Loss of heterozygosity on chromosomes 3, 9, 13, and 17, including the retinoblastoma locus, in uveal melanoma.
OBJECTIVE
To identify tumor-suppressor loci that may contribute to the pathogenesis of uveal melanoma.


METHODS
Multiplex fluorescence microsatellite assays were performed on 27 uveal melanomas using markers at 3p25-p26, 3p14.2, 9p21-p23, 13q14, 13q12.3-q13, and 17p13, close to or within the von Hippel Lindau (VHL), fragile histidine triad (FHIT), p16/cyclin-dependent kinase inhibitor 2 (CDKN2A), retinoblastoma (RB1), breast cancer 2 (BRCA2), and p53 tumor suppressor loci, respectively. Further markers on chromosomes 3 and 9 were analyzed individually.


RESULTS
Loss of heterozygosity (LOH) was identified in 63% of tumors, most frequently on chromosome 3 (52%), in association with epithelioid cells (P = 0.0002) and microvascular loops (P = 0.0008). In the majority of cases, LOH on chromosome 3 was detected at all informative markers. The second most common alteration was LOH at an RB1 intragenic marker (21% tumors), with retention of a more centromeric 13q marker (near BRCA2). The pattern of LOH on chromosome 9p was consistent with the involvement of a region telomeric to CDKN2A. LOH at TP53 was infrequent.


CONCLUSIONS
In the majority of cases, chromosome 3 LOH involves an entire chromosome homologue, which hampers identification of the relevant suppressor loci. This LOH correlates with the presence of microvascular loops and epithelioid cells, two of the recognized histologic indicators of poor prognosis. Data for chromosomes 13 and 9 support a role for RB1 in the pathogenesis of uveal melanoma but also raise the possibility of the involvement of additional loci close to RB1 and CDKN2A.
Scholes
A G
AG
Unit of Ophthalmology, Department of Medicine, The University of Liverpool, United Kingdom. agms@liv.ac.uk
Liloglou
T
T
Maloney
P
P
Hagan
S
S
Nunn
J
J
Hiscott
P
P
Damato
B E
BE
Grierson
I
I
Field
J K
JK
D017766:Acid Anhydride Hydrolases; D024682:BRCA2 Protein; D002882:Chromosomes, Human, Pair 13; D002886:Chromosomes, Human, Pair 17; D002893:Chromosomes, Human, Pair 3; D002899:Chromosomes, Human, Pair 9; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D006801:Humans; D019656:Loss of Heterozygosity; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D018895:Microsatellite Repeats; D009363:Neoplasm Proteins; D011506:Proteins / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics*; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014604:Uveal Neoplasms / Q000235:genetics* / Q000473:pathology; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D024682:BRCA2 Protein; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011506:Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000099170:Bis(5'-adenosyl)triphosphatase