Tilmann Bochtler1,2,3, Maximilian Merz1, Thomas Hielscher4, Martin Granzow2,5, Korbinian Hoffmann1, Alwin Krämer1,3, Marc-Steffen Raab1, Jens Hillengass1,6, Anja Seckinger1,2, Christoph Kimmich1,2, Tobias Dittrich1,2,3, Carsten Müller-Tidow1, Dirk Hose1, Hartmut Goldschmidt1,7, Ute Hegenbart1,2, Anna Jauch2,5, Stefan O. Schönland1,2
1Department of Medicine V, Hematology/Oncology/Rheumatology, University of Heidelberg, Heidelberg, Germany;
2Amyloidosis Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany;
3Clinical Cooperation Unit, Molecular Hematology/Oncology, German Cancer Research Center, Heidelberg, Germany;
4Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany
5Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
6Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY
7National Center for Tumor Diseases, Heidelberg, Germany
Tóm tắt
Abstract
Analysis of intraclonal heterogeneity has yielded insights into the clonal evolution of hematologic malignancies. We compared the clonal and subclonal compositions of the underlying plasma cell dyscrasia in 544 systemic light chain amyloidosis (PC-AL) patients with 519 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or symptomatic MM; ie, PC–non-AL patients). Using interphase fluorescence in situ hybridization, subclones were stringently defined as clone size below two thirds of the largest clone and an absolute difference of ≥30%. Subclones were found less frequently in the PC-AL group, at 199 (36.6%) of 544 as compared with 267 (51.4%) of 519 in the PC–non-AL group (P < .001), and were not associated with the stage of plasma cell dyscrasia in either entity. In both groups, translocation t(11;14), other immunoglobulin heavy chain translocations, and hyperdiploidy were typically found as main clones, whereas gain of 1q21 and deletions of 8p21, 13q14, and 17p13 were frequently found as subclones. There were no shifts in the subclone/main clone ratio depending on the MGUS, SMM, or MM stage of plasma cell dyscrasia. In multivariate analysis, t(11;14) was associated with lower rates of subclone formation and hyperdiploidy with higher rates. PC-AL itself lost statistical significance, demonstrating that the lower subclone frequency in AL is a reflection of its exceptionally high t(11;14) frequency. In summary, the subclone patterns in PC-AL and PC–non-AL are closely related, implying that subclone formation depends on the main cytogenetic categories and is independent of disease entity and stage.
