14. Clinical mate-pair sequencing reveals complex genomic rearrangements in B-lymphoblastic leukemia/lymphoma (B-ALL)

B-lymphoblastic leukemia/lymphoma (B-ALL) is an aggressive hematologic malignancy currently subcategorized into multiple genetic subtypes based on the identification of recurrent acquired chromosome abnormalities. Identification and accurate characterization of these multiple and varied chromosome abnormalities is essential to the diagnosis, prognosis and emerging predictive therapeutic targets in B-ALL patients and is typically achieved through standard karyotyping and fluorescence in situ hybridization (FISH) testing. In this study, we characterized the genomic profiles of 16 B-ALL cases with normal and complex karyotypes and their associated complex and/or inconclusive FISH results using a next-generation mate-pair sequencing strategy (MPseq). Clinical MPseq revealed four cases with complex translocations, including t(1;3;4), t(1;8;1;6), t(4;14;9;8), and a 10-way translocation involving CSF1R. Translocation partners were molecularly defined in cytogenetically visible abnormalities, including t(9;14)[JAK2/C14orf93], t(5;12)[IL3/ETV6], t(8;22)[FGFR1/BCR], t(2;10) [MTA3/HK1, PPM1B/MRPS16], and t(1;12) [ETV6]. Two patients with atypical ABL2 rearrangements linked to chromosome 1 inversions, demonstrated RCSD1/ABL2 fusion, and an apparent dup(5)(q13q33) by karyotype was clarified to be an inversion resulting in SSBP2/CSF1R fusion. Finally, an apparently balanced JAK2 rearrangement by FISH testing was demonstrated to be a complete JAK2 gene deletion associated with chromosome 9p chromothripsis. Overall, the MPseq results from these 16 B-ALL cases highlight the utility of using a precise molecular method to more fully characterize chromosome abnormalities in conjunction with standard karyotype and FISH approaches. The judicious addition of MPseq will further enhance the clinical laboratory's ability to provide accurate diagnostic, prognostic and predictive results for the management of these patients with complex leukemic clones.