Identification of cryptic aberrations and characterization of translocation breakpoints in high hyperdiploid childhood ALL using genome-wide array CGH
Although the characteristic cytogenetic feature of high hyperdiploid (>50 chromosomes) childhood acute lymphoblastic leukemia (ALL) is the presence of nonrandom trisomies and tetrasomies, the facts that this abnormality pattern in general occurs prenatally, years before the diagnosis of leukemia, and that it commonly arises in a single and presumably highly abnormal mitosis, suggest that additional genetic changes may be present. In the present study, we utilized the recently developed 32K BAC array set, which enables detection of chromosome changes involving as little as 100 kb, for array-based comparative genome hybridization (array CGH) analysis of eight cases of hyperdiploid childhood ALL. The investigation narrowed down rearrangement breakpoints to a few hundred kb in three cases with previously identified unbalanced translocations. Furthermore, it disclosed three cytogenetically cryptic imbalances which were confirmed by fluorescence in situ hybridization (FISH); a 3.7 Mb hemizygous deletion at 12p13.3, encompassing the ETV6 gene, a 1.7 Mb segmental duplication at 12q24.31, and a 2.5 Mb hemizygous deletion at 13q32.31. Most notably, locus-specific FISH of the latter revealed that it was associated with a hidden reciprocal translocation involving distal 3q and 13q. This translocation has not been previously described; its pathogenetic impact is unclear, but it is probably involved in the leukemogenesis. Because the t(3;13) is cryptic by standard banding techniques, its frequency in pediatric ALL remains unknown. In conclusion, cryptic chromosome changes, detectable by array CGH analysis, are present in addition to the trisomies and tetrasomies in high hyperdiploid childhood ALL. Further studies are warranted to elucidate the frequency and pathogenetic consequences of these novel genetic aberrations.