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Follicular lymphoma (FL) is a common form of non-Hodgkin lymphoma with an ability to transform into a more aggressive disease, albeit infrequently to B-lymphoblastic leukemia/lymphoma. While t(14;18)(q32;q21) has been associated with approximately 90% cases of FL, that alteration alone is insufficient to cause FL and associated mutations are still being elucidated. The transformation of FL to B-lymphoblastic leukemia generally includes the dysregulation of MYC gene expression, typically through IGH rearrangement. Such cases of “double-hit” leukemia/lymphoma with both BCL2 and MYC translocations warrant further study as they are often not identified early, are associated with a poor prognosis, and are incompletely understood in molecular terms. Here we describe a patient with a diagnosis of FL that transformed to B-lymphoblastic leukemia. Detailed cytogenetic characterization of the transformed specimen using karyotype, fluorescence in situ hybridization, microarray and gene rearrangement analyses revealed a complex karyotype comprised principally of whole chromosome or whole arm copy number gains or losses. Smaller, single-gene copy number alterations identified by microarray were limited in number, but included amplification of a truncated EP300 gene and alterations in NEIL1 and GPHN. Analyses defined the presence of an IGH/BCL2 fusion due to a translocation as well as a MYC/IGH fusion due to an insertion, with both rearrangements involving the same IGH allele. The data illustrate the value in characterizing double-hit lymphoma cases with both traditional and novel technologies in the detailed cytogenetic workup.

Background Microarray-based comparative genomic hybridization (aCGH) is a powerful diagnostic tool for the detection of DNA copy number gains and losses associated with chromosome abnormalities, many of which are below the resolution of conventional chromosome analysis. It has been presumed that whole-genome oligonucleotide (oligo) arrays identify more clinically significant copy-number abnormalities than whole-genome bacterial artificial chromosome (BAC) arrays, yet this has not been systematically studied in a clinical diagnostic setting. Results To determine the difference in detection rate between similarly designed BAC and oligo arrays, we developed whole-genome BAC and oligonucleotide microarrays and validated them in a side-by-side comparison of 466 consecutive clinical specimens submitted to our laboratory for aCGH. Of the 466 cases studied, 67 (14.3%) had a copy-number imbalance of potential clinical significance detectable by the whole-genome BAC array, and 73 (15.6%) had a copy-number imbalance of potential clinical significance detectable by the whole-genome oligo array. However, because both platforms identified copy number variants of unclear clinical significance, we designed a systematic method for the interpretation of copy number alterations and tested an additional 3,443 cases by BAC array and 3,096 cases by oligo array. Of those cases tested on the BAC array, 17.6% were found to have a copy-number abnormality of potential clinical significance, whereas the detection rate increased to 22.5% for the cases tested by oligo array. In addition, we validated the oligo array for detection of mosaicism and found that it could routinely detect mosaicism at levels of 30% and greater. Conclusions Although BAC arrays have faster turnaround times, the increased detection rate of oligo arrays makes them attractive for clinical cytogenetic testing.