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Immunoglobulin light-chain amyloidosis shares genetic susceptibility with multiple myeloma

Leukemia volume 28, pages 2254–2256 (2014)Cite this article

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Amyloid light-chain (AL) amyloidosis is a rare clonal plasma cell disorder with an estimated incidence of 3 per million.1 The disease is characterized by deposition of amyloid fibers derived from immunoglobulin light chains systematically in many organs.2 The symptoms arise in the organs where amyloids accumulate, including the heart, kidney, liver and peripheral nerves; heart failure is the critical life-threatening condition that may ensue in a few months after diagnosis.2 Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic pre-malignant clonal condition, through which all cases of multiple myeloma (MM) pass with a relative risk of 25.3,4 AL amyloidosis, MGUS and MM are hypothesized to be the same disease entity at the cellular level, with AL amyloidosis just being a clonal plasma cell disorder with an ‘unlucky protein’.5 Nevertheless, the genetic etiology of AL amyloidosis is poorly understood. According to a 15-year follow-up study of MGUS patients the relative risk for AL amyloidosis was 8.4.3 Two recent genome-wide association studies (GWAS) of MM have identified seven single-nucleotide polymorphisms (SNPs) that are associated with disease risk, including loci mapping to 2p23.3 (rs6746082), 3p22.1 (rs1052501), 3q26.2 (rs10936599), 6p21.33 (rs2285803), 7p15.3 (rs4487645), 17p11.2 (rs4273077) and 22q13.1 (rs877529).6,7 These seven SNPs also independently influence MGUS risk.8 MM and MGUS are characterized by a high cytogenetic heterogeneity.5,9 The two main pathogenetic groups hyperdiploidy and non-hyperdiploidy can be further subdivided based on the presence of IgH translocations.9 The cytogenetic patterns of AL amyloidosis are similar, but the frequencies of aberrations differ.5 Recently we showed by stratified analyses that the CCND1 c.870G>A splice site polymorphism (rs603965) was strongly associated with the t(11;14)(q13;q32) in MM and MGUS.9 This IgH translocation can only be detected in ~20% of MM and MGUS cases.9 In contrast, it is a common event (53%) in AL amyloidosis.5

In the present study we analyzed the seven MM risk alleles in 443 German AL amyloidosis cases and used published data on German MM and control samples as references. We additionally tested the possible association between rs603965 and the translocation t(11;14) in 329 AL amyloidosis cases with FISH data.

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Acknowledgements

Funding was provided to Dietmar-Hopp-Stiftung in Walldorf, The German Ministry of Education and Science (Gliommics 01ZX1309B), the German Cancer Aid no. 110131, GERAMY (BMBF 01GM1107A) and the University Hospital Heidelberg. Additional funding was also provided by the German Ministry of Education and Science and the German Research Council (DFG; Projects SI 236/8-1, SI236/9-1 and ER 155/6-1).

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Authors and Affiliations

  1. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    N Weinhold, J Nickel, D Hose, H Goldschmidt, U Hegenbart & S O Schönland

  2. German Cancer Research Center, Heidelberg, Germany

    A Försti, M I da Silva Filho, C Campo & K Hemminki

  3. Center for Primary Health Care Research, Lund University, Malmo, Sweden

    A Försti & K Hemminki

  4. Institute of Human Genetics, University of Bonn, Bonn, Germany

    P Hoffmann & M M Nöthen

  5. Department of Biomedicine, University of Basel, Basel, Switzerland

    P Hoffmann

  6. Department of Genomics, Life & Brain Research Center, University of Bonn, Bonn, Germany

    M M Nöthen

  7. National Centre of Tumor Diseases, Heidelberg, Germany

    D Hose & H Goldschmidt

  8. Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany

    A Jauch

  9. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    C Langer

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  1. N Weinhold
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Correspondence to N Weinhold.

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Weinhold, N., Försti, A., da Silva Filho, M. et al. Immunoglobulin light-chain amyloidosis shares genetic susceptibility with multiple myeloma. Leukemia 28, 2254–2256 (2014). https://doi.org/10.1038/leu.2014.208

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