Next-generation antigen receptor sequencing of paired diagnosis and relapse samples of B-cell acute lymphoblastic leukemia: Clonal evolution and implications for minimal residual disease target selection
Antigen receptor gene rearrangements are frequently applied as molecular targets for detection of minimal residual disease (MRD) in B-cell precursor acute lymphoblastic leukemia patients. Since such targets may be lost at relapse, appropriate selection of antigen receptor genes as MRD-PCR target is critical. Recently, next-generation sequencing (NGS) – much more sensitive and quantitative than classical PCR-heteroduplex approaches – has been introduced for identification of MRD-PCR targets. We evaluated 42 paired diagnosis-relapse samples by NGS (IGH, IGK, TRG, TRD, and TRB) to evaluate clonal evolution patterns and to design an algorithm for selection of antigen receptor gene rearrangements most likely to remain stable at relapse. Overall, only 393 out of 1446 (27%) clonal rearrangements were stable between diagnosis and relapse. If only index clones with a frequency >5% at diagnosis were taken into account, this number increased to 65%; including only index clones with an absolute read count >10,000, indicating truly major clones, further increased the stability to 84%. Over 90% of index clones at relapse were also present as index clone at diagnosis. Our data provide detailed information about the stability of antigen receptor gene rearrangements, based on which we propose an algorithm for selecting stable MRD-PCR targets, successful in >97% of patients.
|B-cell precursor ALL, Immunoglobulin and T-cell receptor gene rearrangements, Minimal residual disease, Next generation sequencing, Relapse|
|Leukemia Research: clinical and laboratory studies|
|Organisation||Department of Immunology|
Theunissen, P.M.J, de Bie, M, van Zessen, D, de Haas, V, Stubbs, A.P, & van der Velden, V.H.J. (2018). Next-generation antigen receptor sequencing of paired diagnosis and relapse samples of B-cell acute lymphoblastic leukemia: Clonal evolution and implications for minimal residual disease target selection. Leukemia Research: clinical and laboratory studies. doi:10.1016/j.leukres.2018.10.009