Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study

TLDR

The study demonstrates that iFISH is a valuable complementary method to cytogenetics for routine screening of prognostically significant chromosomal abnormalities in acute lymphoblastic leukemia. Interphase FISH was applied independently to a cohort of 2,367 children with ALL to detect prognostically relevant chromosomal abnormalities. iFISH identified TEL/AML1 (22%), BCR/ABL (2%), and MLL (2%) fusions, revealed extensive signal variation—including a novel AML1 amplification linked to poor prognosis—and uncovered hidden hyperdiploidy, achieving a 91 % success rate and an 89 % abnormality detection rate in the cohort.

Abstract

Summary Interphase fluorescence in situ hybridization (iFISH) was used independently to reveal chromosomal abnormalities of prognostic importance in a large, consecutive series of children ( n = 2367) with acute lymphoblastic leukaemia (ALL). The fusions, TEL/AML1 and BCR/ABL , and rearrangements of the MLL gene occurred at frequencies of 22% ( n = 447/2027) (25% in B‐lineage ALL), 2% ( n = 43/2027) and 2% ( n = 47/2016) respectively. There was considerable variation in iFISH signal patterns both between and within patient samples. The TEL/AML1 probe showed the highest incidence of variation (59%, n = 524/884), which included 38 (2%) patients with clustered, multiple copies of AML1 . We were thus able to define amplification of AML1 as a new recurrent abnormality in ALL, associated with a poor prognosis. Amplification involving the ABL gene, a rare recurrent abnormality confined to T ALL patients, was identified for the first time. The use of centromeric probes revealed significant hidden high hyperdiploidy of 33% and 59%, respectively, in patients with normal ( n = 21/64) or failed ( n = 32/54) cytogenetic results. The iFISH contributed significantly to the high success rate of 91% ( n = 2114/2323) and the remarkable abnormality detection rate of 89% ( n = 1879/2114). This study highlights the importance of iFISH as a complementary tool to cytogenetics in routine screening for significant chromosomal abnormalities in ALL.