Incidence and significance of cryptic chromosome aberrations detected by fluorescence in situ hybridization in acute myeloid leukemia with normal karyotype

Abstract

To better define the incidence and significance of cryptic chromosome lesions in acute myeloid leukemia (AML), fluorescence in situ hybridization (FISH) studies were performed in interphase cells and, when appropriate, in metaphase cells and in morphologically intact BM smears. Fifty-five adult de novo AML (group A) and 27 elderly AML or AML after myelodysplastic syndrome (AML-MDS) (group B) were tested using probes detecting the following anomalies: −5, −7, +8, deletions of 5q31, 7q31, 12p13/ETV6, 17p13/p53, 20q11. All the patients had a normal karyotype in more than 20 cells and tested negative for the common AML-associated fusion genes. No patient in group A was found to carry occult chromosome anomalies, whereas 8/27 patients in group B (P Ͻ 0.0001) showed 5q31 or 7q31 deletion (three cases each), a 17p13/p53 deletion or trisomy 8 (one case each) in 33-60% interphase cells. Metaphase cells showed only one hybridization signal at 5q31 (three cases) and 7q31 (one case), whereas two normal signals at 7q31 and chromosome 8 centromeres were seen in two patients with 7q deletion and trisomy 8 in interphase cells. The majority of blast cells (76-94%) carried the chromosome anomaly in all cases; erythroid involvement in a minority of cells was seen in three patients. In group B, the presence of occult chromosome anomalies was associated with exposure to myelotoxic agents in the workplace (5/8 cases vs 3/19, P = 0.026) and with a lower complete remission rate (0/6 patients vs 7/12, P = 0.024). We arrived at the following conclusions: (1) cryptic chromosome deletions in the order of a few hundred kb magnitude may be found in a fraction of elderly AML or MDS-related AML and not in de novo adult AML with normal karyotype; (2) these chromosome lesions are usually represented by submicroscopic rearrangements; (3) they display a specific pattern of cell-lineage involvement arguing in favor of their role in the outgrowth of the leukemic blast cells; (4) they are associated with a history of exposure to myelotoxic agents in the workplace and, possibly, with resistance to induction treatment.

Is FISH a relevant prognostic tool in myelodysplastic syndromes with a normal chromosome pattern on conventional cytogenetics? A study on 57 patients

“…Our data are also in line with a recent study, which suggested that the loss of chromosome material is a pathogenetic mechanism operative in a fraction of MDS/AML carrying an apparently normal karyotype. 26 In our series, a FISH minor aneuploid cell population (18-25% cells) was identified on clinical diagnosis in three patients (one each with þ 11, À7 and þ 8), who presented at least one monosomic or trisomic cell on metaphase FISH. This datum suggests that CC failed to reveal the chromosome defect not because of its low sensitivity, but rather because of the inability of the dysplastic clone to divide properly in vitro.…”

“…29,39,40 In contrast, other studies have pointed out that FISH identifies minor clonal cell populations marked by À7 or by other structural defects in a significant number of CC normal patients. [22][23][24][25][26]33 Two recent reports, which revealed occult karyotype abnormalities in 17.8 and 29.6% of patients, have further stressed the crucial role of interphase/metaphase FISH in the definition of chromosomally normal MDS/AML. 25,26 In the present study, which includes more RAEB and RAEB-t patients (49 vs 40%) than that of Rigolin et al, 25 the incidence of occult defects was 15%.…”

“…[22][23][24][25][26]33 Two recent reports, which revealed occult karyotype abnormalities in 17.8 and 29.6% of patients, have further stressed the crucial role of interphase/metaphase FISH in the definition of chromosomally normal MDS/AML. 25,26 In the present study, which includes more RAEB and RAEB-t patients (49 vs 40%) than that of Rigolin et al, 25 the incidence of occult defects was 15%. Our data are also in line with a recent study, which suggested that the loss of chromosome material is a pathogenetic mechanism operative in a fraction of MDS/AML carrying an apparently normal karyotype.…”

“…Various studies have reported on the ability of FISH to reveal masked karyotype defects. [24][25][26][33][34][35][36][37][38][39][40][41] Some have demonstrated that CC and FISH detect chromosome abnormalities at a similar frequency in MDS/AML patients and have concluded that CC is an excellent technique for identifying the most common chromosome defects in these patients, whereas FISH on interphase or mitotic cells has only limited utility. 29,39,40 In contrast, other studies have pointed out that FISH identifies minor clonal cell populations marked by À7 or by other structural defects in a significant number of CC normal patients.…”

“…Some FISH studies have already shown that occult defects (mainly monosomy 7, trisomy 8, deletions of the long arm of chromosome 5 or of chromosome 7) may be detected in chromosomally normal MDS. [19][20][21][22][23][24][25][26][27][28] In addition, those reports suggested that FISH is a convenient complement to CC and have tried to define the most accurate 'FISH panel testing' for the analysis of chromosomally normal patients. [29][30][31] In the present study, we have performed FISH with seven single locus and four alphoid probes for the most frequent MDS chromosome aberrations in 57 patients, who were considered cytogenetically normal after the analysis of more than 20 metaphases.…”