High Hyperdiploidy and t(12; 21) (p13; q22) Translocation Is Not a so Rare Association: A Report of 4 Cases in the Experience of Armand Trousseau Hospital (Paris).
Authors: Ballerini Paola , Perot Christine , Bellmann Francoise , Auvrignon Anne , Tabone Marie-Dominique , Haouy Stephanie , Adjaoud Dalila , Van Den Akker Jacqueline , Portnoi M.F. , Douay Luc , Leverger Guy , Landman-Parker Judith 
Published: October 2019

INTRODUCTION. Since the discovery of the cryptic t(12; 21) translocation, many secondary genetic abnormalities have been described in association with TEL-AML1 fusion gene. Extensive studies of karyotypes in a few series of TEL-AML1 positive leukaemia revealed a heterogeneous pattern of chromosomal abnormalities. Numerical and structural abnormalities are often present together. The modal chromosome number does not exceed 49 so that high hyperdiploidy and TEL-AML1 fusion are so far considered mutually exclusives. Here we reported that such association is found in a small group of patients and that relapse may still occur in those patients despite the good prognostic impact commonly attributed to each lesion.

PATIENTS and METHODS. Between April 1994 and April 2006, 105 children were consecutively diagnosed with TEL-AML1 positive B-ALL. TEL-AML1 expression was detected by RT-PCR in Bone Marrow (BM) diagnostic samples and the t(12;21) explored by FISH with LSI TEL-AML1 dual-color probe (Vysis) in cases with low level of fusion gene expression or lacking molecular study. Conventional cytogenetics with G and R banding was performed on BM cells after overnight and 24 hours culture

RESULTS and DISCUSSION. We detected numerical and/or structural abnormalities in 82/105 (78%) of the karyotypes. Aneuploidy alone was found in 4/105(3.8%): two cases had an extra chromosome 21, one an extra chromosome 10 and one lost 1 chromosome X. Structural abnormalities alone were present in 18/105 (17.1%) and up to 58 /105 (55.2%) presented both. The most frequent structural change was observed on chromosome 12p13 (50% of all structural abnormalities) whereas the most frequent chromosome gain was +21 (14%) and +10 (6.6%). Interestingly, in four cases (3.8%) we detected high hyperdiploidy with classical supplementary chromosomes; in two of these cases a partial trisomy of chromosome 1 was also present. Karyotypes are presented:

Pt1: 52,XX,+10,+16,+18,+21,+21,+22 [22]/46, XX [4]

Pt 2: 54,XY,+X,+4,+ 6?[del(6q)],+9,+14,+15,+18,+21,+21,-22 [17]/46,XY [3]

Pt 3: 55,XX,+X,dup(1)(q21q31),+4,+6,+10,+14,+17,+18,+21,+21 [1]/56,idem+19 [4]/56,idem,+14 [5] / 46,XX [10]

Pt 4: 7,XX,+der(X)(t(X;1)(q26;q12),+4,+5,+6,+8,+10,+14,+17,+18,+21,+21 [17]/46,XX [3]

Pt1 present CNS relapse at 24 months follow up without involvement of BM which tested negative for TEL-AML1 expression. Patients 2,3,4 are in continuous complete remission at respectively 6, 6 and 4 years follow up. Since t(12;21) translocation and high hyperdiploidy seem to be primary events in leukaemia our observation raises the question if the two lesions coexist in a same cell or are independent events in different clones. In two cases (Pt 3,4), FISH analysis indicated the presence of TEL-AML1 gene fusion in 7% and in 5% of nuclei respectively. The distribution and the number of the signals on AML1 locus let think that t(12;21) occurred independently from hyperdiploidy. Microarrays studies have revealed distinct gene expression signatures associated to TEL-AML1 fusion and hyperdiploidy over 50 chromosomes, our observation points out the existence of cases which could be difficult to assign to one or the other of these classes.