ACQUIRED HOMOZYGOSITY (ISODISOMY) OF CHROMOSOME-3 DURING CLONAL EVOLUTION OF A UVEAL MELANOMA - ASSOCIATION WITH MORPHOLOGIC HETEROGENEITY

Cytogenetic investigation of untreated uveal melanoma has shown that t he most frequent abnormality is monosomy 3, which occurs in approximat ely 60% of cases. One of our cases showed distinct pigmented and nonpi gmented areas at gross dissection; representative tissue was collected separately from each area, cultured, and harvested using standard cyt ogenetic techniques. On histologic examination, the pigmented area was found to be composed of small epithelioid cells, whereas the nonpigme nted area contained large, pleomorphic epithelioid cells. The karyotyp e of the pigmented tumor revealed monosomy 3, whereas the nonpigmented tumor showed two apparently normal chromosomes 3. Our purpose in the present study was to investigate the two tumor areas by molecular tech niques to determine whether the karyotype of the nonpigmented tumor ev olved directly from the pigmented tumor with duplication of the remain ing chromosome 3 or whether the two sublines evolved in a divergent fa shion from a common precursor stemline. DNA was extracted from normal lymphocytes and separately from both areas of the tumor. The DNA was a nalyzed using the polymerase chain reaction for polymorphic dinucleoti de and tetranucleotide repeat sequences on chromosome 3. Both pigmente d and nonpigmented areas of the tumor showed loss of heterozygosity at all informative loci on chromosome 3 that were tested. These results support our hypothesis that an abnormality on chromosome 3 plays a cen tral role in the molecular pathogenesis of uveal melanoma and that som e melanomas develop acquired homozygosity (isodisomy) by loss and dupl ication of the remaining, presumably abnormal, chromosome 3. (C) 1996 Wiley-Liss, Inc.