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.
Immunoglobulin light chain (AL) amyloidosis is a rare plasma cell dyscrasia characterized by the deposition of abnormal amyloid fibrils in multiple organs, thus impairing their function. In the largest cohort studied up to now of 118 CD138-purified plasma cell samples from previously untreated immunoglobulin light chain amyloidosis patients, we assessed in parallel copy number alterations using high-density copy number arrays and interphase fluorescencein situhybridization (iFISH). We used fluorescencein situhybridization probes for the IgH translocations t(11;14), t(4;14), and t(14;16) or any other IgH rearrangement as well as numerical aberrations of the chromosome loci 1q21, 8p21, 5p15/5q35, 11q22.3 or 11q23, 13q14, 15q22, 17p13, and 19q13. Recurrent gains included chromosomes 1q (36%), 9 (24%), 11q (24%), as well as 19 (15%). Recurrent losses affected chromosome 13 (29% monosomy) and partial losses of 14q (19%), 16q (14%) and 13q (12%), respectively. In 88% of patients with translocation t(11;14), the hallmark chromosomal aberration in AL amyloidosis, a concomitant gain of 11q22.3/11q23 detected by iFISH was part of the unbalanced translocation der(14)t(11;14)(q13;q32) with the breakpoint in theCCND1/MYEOVgene region. Partial loss of chromosome regions 14q and 16q were significantly associated to gain 1q. Gain 1q21 detected by iFISH almost always resulted from a gain of the long arm of chromosome 1 and not from trisomy 1, whereas deletions on chromosome 1p were rarely found. Overall and event-free survival analysis found a potential adverse prognostic effect of concomitant gain 1q and deletion 14q as well as of deletion 1p. In conclusion, in the first whole genome report of clonal plasma cells in AL amyloidosis, novel aberrations and hitherto unknown potential adverse prognostic effects were uncovered.
Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany granzow@uni-heidelberg.de.
Martin
M
Granzow
Department of Internal Medicine V, Hematology/Oncology, Amyloidosis Center, University of Heidelberg, Heidelberg, Germany.
Ute
U
Hegenbart
Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
Katrin
K
Hinderhofer
Department of Internal Medicine V, Hematology/Oncology, Amyloidosis Center, University of Heidelberg, Heidelberg, Germany.
Dirk
D
Hose
Department of Internal Medicine V, Hematology/Oncology, Amyloidosis Center, University of Heidelberg, Heidelberg, Germany.
Anja
A
Seckinger
Department of Internal Medicine V, Hematology/Oncology, Amyloidosis Center, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
Tilmann
T
Bochtler
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Kari
K
Hemminki
Department of Internal Medicine V, Hematology/Oncology, Amyloidosis Center, University of Heidelberg, Heidelberg, Germany.|National Center for Tumor Diseases, Heidelberg, Germany.
Hartmut
H
Goldschmidt
Department of Internal Medicine V, Hematology/Oncology, Amyloidosis Center, University of Heidelberg, Heidelberg, Germany.
Stefan O
SO
Schönland
Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
Anna
A
Jauch
D000483:Alleles; D000686:Amyloidosis / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations; D055106:Genome-Wide Association Study; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000235:genetics* / Q000378:metabolism*; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation; D010950:Plasma Cells / Q000378:metabolism* / Q000473:pathology; D011123:Polyploidy; D011379:Prognosis; D016019:Survival Analysis; D014178:Translocation, Genetic
D007147:Immunoglobulin Light Chains