Unbalanced Chromosome Rearrangements Involving the 20q11.2 Region in Myeloid Malignancy.

Abstract Deletions of the long arm of chromosome 20 (del 20q) are a recurring abnormality associated with haematological malignancy (Mitelman 1995, Sandberg 1991, Heim and Mitelman,1995, Asimakopoulos & Green, 1996). The 20q deletions are seen in approximately 10% of the cases with PV and IMF, 4% of cases with myelodyspalstic syndrome (MDS) (Fenaux et al., 1996), 1–2% of patients with acute myeloid leukaemia (AML) as well as other myeloproliferative disease (MPD) (Bench et al. 2000). Deletions of chromosome 20q are well recognised in myeloid disorders and have been seen alone or as part of a complex karyotype (Johansson et al, 1993, Schoch et al 2002). A common deleted region (CDR) of chromosome 20q was observed by fluorescence in situ hybridization (FISH) mapping within 20q11.2/q12 region (Roulston et al., 1993, Bench et al, 2000). The breakpoints within this CDR have been shown to be heterogeneous (Asimakopoulos et al., 1994) and more recently a considerable overlap of this region has been observed in myeloid malignancy (Douet-Guilbert et al, 2008). Previous studies have been performed on cases with simple deletions of chromosome 20q as assessed by G-banding and confirmed by FISH, to be interstitial and no other rearrangements involving 20q have been reported so far. Here we present 43 patients with non-random translocations of chromosome 20q that appear to have a common breakpoint within the 20q11.2 region. Karyotypically some of the cases presented with the classical del(20q) morphology while in other cases translocations were identified, such as t(1;20)(q21;q11.2). Of these cases 44% have been shown to carry an unbalanced chromosome rearrangement with loss of material at the region of the breakpoint at 20q11.2 both with and without loss material on the partner chromosome. An example of the latter is the rearrangement t(17;20)(p13;q11.2) where 20q11.2 loss was accompanied by a p53 deletion (17p13). FISH mapping located the 20q11.2 breakpoint to be within the BAC clone RP1-1J6, which covers only the sequences of one gene, Topoisomerase 1 (TOP1). This gene is reported to form a fusion with NUP98 in therapy related MDS. Indeed we confirmed by FISH the presence of this fusion in 6 of our cases, all of which carried the t(11;20)(p15;q11.2). Unexpectedly, the rest of the cases also showed breaks within the same BAC clone, where the partner chromosomes were Yp11, 1q21, 17p11 and 21q11. These findings highlight the consistent involvement of the TOP1 gene at 20q11.2 in rearrangements occurring in MDS and MPD.