Concomitant loss of chromosome 3 and whole arm losses and gains of chromosome 1, 6, or 8 in metastasizing primary uveal melanoma

Abstract

Purpose: To elucidate the genetic differences between metastasizing and nonmetastasizing primary tumors, uveal melanoma samples were screened for DNA copy number alterations by comparative genomic hybridization (CGH).

Methods: DNA copy number changes were studied on 14 primary uveal melanomas that had not metastasized, 15 primary uveal melanomas that had metastasized, and on 6 metastases that were available from 6 primary uveal melanomas. CGH is based on quantitation of the fluorescence intensity of differentially labeled DNAs. Tumor DNA labeled with FITC dCTP and dUTP and normal DNA labeled with Texas red dCTP and dUTP were hybridized to normal metaphase chromosomes. The hybridizations were analyzed using an Olympus fluorescence microscope and the ISIS digital image analysis system to identify gain or loss of genetic material.

Results: Primary uveal melanomas that had metastasized and metastases had significantly more changes than primary uveal melanomas that had not metastasized. Comparison between primary nonmetastasizing tumors, metastasizing tumors, and metastases showed that the most common DNA copy number changes were -3 (21%, 73%, 67%, respectively), -6q (7%, 40%, 83%), -1p (0, 33%, 33%), -13q (14%, 13%, 50%), -8p (14%, 27%, 0), -18 (7%, 13%, 33%), +8q (14%, 53%, 100%), +6p (29%, 20%, 17%), +1q (0, 7%, 33%), and +16p (0, 7%, 33%).

Conclusions: Loss of chromosome 3, loss of 6q, and gain of 8q were significantly associated with poor overall survival. In addition, losses of 1p were only found in primary uveal melanomas that had metastasized and in metastases, which suggests that this region may harbor a tumor suppressor gene important in the tumor progression. Finally, loss of chromosome 3 may be associated with isochromosome formation of 1q, 6p, 8q, 16p, 20q, and 22q.