Independent coexistence of clones with 13q14 deletion at reciprocal translocation breakpoint and 13q14 interstitial deletion in chronic lymphocytic leukemia

13q14 deletion is the most frequent chromosomal aberration in chronic lymphocytic leukemia (CLL), found by interphase fl uorescence in situ hybridization (FISH) in more than 50% of cases of CLL [1]. As a sole aberration it is associated with a favorable prognosis; however, it (13q14 deletion) does not improve the impaired prognosis of complex karyotype [1,2]. A minimal deleted region (MDR) of approximately 900 kbp in size was established by genomic profi ling [3], containing several genes including DLEU7 and miR15a and miR16 1, recognized as tumor suppressor genes [4 – 6]. Deletion larger than the MDR was repeatedly associated with an increased risk of disease progression [3,7]. 13q14 deletion is found predominantly as an interstitial deletion, but it has previously been described as a form of reciprocal translocation with deletion at the 13q14 breakpoint [8 – 12]. In most cases the translocation was reported to bring about heterozygous loss of the 13q14 region, although in one study it was reported as a cause of homozygous loss [9] and in another as a source of second allele loss along with loss of the fi rst by interstitial deletion [10]. Th e parallel presence of two clones with monoallelic 13q14 region loss, in one clone via the mechanism of interstitial deletion and in the second via reciprocal translocation with deletion at the breakpoint, has been noted only once to date [10]. No relevant information about the mechanism of formation of the 13q14 translocation with deletion has been reported so far. Th e coexistence of clones with interstitial deletion and with deletion at the translocation breakpoint provides two possibilities for the formation of translocation with deletion: either by consecutive clonal evolution from the clone with interstitial deletion, or as a separate event, independent from the clone with interstitial deletion. In contrast with 13q14 deletion, the presence of even one translocation aff ecting any chromosome in CLL is associated with impaired prognosis [13,14]. However, an unfavorable infl uence of the translocation form of 13q14 deletion on prognosis has not been proven [10]. Th e 13q14 translocation has been described with various translocation partners, but nevertheless activation of any oncogene has not yet been revealed. Th us, the leukemic eff ect of the 13q14 reciprocal translocation with deletion is presumed to occur only through the loss of tumor suppressor genes caused by the concomitant 13q14 deletion. In this report we present fi ve cases of CLL with the coexistence of clones with interstitial deletion and with deletion at the reciprocal translocation breakpoint. In one of the cases a subsequent clonal analysis proved an independent origin of both clones, providing evidence for their purely coincidental presence. 13q14 deletion was found by interphase FISH performed on bone marrow or peripheral blood cells in 62% of our cohort of unselected patients with CLL (146/235). Detailed metaphase analysis (G-banding, FISH) could be accomplished in 135 patients, and revealed the translocation form of 13q14 deletion in 10% of them (13/135). Th e coexistence of a clone with deletion at the reciprocal translocation breakpoint and another clone with interstitial deletion was found in 38% of the translocation cases (5/13). Th is study focused on the fi ve patients with coexistence of clones with both forms of 13q14 deletion: interstitial deletion and deletion at the translocation breakpoint. In three patients (numbers 2, 3 and 5), cytogenetic analyses were accomplished at the time of diagnosis, and in the two other cases (numbers 1 and 4) at disease progression. Only patient 4 had received previous chemotherapy, including fl udarabine with cyclophosphamide. In three patients (numbers 2, 4 and 5) elevated expression of CD38 was found, and ZAP70 expression was high in two patients (numbers 1 and 2); immunoglobulin heavy chain variable gene (IGHV) mutational status was not analyzed. Cytogenetic analysis was performed on bone marrow (patients 1 – 4) or peripheral blood (patient 5) cells stimulated L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re . c om b y D uk e U ni ve rs ity o n 12 /2 8/ 14