Fine Mapping of Chromosome 3 in Uveal Melanoma: Identification of a Minimal Region of Deletion on Chromosomal Arm 3P25.1-P25.2

[CANCER RESEARCH 63, 8507–8510, December 1, 2003] Fine Mapping of Chromosome 3 in Uveal Melanoma: Identification of a Minimal Region of Deletion on Chromosomal Arm 3p25.1-p25.2

Paola Parrella,1 Vito M. Fazio,1,2 Antonietta P. Gallo,1 David Sidransky,3 and Shannath L. Merbs4 1Istituto di Ricovero e Cura a Carattere Scientifico H. “Casa Sollievo della Sofferenza” Laboratory of Gene Therapy and Oncology, San Giovanni Rotondo (FG), Italy; 2Interdisciplinary Center for Biomedical Research, Laboratory for Molecular Medicine and Biotechnology, Universita` Campus BioMedico, Rome, Italy; and 3Otolaryngology Head and Neck Surgery and 4Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland

ABSTRACT rearranged in tumors and are therefore believed to contain TSGs. Two of these regions are located on the centromeric portion of the short To identify minimal common areas of allelic loss on chromosome 3, we arm (12). The 3p12-13 region contains the gene ROBO1/DUTT1 and have mapped both arms of the chromosome in 21 uveal melanomas that the 3p14.2 region spans the FHIT gene. Three other hot spots for did not show monosomy 3 in our previous allelotype study. DNA was isolated from microdissected paraffin sections and amplified by PCR. In rearrangements were reported on 3p21. The first is located on 3p21.1- an initial screening, 14 microsatellite markers on chromosomal arm 3p p21.2 and includes the gene BAP1 that binds the RING finger domain and 13 on chromosomal arm 3q were used. Loss of heterozygosity for at of the BRCA1 gene. The second is the lung cancer TSG region least one marker was found in 9 of 21 tumors (43%) on 3p and 8 of 21 (LUCA) that includes the RASSF1 gene frequently hypermethylated tumors (38%) on 3q. The initial analysis defined two common regions of in cancer. The third is located on 3p21.3 and contains the DLC1 gene allelic loss on 3p, a 7.3-Mb region between markers D3S1263 and D3S3510 found deleted in a number of small cell lung cancer cell lines and spanning 3p25.3-24.3 and a larger region between markers D3S1578 and primary tumors. The telomeric region 3p25-26, containing the VHL D3S1284. The two common regions of allelic loss were further mapped gene, has also been reported to be frequently rearranged (12). with an additional 14 microsatellite markers. A 1.4-Mb minimal region of Although monosomy or isodisomy 3 are very common in uveal allelic loss was identified between microsatellite markers D3S3610 and melanoma, only a few partial deletions of this chromosome have been D3S1554 on 3p25.1-3p25.2. A total of 10 tumors had allelic loss in this region; 2 of these tumors had corresponding putative homozygous dele- described (13, 14). To gain more insight into the patterns of chromo- tions. These homozygous deletions may further narrow the region of some 3 deletion and possible genes involved in the carcinogenesis of interest to 0.1 Mb. This 1.4-Mb minimum region of deletion includes uveal melanoma, we analyzed 21 tumors from our allelotype cohort several genes that might be involved in the carcinogenesis of uveal mela- that did not show monosomy 3, with a total of 41 microsatellite noma as well as other important tumor types. markers (11). We identified a 1.4-Mb shared MRD on chromosome 3p25.1-p25.2 between markers D3S3610 and D3S1554 that contains INTRODUCTION 9 National Center for Biotechnology Information reference sequences and a number of predicted genes. Carcinogenesis occurs as a stepwise accumulation of genetic alterations in genes that control cell growth, cell death, and DNA repair (1). One of the critical events that lead to carcinogenesis is the MATERIALS AND METHODS inactivation of one or more TSGs.5 Allelic loss, manifested as LOH of microsatellite markers flanking the TSG, is recognized as hallmark of Specimens and DNA Extraction. We evaluated 21 cases of posterior sporadic tumors, with inactivation of the second allele by gene dele- uveal melanoma treated by enucleation from 1993 to 1998 and archived as tion, point mutations or promoter hypermethylation (1). paraffin blocks by the Eye Pathology Laboratory of the Wilmer Ophthalmo- logical Institute. DNA was extracted from paraffin-embedded tissue as de- Posterior uveal melanoma is a relatively rare tumor, but it is scribed previously (15). Briefly, unstained paraffin sections of each block were associated with a high visual morbidity and can pose a serous treat to manually dissected into tumor and normal tissue samples under a microscope life (2). About 30% of patients will develop distant metastases within to ensure that tumor samples contained at least 80% cancer cells (15). The 10 years of successful management of the local tumor (3). The most normal ocular tissue was used as the source of normal control DNA for each common genetic abnormality in uveal melanoma is the loss of one patient. Normal and tumor tissue was digested with SDS/proteinase K for 24 h copy of chromosome 3. Cytogenetic and comparative genomic hy- at 48°C, and samples were extracted with phenol/chloroform. Pigments, which bridization studies have demonstrated monosomy 3 in ϳ50% of cases coisolated with the DNA after the extraction, tended to inhibit the PCR. (4–8). Complete or partial deletions of chromosome 3 have been Therefore, DNA samples were additionally purified using Geneclean II ac- detected by microsatellite marker analysis (9, 10). In our allelotype of cording to the manufacturer’s instructions (Bio101; Vista, CA). 50 uveal melanomas, ϳ60% of tumors had LOH of all markers on Fine Deletion Mapping. Twenty-one uveal melanomas from the original allelotype cohort (15 tumors with retention of all tested markers on 3p, 4 chromosome 3 consistent with monosomy or isodisomy 3 (11). tumors with LOH of 3p or 3q, and 2 tumors noninformative for markers on 3p Genetic abnormalities of chromosome 3 and, in particular 3p, are or 3q) were tested (11). DNA from normal and tumor tissues were analyzed for also critical to the development of in several other tumor types, LOH by amplification of STS microsatellite markers using PCR and the including small cell lung carcinoma, breast cancer, ovarian cancer, conditions described below. adenocarcinoma of the cervix, renal cell carcinoma, and head and For an initial screening, 27 primer pairs (Research Genetics. Huntsville, neck tumors (12). Several regions on chromosome 3p are frequently AL) were analyzed: 14 on chromosomal arm 3p (D3S1270, D3S1597, D3S1263, D3S1252, D3S1286, D3S3510, D3S1293, D3S1283, D3S1007, Received 5/14/03; revised 8/10/03; accepted 9/16/03. D3S1358, D3S1578, D3S1234, D3S1210, D3S1284) and 13 on chromosomal Grant support: National Eye Institute K08-EY00378 (to S. L. M.), the Research to arm 3q (D3S2318, D3S1251, D3S1603, D3S1546, D3S1310, D3S1292, Prevent Blindness, Inc. (to S. L. M.), the Niuta and Roy Titus Faculty Development D3S1238, D3S1764, D3S1268, D3S3715, D3S1580, D3S2748, D3S1311). The Award (S. L. M.), and Progetto Ministero della Salute Istituto di Ricovero e Cura a microsatellite markers were chosen to span ϳ5-Mb intervals on chromosome Carattere Scientifico Grant RCO202TG08 (to P. P.). ϳ The costs of publication of this article were defrayed in part by the payment of page 3p and 8-Mb intervals on chromosome 3q. The relative positions of the charges. This article must therefore be hereby marked advertisement in accordance with markers were determined using the Human Genome Working Draft Sequence 18 U.S.C. Section 1734 solely to indicate this fact. Browser November 2002 (Ref. 16; Fig. 1).6 Markers D3S1597, D3S1284, Requests for reprints: Shannath L. Merbs. 5 The abbreviations used are: TSG, tumor suppressor gene; LOH, loss of heterozygosity; MRD, minimal region of deletion; STS, sequence-tagged site. 6 Internet address: http://www.ucsc.edu. 8507

Fig. 1. Chromosome 3 mapping. Twenty-one uveal melanomas were tested with 27 microsatellite markers (14 for chromosomal arm 3p and 13 for chromosomal arm 3q), , retention of both alleles; f, loss of heterozygosity; NI, noninformative; ND, not determined; the first row indicates tumor sample number; the first column indicates the STS microsatellite marker. Two common regions of allelic loss (CRL) were identified on 3p, D3S1263- D3S3510 (CRL1) and D3S1578-D3S1284 (CRL2). Positions of the markers on the physical map were determined using the Human Genome Working Draft Sequence Browser (16).

D3S1292 and D3S1268 had been previously used in the allelotype (11). The used to map the 3p14-12 region (Fig. 2B). With the additional mark- common regions of loss on 3p were further mapped with additional 14 ers, 4 more tumors (UM22, UM13, UM14, and UM26) were found to microsatellite markers (D3S1259, D3S3701, D3S656, D3S3610, D3S100, have LOH in the common region of loss on 3p25.3-24.3, and 2 more D3S2385, D3S1585, D3S1554, D3S1479, D3S1360, D3S1076, D3S1295, tumors (UM14 and UM57) were found to have LOH in the common D3S3635, D3S3507). In total, each tumor was tested with 41 markers. The region of loss on 3p14-11. In total, the 3p chromosomal arm was MRD identified on chromosome 3p25.1-p25.2 was defined using only tumors mapped with 28 STS microsatellite markers, and 15 of the 21 uveal with at least two consecutive losses. Using T4 kinase (Life Technologies, Inc., Gaithersburg, MD), 500 ng of one melanomas (71%) harbored LOH of at least one marker. primer from each pair was end labeled with [32P]ATP (20 mCi; Amersham, A 1.4-Mb shared MRD between microsatellite markers D3S3610 Piscataway, NJ) in a total volume of 20 ␮l. PCR reactions were carried out in and D3S1554 on 3p25.1-p25.2 was identified (Figs. 2A and 3). The a total volume of 10 ␮l containing 20 ng of genomic DNA, 25 ng of centromeric boundary was defined by tumors UM28 and UM6, and end-labeled primer, 60 ng of each unlabeled primer, and 2 units of TaqDNA polymerase (New England Biolabs, Beverly, MA). PCR conditions were as follows: 35 cycles (95°C for 1 min, 54°C–58°C depending on primer pairs for 1 min, 72°C for 1 min) followed by a final 4-min extension at 72°C. About one-quarter of the PCR product was separated on an 8 M urea-formamide- polyacrylamide gel and exposed to film for 6–48 h. Cases were considered informative if two alleles were present in the normal sample. Allelic loss was scored if a reduction of intensity Ն 50% of one of the two alleles was documented visually by two independent observers (P. P. and S. L. M.) in the tumor as compared with the corresponding normal tissue.

RESULTS

After the initial screening with 27 STS microsatellite markers, LOH for at least one marker was found on 3p in 9 of the 21 uveal melanomas (43%) and on 3q in 8 of the 21 tumors (38%; Fig. 1). A 7.3-Mb common region of LOH (CRL1) on 3p25.3-24.3 between markers D3S1263 and D3S3510 was identified (Fig. 1). Six of the 9 uveal melanomas with loss on 3p displayed LOH in at least one marker in this region (UM55, UM28, UM6, UM35, UM10, and UM50). Two of these six tumors (UM10 and UM50) showed loss of all informative markers on 3p with the exception of marker D3S1252, included in the 7.3-Mb minimal common region of LOH. This apparent retention of a marker within a region of LOH is consistent with a Fig. 2. Fine mapping of the common regions of allelic loss on chromosome 3p. , possible homozygous deletion in these tumors (see “Discussion”; Ref. retention of both alleles; f, loss of heterozygosity; NI, noninformative; ND, not deter- 17). The remaining 3 tumors with 3p LOH (UM46, UM9, and UM31) mined; the first row indicates tumor sample number; the first column indicates the STS showed losses in a 19.7-Mb region (CRL2) between markers microsatellite marker. A, The D3S1263-D3S3510 region was further mapped with 10 additional microsatellite markers (bold). A 1.4-Mb MRD was identified between markers D3S1578 and D3S1284 on chromosome 3p14-p12 (Fig. 1). D3S3610 and D3S1554. Tumors UM10 and UM50 showed a putative area of homozygous The chromosomal region 3p25.3-p24.3 between markers D3S1263 deletion in the same region. B, the D3S1578-D3S1284 region was further mapped with 4 additional (bold) microsatellite markers. No MRD was identified in this region. Position and D3S3510 was further mapped with 10 additional microsatellite of the markers on the physical map is determined using the Human Genome Working chosen at ϳ0.5-Mb intervals (Fig. 2A). Four additional markers were Draft Sequence Browser, November 2002 (16). 8508

contains the putative TSG FHIT gene that spans the FRA3B fragile site. However, occurrence of intragenic mutations in FHIT are very rare, thus some researches have argued that FHIT abnormalities may only represent alterations in the fragile site. One tumor, UM31, showed loss of the pericentromeric region of the chromosome sug- gesting the presence of a complex rearrangement that cannot be further characterized by microsatellite analysis. Frequent allelic losses on 3p25-26, corresponding to our MRD, have been reported in lung, renal, breast, and other solid tumors, and in vitro studies indicate that this region is able to suppress growth of tumor cells (19). The VHL gene, located on 3p25.3, is associated with a familial cancer syndrome characterized by kidney cancer and multiple benign tumors, but it is telomeric to our 3p25.1-p25.2 region (20). In a previous study of uveal melanoma, Tschentscher et al. (10) defined by comparative genomic hybridization and microsatellite analysis a 2.2-Mb MRD on 3p25-26 between markers D3S2450- D3S3691. On the human draft sequence, their markers map to 3p25.3- 3p26.1 (6.7-8.9 on the physical map), a region slightly telomeric to our 3p25.1-p25.2 MRD (10). This conflict may simply be explained by the presence of two TSGs closely spaced and both important in the tumorigenesis of uveal melanoma. Even if we conservatively define our telemetric boundary by D3S656 and 3 tumors (UM6, UM28, UM35), our MRD does not overlap that of Tschentscher et al. (10). If the 6 tumors with partial deletion of 3p in the study by Tschentscher et al. (10) are considered, 5 of them show allelic losses in areas that include our MRD. Two uveal melanomas (UM10 and UM50) showed loss of all Fig. 3. LOH analysis of posterior uveal melanoma. Autoradiographs depicting microsatellite analysis of representative tumors UM6, UM10, and UM28 are shown. Markers informative markers on chromosomal arm 3p except for one marker, are labeled above each normal (N) and corresponding tumor (T) lane. Arrows indicate D3S1252, included in the 1.4-Mb MRD (Figs. 2A and 3). This pattern relative loss of alleles in tumor samples. Tumor UM6 from top to the bottom: retention of both alleles for marker D3S656, LOH of the top allele for marker D3S3610; retention of of apparent retention of at least one marker, flanked by loss of at least marker D3S1554. Tumor UM10 from top to bottom: LOH of the bottom allele for marker two other markers, is the previously described criteria for a homozy- D3S656; apparent retention of both alleles caused by amplification of residual normal gous deletion as determined by microsatellite analysis (17). This DNA for marker D3S1252; LOH of the bottom allele for marker D3S1585. Tumor UM28 from top to bottom: retention of both alleles for marker D3S656; LOH of the bottom allele apparent retention, shown to represent homozygous deletion of this for marker D3S1252; retention of both alleles for marker D3S1286. marker by correlation with Southern blot and FISH analyses, is caused by amplification of a small amount of residual normal DNA, which remains after careful microdissection of uveal melanomas (17). The the telomeric boundary was defined by UM35. Within this MRD, 2 homozygous deletion of the region corresponding to marker D3S1252 tumors had retention of only 1 microsatellite marker D3S1252 (UM10 further limits the region of interest to 100 Kb (between markers and UM50, Figs. 2A and 3). To confirm that this result was not a D3S2385 and D3S1585) and suggests that a TSG may exist in the technical artifact, the PCR reaction for this marker was repeated in region between markers D3S2385 and D3S1585. three independent experiments, and in all cases, a clear retention of Analysis of our 1.4-Mb MRD with the University of California– the alleles was found. These putative homozygous deletions addition- Santa Cruz at Genome Browser (16) indicates the presence of 9 ally localize the region of interest to a 100-kb region between markers National Center for Biotechnology Information reference sequences. D3S1585 and D3S2385. Eight tumors showed LOH of at least one Of those, five have known function. The xeroderma pigmentosum marker on 3p14-12, but no shared MRD was identified (Fig. 2B). complementation group C (XPC) gene is involved in the DNA excision repair pathway and is associated with the Xeroderma pigmento- DISCUSSION sum syndrome in which both cutaneous and uveal melanomas have been described previously (21, 22). The WNT7A gene belongs to the Monosomy 3 is the most common genetic abnormality in uveal wingless-type mouse mammary tumor virus integration site (WNT) melanoma, but only a few reports describe interstitial deletion or family and seems to be involved in embryo development (23). The translocation of this chromosome. Homozygous deletion in the THRB expression of WNT7A was recently found to be reduced in lung cancer locus was described in 3 of 19 uveal melanomas, but this result was (24). The other three genes encode an extracellular matrix protein not confirmed in subsequent studies (9, 18). Translocations of chro- FBLN2 (25), a novel member of the histone deacetylase family mosomal regions 3p14 and 3q23 were found in primary culture but HDAC11 (26), and a protein LSM3 that binds the U6 snRNA, an did not help to pinpoint the region(s) involved in chromosome 3 essential element of spliceosome in humans (27). Each of these genes carcinogenesis (13, 14). represents a good candidate for mutational screening in uveal mela- Chromosomal arm 3p abnormalities are frequently found in tumors. noma. In addition to these genes, four other poorly characterized At least six major regions of chromosomal rearrangement have been RefSeq proteins map in the MRD, and the presence of other genes in described, and they are often multiple and discontinuous (12). We the D3S2385-D3S1554 region is suggested by UNIgene Cluster anal- defined a common region of loss on 3p14-12, which maps to the ysis and gene prediction computer programs. centromeric region of chromosome 3 and includes two of these Allelic losses in the 3p25-26 region that do not overlap the VHL frequently rearranged regions, 3p12-13, and the 3p14.2. The latter gene have been described in several tumor types (12). In uveal 8509

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Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2003 American Association for Cancer Research. Fine Mapping of Chromosome 3 in Uveal Melanoma: Identification of a Minimal Region of Deletion on Chromosomal Arm 3p25.1-p25.2

Paola Parrella, Vito M. Fazio, Antonietta P. Gallo, et al.

Cancer Res 2003;63:8507-8510.

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