LOSS OF HETEROZYGOSITY AT AUTOSOMAL AND X-LINKED LOCI DURING TUMOR PROGRESSION IN A PATIENT WITH MELANOMA

Abstract

Restriction fragment length polymorphisms at 61 autosomal and 7 X-linked loci were screened for heterozygosity in cell lines derived from 6 independent metastases and autologous B-cells from a patient with melanoma. Segregations resulting in the loss of heterozygosity were detected in the tumor cells at 8 of 16 autosomes with at least 1 informative locus and at the 3 informative X-linked loci. With a single exception, karyotypic abnormalities were not detected in the region of loci where loss of heterozygosity had been detected. Three patterns of loss were identified: (a) unique segregations in cells from a single metastasis; (b) segregation of the same alleles in different subsets of metastases; and (c) identical segregations in all 6 metastases. The monoclonal derivation of the 6 metastases is supported by the inactivation of the same X-chromosome and the presence of identical segregation at loci on chromosomes 9 and X. Analysis of the patterns of segregation in the metastatic tumor cells permitted the development of a genealogy of tumor progression in this patient and the development of a model of tumor progression which describes the accumulation of selectivity neutral and advantageous segregations in metastatic tumor cells.