Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma

Blood Advances - Tập 2 - Trang 2607-2618 - 2018
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.

Tài liệu tham khảo

Anderson, 2011, Genetic variegation of clonal architecture and propagating cells in leukaemia, Nature, 469, 356, 10.1038/nature09650 Greaves, 2015, Cancer’s Darwinian dilemma: an evolutionary tale in three acts, BMJ, 351, h6581, 10.1136/bmj.h6581 Ding, 2012, Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing, Nature, 481, 506, 10.1038/nature10738 Bochtler, 2013, Clonal heterogeneity as detected by metaphase karyotyping is an indicator of poor prognosis in acute myeloid leukemia, J Clin Oncol, 31, 3898, 10.1200/JCO.2013.50.7921 Walker, 2012, Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma, Blood, 120, 1077, 10.1182/blood-2012-03-412981 Keats, 2012, Clonal competition with alternating dominance in multiple myeloma, Blood, 120, 1067, 10.1182/blood-2012-01-405985 Morgan, 2012, The genetic architecture of multiple myeloma, Nat Rev Cancer, 12, 335, 10.1038/nrc3257 Bolli, 2014, Heterogeneity of genomic evolution and mutational profiles in multiple myeloma, Nat Commun, 5, 2997, 10.1038/ncomms3997 Lohr, 2014, Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy, Cancer Cell, 25, 91, 10.1016/j.ccr.2013.12.015 de Mel, 2014, Implications of heterogeneity in multiple myeloma, BioMed Res Int, 2014, 232546, 10.1155/2014/232546 An, 2015, The impact of clone size on the prognostic value of chromosome aberrations by fluorescence in situ hybridization in multiple myeloma, Clin Cancer Res, 21, 2148, 10.1158/1078-0432.CCR-14-2576 Fakhri, 2016, Clonal evolution in multiple myeloma, Clin Lymphoma Myeloma Leuk, 16, S130, 10.1016/j.clml.2016.02.025 Dutta, 2017, Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma, Br J Haematol, 178, 196, 10.1111/bjh.14649 Egan, 2012, Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides, Blood, 120, 1060, 10.1182/blood-2012-01-405977 Szalat, 2015, Genomic heterogeneity in multiple myeloma [published correction appears in Curr Opin Genet Dev. 2016;37:158, Curr Opin Genet Dev, 30, 56, 10.1016/j.gde.2015.03.008 Hayman, 2001, Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis, Blood, 98, 2266, 10.1182/blood.V98.7.2266 Bochtler, 2008, Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability, Blood, 111, 4700, 10.1182/blood-2007-11-122101 Bryce, 2009, Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis, Haematologica, 94, 380, 10.3324/haematol.13369 Bochtler, 2011, Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14), Blood, 117, 3809, 10.1182/blood-2010-02-268987 Granzow, 2017, Novel recurrent chromosomal aberrations detected in clonal plasma cells of light chain amyloidosis patients show potential adverse prognostic effect: first results from a genome-wide copy number array analysis, Haematologica, 102, 1281, 10.3324/haematol.2016.160721 Warsame, 2015, Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death, Blood Cancer J, 5, e310, 10.1038/bcj.2015.34 Fonseca, 2004, Genetics and cytogenetics of multiple myeloma: a workshop report, Cancer Res, 64, 1546, 10.1158/0008-5472.CAN-03-2876 Merz, 2017, Prognostic significance of cytogenetic heterogeneity in patients with newly diagnosed multiple myeloma, Blood Adv, 2, 1, 10.1182/bloodadvances.2017013334 Rajkumar, 2014, International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma, Lancet Oncol, 15, e538, 10.1016/S1470-2045(14)70442-5 Neben, 2013, Progression in smoldering myeloma is independently determined by the chromosomal abnormalities del(17p), t(4;14), gain 1q, hyperdiploidy, and tumor load, J Clin Oncol, 31, 4325, 10.1200/JCO.2012.48.4923 Seckinger, 2017, Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment, Cancer Cell, 31, 396, 10.1016/j.ccell.2017.02.002 Wuilleme, 2005, Ploidy, as detected by fluorescence in situ hybridization, defines different subgroups in multiple myeloma, Leukemia, 19, 275, 10.1038/sj.leu.2403586 Gertz, 2005, Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy, Blood, 106, 2837, 10.1182/blood-2005-04-1411 Bochtler, 2016, Prognostic impact of cytogenetic aberrations in AL amyloidosis patients after high-dose melphalan: a long-term follow-up study, Blood, 128, 594, 10.1182/blood-2015-10-676361 Fonseca, 2006, Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma, Leukemia, 20, 2034, 10.1038/sj.leu.2404403 Hanamura, 2006, Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation, Blood, 108, 1724, 10.1182/blood-2006-03-009910 Bochtler, 2014, Gain of chromosome 1q21 is an independent adverse prognostic factor in light chain amyloidosis patients treated with melphalan/dexamethasone, Amyloid, 21, 9, 10.3109/13506129.2013.854766 Hummel, 2017, Clustering of samples and variables with mixed-type data, PLoS One, 12, e0188274, 10.1371/journal.pone.0188274 Bergsagel, 2005, Molecular pathogenesis and a consequent classification of multiple myeloma, J Clin Oncol, 23, 6333, 10.1200/JCO.2005.05.021 Smol, 2017, Combination of t(4;14), del(17p13), del(1p32) and 1q21 gain FISH probes identifies clonal heterogeneity and enhances the detection of adverse cytogenetic profiles in 233 newly diagnosed multiple myeloma, Mol Cytogenet, 10, 26, 10.1186/s13039-017-0327-3 Rasche, 2017, Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing, Nat Commun, 8, 268, 10.1038/s41467-017-00296-y Bianchi, 2014, Biological and clinical implications of clonal heterogeneity and clonal evolution in multiple myeloma, Curr Cancer Ther Rev, 10, 70, 10.2174/157339471002141124121404 Bochtler, 2015, Translocation t(11;14) is associated with adverse outcome in patients with newly diagnosed AL amyloidosis when treated with bortezomib-based regimens, J Clin Oncol, 33, 1371, 10.1200/JCO.2014.57.4947 Dispenzieri, 2004, Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation, Blood, 104, 1881, 10.1182/blood-2004-01-0390
Thông tin
Thông tin xuất bản

Blood Advances

Tập 2

2607-2618

Thông tin tác giả