Increased frequency of dicentric chromosomes in therapy-related MDS and AML compared to de novo disease is significantly related to previous treatment with alkylating agents and suggests a specific susceptibility to chromosome breakage at the centromere

Dicentric chromosomes are observed in many malignant diseases including mye lodysplasia (MDS) and acute myeloid leukemia (AML) and have often been obse rved in a subset of these diseases, namely therapy-related MDS (t-MDS) and AML (t-AML), Using fluorescence in situ hybridization (FISH) with centromer e-specific probes, we investigated the frequency and type of dicentric chro mosomes in 180 consecutive patients with t-MDS and t-AML and in 231 consecu tive patients with de novo MDS and AML, whose karyotypes had been studied p reviously by conventional G-banding. Twenty-seven out of 180 patients with t-MDS or t-AML presented dicentric chromosomes compared to only seven out o f 231 patients with de novo disease (P = 0.00003). A dic(1q;7p) was observe d in 10 cases, a dic(5p;17q) was observed in six cases, whereas various iso dicentric chromosomes were observed in six cases. Excluding these six cases with isodicentrics, all 25 patients with dicentric chromosomes had involve ment of at least one of the chromosome arms 1q, 5p, or 7p resulting in mono somy for 5q or 7q, and/or trisomy for 1q. Patients with dicentric chromosom es presented significantly more often as t-MDS compared to patients without dicentrics (P = 0.046), and the presence of a dicentric chromosome was sig nificantly related to previous therapy with alkylating agents (P = 0.026). Thus, only one out of 27 patients with a dicentric chromosome had not previ ously received an alkylating agent. A specific susceptibility to breakage a t the centromere after exposure to alkylating agents is suggested and may e xplain the frequent loss of whole chromosomes, in particular chromosomes 5 and 7 in t-MDS and t-AML, if the breaks are not followed by rejoining.