Identification of Novel Recurrent Genomic Aberrations by Array-CGH in Adult Acute Lymphoblastic Leukemia.

In acute lymphoblastic leukaemia (ALL), genomic aberrations like translocations t(4;11) or t(9;22) are associated with an adverse prognostic impact and play an important role in the development of risk adapted treatment strategies. So far, chromosomal banding analysis is the standard cytogenetic procedure for routine diagnosis. Genomic array-comparative genomic hybridization (aCGH) has become a useful technique for genomic screening allowing a more precise delineation of small genomic aberrations. We analyzed 44 patients with ALL, which were treated within the GMALL trials, by aCGH analysis using a genomic 2,8K chip. In 27 patients, clinical data were available. Thirteen patients had a common-ALL with normal karyotype, 10 patients had a common-ALL/Pr-B-ALL with t(9;22), two patients had either pre-B-ALL or T-lineage leukaemia, respectively. Ten patients were classified as very high risk (t(9;22) positive), 2 patient as high-risk (pre-T-ALL; c-ALL with high leukocytes) and 15 patients were standard risk according to the risk stratification of the GMALL-studies. We found genomic aberrations in 30 out of 44 patients (68%). The most frequent aberrations were deletions on chromosome band 9p21 (10 cases; 23%), deletions on chromosome band 7q35 (7 cases; 16%); gains on chromosome X and losses on 7p (6 cases; 14% each), deletions on 13q14 (5 cases; 11%) and gains on 8q24 (4 cases; 9%). The consensus region of the 9p21 deletion was narrowed down to a size of 420 kilobasepairs. This region covers 3 different genes with potential tumor suppressor gene (TSG) function: p14ARF, p15INK4B/p10 and p16INK4A. An additional TSG gene - methylthioadenosine phosphorylase (MTAP) - was found in 9 out of these 10 cases. In 3 cases with 9p21 deletions, none of the patients expressed the p16INK4A protein using western blot analysis. Two patients where also negative for the MTAP protein, whereas another patient whithout a genomic deletion on MTAP remains positive. There was a tendency to a higher number of aberrations per case in the standard risk group in contrast to the t(9;22) positive group (2.1 vs. 1.0 aberrations per case). aCGH analysis is useful for the identification of recurrent genomic aberrations which are not detectable using standard cytogenetic techniques.