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Els05009 1170 1177.Pdf LABORATORY SCIENCES Identification of Candidate Tumor Oncogenes by Integrative Molecular Analysis of Choroidal Melanoma Fine-Needle Aspiration Biopsy Specimens Tara A. McCannel, MD, PhD; Barry L. Burgess, BSc; Nagesh P. Rao, PhD; Stanley F. Nelson, MD; Bradley R. Straatsma, MD, JD Objective: To report integrative molecular analysis of gain. Comparative RNA analysis for these 2 groups revealed choroidal melanoma fine-needle aspiration biopsy speci- 49 genes with greater than 4-fold higher expression and 31 mens to identify candidate tumor oncogenes. genes with greater than 4-fold lower expression in chromo- some3–losstumorsrelativetochromosome6p–gaintumors. Methods: Thirty-one choroidal melanoma fine-needle as- piration biopsy specimens were analyzed using cytopatho- Conclusions: Molecular analysis of choroidal melanoma logic diagnosis of melanoma, fluorescence in situ hybrid- fine-needle aspiration biopsy specimens demonstrated 2 cy- ization for chromosome 3, cytogenetic characterization togenetically distinct groups characterized by chromo- (GeneChip Human 250K NSPI Mapping Arrays; Af- some 3 loss or chromosome 6p gain. In chromosome 3–loss fymetrix, Santa Clara, California), and gene expression pro- melanomas relative to chromosome 6p–gain melanomas, files (GeneChip Human Genome U133 Plus 2.0 Arrays, Af- integrative RNA analysis revealed genes with higher ex- fymetrix). These analyses were performed by clustering of pression and lower expression and identified several genes cytogenetic aberrations, sorting by chromosome 3 loss and that have not been reported in previous studies. chromosome 6p gain, and comparing gene expression pro- files in chromosome 3 loss– and chromosome 6p–gain tu- Clinical Relevance: Genes differentially expressed be- mors to identify genes with differential expression based tween chromosome 3–loss and chromosome 6p–gain on cytogenetic characteristics. melanomas may provide new knowledge about the bio- logic nature of choroidal melanoma and may contribute Results: Of 31 choroidal melanoma biopsy specimens in- to the development of targeted therapies. cluded in this study, 19 tumors had chromosome 3 loss, and 12 tumors without chromosome 3 loss had chromosome 6p Arch Ophthalmol. 2010;128(9):1170-1177 VEAL MELANOMA, ARISING Tschentscheretal5 reportedthatunsuper- from the choroid, ciliary vised hierarchical cluster analysis of gene ex- body, and iris of the eye, is pression data in primary uveal melanoma themostcommonprimary treated by enucleation identified 2 distinct intraocularmalignantneo- entities characterized by the presence or Uplasm in adults. Despite improvements in di- absence of monosomy 3. In a larger series of agnosis and local tumor control, almost half primary uveal melanomas treated by enucle- of the patients with uveal melanoma develop ation,Onkenetal6 alsousedhierarchicalclus- metastasis during long-term follow-up, and ter analysis of gene expression to show 2 melanoma-related mortality rates have been groups of uveal melanomas (class 1 and class virtually unchanged for decades.1,2 2) that predicted greater melanoma-related Author Affiliations: As predictors of metastasis, clinical and death in patients with class 2 melanomas. In Departments of Ophthalmology (Drs McCannel and Straatsma histopathologic factors have been super- subgroup analysis, gain of chromosome 6p and Mr Burgess), Pathology and ceded by cytogenetic and molecular char- was associated with the better prognosis of Laboratory Medicine (Dr Rao), acteristics of the primary tumor. Loss of class1melanomas,whilelossofchromosome and Human Genetics heterozygosity in chromosome 3, which 3 was associated with a poor prognosis.6 (Dr Nelson), David Geffen occurs in approximately 50% of uveal In a further series of choroidal melano- School of Medicine at UCLA, melanomas, is associated with an in- mas treated by enucleation, van Gils et al7 Jules Stein Eye Institute and creased risk for the development of me- combinedclinicaloutcome,cytogeneticdata, Ophthalmic Oncology Center tastasis and for melanoma-related death.3-6 RNA hybridization, and unsupervised hier- (Drs McCannel and Straatsma), and Jonsson Comprehensive Loss of chromosome 3 is usually associ- archical cluster analysis to place tumors into Cancer Center (Drs McCannel, ated with multiplication of chromosome 2 groups based on gene expression and prog- 3,4 Nelson, and Straatsma), 8, 8q, or parts of 8q, and additional cop- nosis. Chromosome 6p gain corresponded University of California, ies of chromosome 8q are significantly re- to a favorable prognosis, and chromosome Los Angeles. lated to reduced survival.4 3 loss (often associated with 6p gain, 8p loss, (REPRINTED) ARCH OPHTHALMOL / VOL 128 (NO. 9), SEP 2010 WWW.ARCHOPHTHALMOL.COM 1170 ©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 and 8q gain) was associated with metastasis and shortened matoxylin-eosin, and subsequently evaluated for cytologic evi- survival. dence of melanoma by the pathologist.12 In 2007, our group described 59 choroidal melano- mas subjected to fine-needle aspiration biopsy (FNAB) INTERPHASE FISH immediately before globe-conserving iodine 125 (125I) plaque brachytherapy (57 patients) or immediately af- To corroborate our genome-mapping array findings, FISH was ter enucleation (2 patients).8 These patients were ana- performed. In a standard manner described elsewhere,8,10,11 a lyzed using fluorescence in situ hybridization (FISH) and Spectrum Orange–conjugated probe (Abbott-Vysis, Des Plaines, high-density whole-genome mapping arrays to show that Illinois) specific for the centromeric region of chromosome 3 was used for interphase FISH. From 100 to 300 hybridization chromosomal aberrations were aligned into 2 discrete signals were manually counted in nonoverlapping nuclei of cells groups: tumors with chromosome 3 loss and tumors with under a fluorescence microscope (Zeiss Axiophot; Zeiss, Jena, chromosome 6p gain. Germany) equipped with a triple filter (4Ј,6Ј-diamidino-2- Focused on choroidal and ciliary body melanoma, this phenylindole, fluorescein isothiocyanate, and Texas Red) at the study presents an integrative molecular analysis of cho- UCLA Clinical Cytogenetics Laboratory. roidal melanoma FNAB specimens. Our analysis com- bines hierarchical clustering of chromosomal aberra- ISOLATION OF DNA AND RNA tions, sorting by chromosome 3 loss and chromosome 6p gain, and comparing of RNA expression profiles to In the operating room, biopsy aspirates were expelled directly identify candidate oncogenes. into a cell reagent (RNAProtect Cell Reagent; QIAGEN Sci- ences Inc, Valencia, California) within 15 seconds of collec- tion, and the needle hubs were rinsed with the same reagent METHODS to maximize recovery. Stabilized pooled aspirates were pel- leted, and DNA and RNA were simultaneously isolated from Among 82 patients with primary choroidal melanoma subjected the pooled sample using a kit (AllPrep DNA/RNA Mini Kit, 125 to FNAB immediately before I plaque brachytherapy or imme- QIAGEN Sciences Inc) per the manufacturer’s instructions. diately (Ͻ5 minutes) after enucleation between May 16, 2006, and July 22, 2008, 31 eyes (31 patients) met the following criteria for inclusion in the study: (1) voluntary consent to participate in the DNA ANALYSIS BY MAPPING ARRAYS research study, (2) cytopathologic diagnosis of melanoma, (3) suf- ficient FISH material for the chromosome 3 centromere, (4) ad- Isolated DNA was quantified using a commercial product equate material for nucleic acid analyses, (5) successful analysis (ND-1000; NanoDrop, Wilmington, Delaware). No DNA sample by cytogenetic characterization (GeneChip Human 250K NSPI was subjected to whole-genome amplification techniques. The Mapping Arrays; Affymetrix, Santa Clara, California), (6) com- DNA copy number was assessed using mapping arrays (Gene- pleted gene expression profiles (GeneChip Human Genome U133 Chip Human 250K NSPI). Probe preparation, hybridization, and Plus 2.0 Arrays, Affymetrix), and (7) a positive finding of cyto- reading were performed by the UCLA DNA Microarray Core Fa- genetic aberration by copy number analysis of the mapping cility according to the standard 96-well protocol provided by Af- array data. Any patient whose biopsy sample was deficient in any fymetrix. Copy number variation was computed using commer- 1 of these 7 criteria was excluded from the study. The most com- cially available software (CNAT version 4.0.1, Affymetrix). mon reasons for exclusion were insufficient RNA (n=20), inad- Chromosomalaberrationfrequencyanalysiswasperformedusing equate material by FISH (n=20), and undetectable cytogenetic Fisher exact test. Chromosomal aberration clustering for each bi- abnormality in chromosome 3 or 6 (n=12). opsy specimen was performed using 1 minus the Pearson prod- uct moment correlation matrix as an input of the mean linkage hi- STUDY CONSENT erarchical clustering to arrive at a dendrogram clustering tree. This research was approved by the Institutional Review Board of ANALYSIS OF RNA EXPRESSION the University of California, Los Angeles (UCLA). Work was in BY GENE EXPRESSION PROFILES compliance with the Health Insurance Portability and Account- ability Act of 1996. Before treatment, evaluation of each patient The RNA was quantified on a spectrophotometer (NanoDrop) included comprehensive ophthalmic examination, ultrasonogra- and analyzed on a bioanalyzer (2100; Agilent, Santa Clara) for phy, photography, optical coherence tomography, and fluores- integrity.
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