration of 8q was found more often in tumors with ciliary body involvement (80%) than in tumors restricted to the choroid (66%), but the difference was not statistically significant.
A weak association was found between AH and allelic imbalance of chromosomal arm 8q. AH was 7.9 mm ± 4.2 in tumors with 8q alterations and 5.8 mm ± 2.9 in tumors without 8q alterations (P = 0.05).
Fig. 2B
demonstrates the two histologically distinct regions of tumor UM58, which were microdissected separately. Although both the unpigmented region (UM58A) and the pigmented region (UM58B) had loss of the same allele for all informative markers on chromosome 3, UM58A and UM58B had relative loss of different alleles for a marker on 8q (Fig. 2C)
, consistent with the hypothesis that 8q alteration follows the alteration of chromosome 3. Both regions had retention of 6p markers (Fig. 2C)
. On chromosome 22, LOH of the same allele was also seen for both regions (data not shown). UM58A had a total of 10 additional chromosomal arms with LOH when compared to UM58B (data not shown). We chose to include the results from UM58A in the allelotype because it had the more complex pattern of LOH.
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Discussion |
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We found that 28 of 50 (59%) posterior uveal melanomas showed LOH at all informative loci on both arms of chromosome 3, consistent with the karyotypic detection of M3 in 50–60% of cases (8) . The exact mechanism by which M3 may lead to uveal melanoma is not known, but many candidate genes implicated in carcinogenesis (e.g., VHL, FHIT, and THRB) have been mapped to chromosome 3 (19, 20, 21) .
A total of 60% of tumors studied showed allelic imbalance of chromosomal arm 8q. Allelic imbalance, as detected by microsatellite analysis, can derive from the deletion of one of two chromosomal homologues (true LOH) or from the amplification of one of two chromosomal homologues (amplification). Because duplication of chromosomal arm 8q has been demonstrated in approximately 50% of uveal melanomas by many cytogenetic studies, our detected imbalance most likely represents duplication, but this remains to be confirmed by CGH or FISH analysis. The smallest duplicated region appears to be 8q21
ter, spanning the c-myc oncogene locus (22)
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Loss of chromosomal arm 6q and gain of chromosomal arm 6p have also been reported in several karyotypic and CGH studies with different frequencies of occurrence (8, 9, 10, 11) . We found more 6p alterations (28%) than 6q alterations (18%). Interestingly, alterations in 6p occurred much more frequently in tumors with retention of chromosome 3 (P = 0.0005). As with the 8q alterations we detected, the 6p alterations most likely represent amplification when the results from karyotypic and CGH studies are considered. WAF1/CIP1, a cyclin-dependent kinase inhibitor, has been mapped to 6p and may be involved in the development of cutaneous melanoma (23, 24, 25, 26) . The genes encoding MHC class I molecules are also located on 6p, and expression of HLA molecules has been found to be altered in uveal melanoma by immunohistochemistry (27) .
Solid tumor induction and progression are characterized by the accumulation of multiple genetic alterations in the evolution of a normal cell to a malignant cell (7)
. It has been suggested that loss of chromosome 3 is an early event in the neoplastic transformation of uveal melanomas (22)
, and we found eight cases of M3 without chromosome 8 abnormalities. Our observation that M3 and alterations of 6p are essentially mutually exclusive in our population has led us to propose a bifurcated tumor progression model for uveal melanoma. As shown in Fig. 3
, the most common pathway would involve the loss of one copy of chromosome 3, with a divergent pathway characterized by alteration of 6p.
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. In our population of 50 uveal melanomas, we found no tumors with 8q alterations without M3 or 6p alterations. In a karyotypic study of 54 tumors, White et al. (13)
also found no tumors with only 8q abnormalities. Our model is further supported by the microsatellite analysis of tumor UM58 with two histopathologically distinct areas (Fig. 2, B and C)
. LOH of the same allele for all informative markers on chromosome 3, as well as for a marker on chromosome 22, was observed for both areas of the tumor. However, each area showed imbalance of a different allele using an 8q marker, suggesting that these imbalances occurred after the alterations in chromosomes 3 and 22. When we compared average tumor size with alterations of 8q, we found that thicker tumors were more likely to have an 8q imbalance than thinner tumors (P = 0.05), consistent with the proposal that tumors accumulate 8q changes as they grow. Additional studies of tumors showing intralesional variation will help to clarify our tumor progression model for uveal melanoma. An association between cytogenetic abnormalities on chromosomes 3, 6, and 8 in uveal melanoma and patient outcomes has been reported (29, 30, 31) . Most recently, White et al. (31) found a correlation between poor prognosis and the presence of M3 and amplification of 8q together and a correlation between better prognosis and the presence of chromosome 6 abnormalities. It is tempting to consider that the observations of White et al. may represent the two arms of our proposed progression model.
Although we did not find an association between M3 and ciliary body involvement (29) , we did find M3 with alterations of 8q more often in ciliochoroidal melanomas, consistent with a prior observation (31) . However, in our population, the difference was not statistically significant. Several reasons could explain this discrepancy. The most obvious explanation is the difference in technique used to detect genetic alterations. Microsatellite analysis, like CGH, is performed using DNA isolated directly from many tumor cells without cell culture and more accurately represents the tumor cell population in vivo. Differences in the frequency of genetic alterations have previously been observed when both CGH and cytogenetics were used to study a group of tumors (9) . As an example, higher frequencies of chromosome 6 alterations were found by CGH when compared to chromosome banding analysis of the same tumors (9) . Additionally, using CGH, Gordon et al. (10) did not find an association between abnormalities of chromosomes 3 and 8 and tumor location or cell type.
Another possibility to explain the discrepancy is a difference in our tumor population. We included a wide range of tumor sizes in our analysis to get a broad view of the genetic changes that lead to uveal melanoma. In contrast, most karyotypic studies for which tumor size has been provided have only included medium to very large tumors.
To date, only a few studies have analyzed uveal melanomas using microsatellite analysis, and these studies tested only chromosomes 3 and 9 (13 , 16 , 32) . We were able to detect LOH in 86% of tumors using a total of six microsatellite markers for chromosome 3 and 6p. Microsatellite analysis of tissue from fine needle aspirate biopsies or enucleations could be used to detect the genetic alterations, which correlate with prognosis (33) . This method might also be useful in identifying metastatic disease because microsatellite alterations have been found in the serum of patients with metastases from head and neck cancer, small cell lung carcinoma, and colon cancer (34, 35, 36) and, most recently, in the plasma of patients with cutaneous melanoma (37) .
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by National Eye Institute Grant K08 EY00378-01 and the Niuta and Roy Titus Faculty Development Award (to S. L. M.) and by Specialized Program of Research Excellence in Lung Cancer Grant CA58-184 and National Institute for Dental and Craniofacial Research Grant R01 DE012588-01 (to D. S.). P. P. was supported by a fellowship from Progetto Sanita 96/97, Fondazione Cassa di Risparmio di Verona, Vicenza, Belluno, ed Ancona, Italy. 
2 To whom requests for reprints should be addressed, at Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Maumenee 127, Baltimore, MD 21287. Phone: (410) 955-1112; Fax: (410) 614-9987; E-mail: smerbs{at}jhmi.edu
3 The abbreviations used are: CGH, comparative genomic hybridization; FISH, fluorescence in situ hybridization; LOH, loss of heterozygosity; AH, apical height; BD, basal diameter; M3, monosomy 3; R3, disomy 3.
Received 4/ 8/99. Accepted 5/17/99.
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, p; 
, q.
) and retention of alleles in both tumor regions for marker D6S265 (6p). For marker D8S285, TA shows relative LOH of the upper allele (