Clinical Relevance of Complex Chromosomal Aberrations in Bone Marrow Cells of 107 Children with ETV6/RUNX1 Positive Acute Lymphoblastic Leukemia (ALL).

Cryptic translocation t(12;21)(p13;q22) which give origin to the ETV6/RUNX1 hybrid gene can be found by I-FISH in approximately 20–25% of children with B precursor ALL as the most frequent specific aberration. This translocation is generally associated with good outcome. Despite of its favorable prognostic value, late relapses may occur within this group of patients. One of the reasons could be the high instability of the genome of leukemic cells, which is manifested at the chromosomal level by additional aberrations and/or complex chromosomal rearrangements. The aim of the study was to evaluate the significance of the additional chromosomal aberrations for prognosis of children with ETV6/RUNX1 positive ALL.

For the assessment of ETV6/RUNX1 fusion gene RT-PCR and/or double target interphase FISH with locus-specific probe (Abbott-Vysis, Des Plaines, Illinois, USA) were used (200 interphase nuclei analyzed, cut-off level 2.5% tested on controls, standard deviation ≤0.5%). Karyotypes were analyzed by conventional and molecular cytogenetic methods. Structural and/or complex chromosomal aberration were verified by FISH with whole chromosome painting probes (Cambio, Cambridge, UK) and/or by mFISH with the "24XCyte" probe kit (MetaSystems GmbH, Altlussheim, Germany).

We performed prospective and retrospective study of 107 children with ALL and ETV6/RUNX1 fusion gene detected by RT-PCR and/or I-FISH. Patients were diagnosed between 1995 and 2006, age ranged between 15 months and 16.9 years (median 4.2 years). Relapse appeared in 19 children (17.8%), four of them died. In 64 children (59.8%) we found besides t(12;21)(p13;q22) additional chromosomal aberrations, the most frequently trisomy or tetrasomy of chromosome 21 (20 cases), deletion of non-translocated ETV6 allele (24 cases), deletion of 6q (7 cases) and/or rearrangements of the long arm of chromosome X (6 cases). Complex karyotypes were identified in 38 children (35.5%). In twelve of them variant translocations of chromosomes 12 and 21 with other partners were observed. Event-free survival (EFS) was significantly shorter in patients with additional structural and/or complex aberrations in ETV6/RUNX1 positive cells (p=0.01).

In our cohort complex karyotypes indicated poor prognosis. Finding of complex chromosomal aberrations in leukemic cells is accompanied by higher risk of relapse even in those cases where the prognostically positive aberration is primarily present.