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Eight novel loci implicate shared genetic etiology in multiple myeloma, AL amyloidosis, and monoclonal gammopathy of unknown significance

Authors:
Subhayan Chattopadhyay at Lund University
Subhayan Chattopadhyay
Hauke Thomsen at MSB Medical School Berlin
Hauke Thomsen
Niels Weinhold at University of Arkansas for Medical Sciences
Niels Weinhold
Iman Meziane
Iman Meziane
Iman Meziane
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Abstract and Figures

The presented data show strong evidence on shared germline genetics for the three plasma cell dyscrasias. However, future studies are needed to decipher the functional basis of the risk SNPs. The most significant association at chromosome 7p15.3 (rs75341503) has been identified as a binding site for IRF4 and may offer a therapeutic target for the three dyscrasias. On the otherhand, the cyclin D1 locus, discussed above, appears to be more prominent for AL amyloidosis than for MM and MGUS, and may offer explanation to deposition of light chains in that disease and possible therapeutic intervention.
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Leukemia (2020) 34:1187–1191
https://doi.org/10.1038/s41375-019-0619-1
LETTER
Multiple myeloma gammopathies
Eight novel loci implicate shared genetic etiology in multiple
myeloma, AL amyloidosis, and monoclonal gammopathy of
unknown significance
Subhayan Chattopadhyay 1,2 ●Hauke Thomsen 1●Niels Weinhold3●Iman Meziane1●Stefanie Huhn3●
Miguel Inacio da Silva Filho1●Pavel Vodicka4,5,6 ●Ludmila Vodickova4,5,6 ●Per Hoffmann7,8 ●Markus M. Nöthen7,9 ●
Karl-Heinz Jöckel10 ●Börge Schmidt10 ●Stefano Landi11 ●Roman Hajek12 ●Göran Hallmans13 ●
Ulrika Pettersson-Kymmer14 ●Claes Ohlsson15 ●Paolo Milani16 ●Giampaolo Merlini16 ●Dorota Rowcieno17 ●
Philip Hawkins17 ●Ute Hegenbart 3●Giovanni Palladini 16 ●Ashutosh Wechalekar17 ●Stefan O. Schönland3●
Richard Houlston 18,19 ●Hartmut Goldschmidt3,20 ●Kari Hemminki1,2,6 ●Asta Försti1,21,22
Received: 12 August 2019 / Accepted: 24 October 2019 / Published online: 6 November 2019
© Springer Nature Limited 2019
To the Editor:
Multiple myeloma (MM) is caused by a clonal proliferation
of malignant plasma cells in the bone marrow preceded
by monoclonal gammopathy of unknown significance
(MGUS) [1]. This indolent stage can also progress to
immunoglobulin light chain amyloidosis (AL amyloidosis)
characterized by deposition of free light chains in multiple
organs [2].
Genome-wide association studies (GWASs) have iden-
tified 23 risk loci for MM [3]. Six of these were associated
with AL amyloidosis at a significance level of P< 1.0 ×
10−5and additionally four single nucleotide polymorphisms
(SNPs), unrelated to MM reached that significance level [4].
A recent meta-analysis found eight MGUS-specific loci and
two loci shared between MGUS and MM reaching a meta-
analyzed Pvalue below 1.0 × 10−5[5]. In addition, ten of
the reported MM risk loci were at least weakly associated
with MGUS. Collectively these data are consistent with a
common heritable basis and comparison of the three plasma
cell dyscrasias may discern signals that are related to all
three. To explore this possibility we analyzed European
GWAS data on MM, AL amyloidosis, and MGUS.
The included GWASs have previously been described
for MM [3], AL amyloidosis [4], and MGUS [5]. Meta-
analyses were performed using META v1. Detailed
descriptions are in Supplementary Material.
GWAS data in eight cohorts were generated in previous
studies [3–5] (Supplementary Fig. 1, Supplementary
Table 1) comprising 4403 MM, 1230 AL amyloidosis, and
992 MGUS patients. In the meta-analysis we identified 17
independently associated genomic regions including 1232
SNPs reaching the genome-wide significant threshold (P<
5.0 × 10−8); linkage disequilibrium between the lead SNPs
was r2< 0.2 (Table 1, Supplementary Fig. 2). These SNPs
are henceforward referred as “sentinel SNPs”. The 17 loci
included nine that were first reported in the GWASs of MM
and the rest eight were previously unreported (bolded in
Table 1)[3,6,7].
Two novel loci (rs113030733 and rs4737550) did not map
close to known protein coding genes (Fig. 1). SNP rs3845682
at 2p23.3 is located 8.7 kb 5′of the ASXL2 gene, required for
normal hematopoiesis and acting as a haploinsufficient tumor
suppressor [8]. SNP rs12518688 at 5q31.3 is intronic to
ARHGAP26, a fusion partner with MLL in myelodysplastic
syndrome [9]. SNP rs56911369 at 5q34 is located between
genes GABRA1 and GABRG2. SNP rs6923504 is located 15
kb 3′from HLA-DRA, an HLA class II alpha complex gene.
SNP rs64221980 at 11p15.5 is located next to the B4GALNT4
gene. SNP rs9579173 at 13q12.11 is intronic to TPTE2
encoding a membrane-associated protein tyrosine phospha-
tase, a homolog of PTEN. A detailed functional annotation is
presented in Supplementary Material.
Shared senior authorship: Kari Hemminki and Asta Försti
*Asta Försti
a.foersti@kitz-heidelberg.de
Extended author information available on the last page of the article
Supplementary information The online version of this article (https://
doi.org/10.1038/s41375-019-0619-1) contains supplementary
material, which is available to authorized users.
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Content courtesy of Springer Nature, terms of use apply. Rights reserved
... In the present study we apply a haplotype-based gene mapping approach to monoclonal gammopathy of unknown significance (MGUS) which is a precursor condition for multiple myeloma (MM) and other plasma cell malignancies such as Waldenström macroglobulinemia and immunoglobulin light chain (AL) amyloidosis. The MGUS populations included Swedish, German and Czech individuals and local controls who have been genotyped in previous GWASs [12][13][14][15]. For haplotype analysis diverse populations may be a disadvantage as the haplotype structure may show subtle differences. ...
... We conducted a haplotype-based analysis on MGUS to complement the earlier GWAS analyses where individual SNPs were considered [13][14][15]29]. A previous meta-analysis of the GWAS data from MGUS, MM and AL-amyloidosis identified 17 independent regions with genome-wide significance [13]. ...
... We conducted a haplotype-based analysis on MGUS to complement the earlier GWAS analyses where individual SNPs were considered [13][14][15]29]. A previous meta-analysis of the GWAS data from MGUS, MM and AL-amyloidosis identified 17 independent regions with genome-wide significance [13]. In the present study we identified 23 haplotypes that were associated with the risk of MGUS at the genome-wide significance level p < 5 × 10 −8 and showed increased risk of MGUS in all three study populations. ...
Haplotype analysis identifies functional elements in monoclonal gammopathy of unknown significance
Article
Full-text available
  • Aug 2024
Genome-wide association studies (GWASs) based on common single nucleotide polymorphisms (SNPs) have identified several loci associated with the risk of monoclonal gammopathy of unknown significance (MGUS), a precursor condition for multiple myeloma (MM). We hypothesized that analyzing haplotypes might be more useful than analyzing individual SNPs, as it could identify functional chromosomal units that collectively contribute to MGUS risk. To test this hypothesis, we used data from our previous GWAS on 992 MGUS cases and 2910 controls from three European populations. We identified 23 haplotypes that were associated with the risk of MGUS at the genome-wide significance level (p < 5 × 10⁻⁸) and showed consistent results among all three populations. In 10 genomic regions, strong promoter, enhancer and regulatory element-related histone marks and their connections to target genes as well as genome segmentation data supported the importance of these regions in MGUS susceptibility. Several associated haplotypes affected pathways important for MM cell survival such as ubiquitin-proteasome system (RNF186, OTUD3), PI3K/AKT/mTOR (HINT3), innate immunity (SEC14L1, ZBP1), cell death regulation (BID) and NOTCH signaling (RBPJ). These pathways are important current therapeutic targets for MM, which may highlight the advantage of the haplotype approach homing to functional units.
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... Two separate GWASs were done on MGUS, and the MGUS and AL results were compared with the results from MM [41,42]. To explore the possibility of shared genetic loci, we carried out a joint analysis combining GWAS data on 4403 MM, 992 MGUS, and 1230 AL amyloidosis cases and 10,554 controls [43]. In this analysis, 17 loci reached a genome-wide significance of 5 × 10 −8 , including eight previously unreported loci. ...
... No associations were found for bone mineral density, hemoglobin, serum albumin, or creatinine level. The first MR was based on the above GWAS combining the three dyscrasias [43]. The environmental factors (exposures) included phenotypes possibly linked to plasma cell dyscrasias, including serum albumin and creatinine levels, bone mineral density, hemoglobin, and immunoglobulin (Ig) traits, the latter obtained from healthy individuals [44]. ...
... In a separate study on AL, we used the above GWAS data, but a wider repertoire of phenotypes [46]. However, to maximize our prospects of identifying a causal relationship with AL we restricted the MR analysis by considering 72 phenotypes with a possible mechanistic link to AL [2,43,46]. Associations with Bonferroni-defined significance level were observed for genetically predicted increased monocyte counts (p = 3.8 × 10 −4 ) and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17, alias BCMA) (p = 3.4 × 10 −5 ). Two other associations with the TNFRSF (members 6, alias Fas, and 19L, alias RELT) reached a nominal significance level. ...
Epidemiology of Amyloidosis and Genetic Pathways to Diagnosis and Typing
Article
Full-text available
  • Jul 2021
We reviewed our studies on epidemiology and germline genetics of amyloidosis. In epidemiology, we considered both hereditary and non-hereditary amyloidosis. As the source of data, we used the nationwide Swedish hospital discharge register. We estimated the incidence of hereditary ATTR amyloidosis, for which Sweden is a global endemic area, at 2/million. Surprisingly, the disease was also endemic within Sweden; the incidence in the province with the highest incidence was 100 times higher than in the rest of Sweden. Risk of non-Hodgkin lymphoma increased five-fold in the affected individuals. Among non-hereditary amyloidosis, the incidence for AL amyloidosis (abbreviated as AL) was estimated at 3.2/million, with a median survival time of 3 years. Secondary systemic amyloidosis (most likely AA amyloidosis) showed an incidence of 1.15/million for combined sexes. The female rate was two times higher than the male rate, probably relating to the higher female prevalence of rheumatoid arthritis. The median survival time was 4 years. We also identified patients who likely had familial autoinflammatory disease, characterized by early onset and immigrant background from the Eastern Mediterranean area. Young Syrian descendants had the highest incidence rate, which was over 500 times higher than that in individuals with Swedish parents. Germline genetics focused on AL on which we carried out a genome-wide association study (GWAS) in three AL cohorts (N = 1129) from Germany, UK, and Italy. Single nucleotide polymorphisms (SNPs) at 10 loci showed evidence of an association at p < 10−5; some of these were previously documented to influence multiple myeloma (MM) risk, including the SNP at the IRF4 binding site. In AL, SNP rs9344 at the splice site of cyclin D1, influencing translocation (11;14), reached the highest significance, p = 7.80 × 10−11; the SNP was only marginally significant in MM. The locus close to gene SMARCD3, involved in chromatin remodeling, was also significant. These data provide evidence for common genetic susceptibility to AL and MM. We continued by analyzing genetic associations in nine clinical profiles, characterized by organ involvement or Ig profiles. The light chain only (LCO) profile associated with the SNP at the splice site of cyclin D1 with p = 1.99 × 10−12. Even for the other profiles, distinct genetic associations were found. It was concluded that the strong association of rs9344 with LCO and t(11;14) amyloidosis offer attractive mechanistic clues to AL causation. Mendelian randomization analysis identified associations of AL with increased blood monocyte counts and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17 alias BCMA) protein. Two other associations with the TNFRSF members were found. We discuss the corollaries of the findings with the recent success of treating t(11;14) AL with a novel drug venetoclax, and the application of BCMA as the common target of plasma cell immunotherapies.
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... 12 AL amyloidosis, MGUS, and MM share genetic risk factors, including single-nucleotide polymorphisms (SNPs) that have been found in large genome-wide association studies (GWASs) of plasma cell dyscrasias. 13,14 Other than heritable factors, little is known about the etiology of AL amyloidosis, which is also the case for MM and MGUS. 3,15 The annual incidence of AL amyloidosis is only $3 per million. ...
... 29 In previous studies, we showed an association between SNPs in TNFRSF13B (also known as TACI) with AL amyloidosis, as well as with MM and MGUS. 13,37 The protein encoded by TNFRSF13B is a lymphocytespecific member of the TNFRSF, and it induces activation of the transcription factors NFAT, AP1, and NF-kB. 29 It stimulates B-and T-cell function and regulates humoral immunity. ...
Search for AL amyloidosis risk factors using Mendelian randomization
Article
Full-text available
  • Jul 2021
In amyloid light chain (AL) amyloidosis, amyloid fibrils derived from immunoglobulin light chain are deposited in many organs, interfering with their function. The etiology of AL amyloidosis is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited by Mendelian randomization (MR) methodology to search for factors influencing AL amyloidosis risk. We performed a 2-sample MR analyzing 72 phenotypes, proxied by 3461 genetic variants, and summary genetic data from a GWAS of 1129 AL amyloidosis cases and 7589 controls. Associations with a Bonferroni-defined significance level were observed for genetically predicted increased monocyte counts (P = 3.8 × 10−4) and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17) gene (P = 3.4 × 10−5). Two other associations with the TNFRSF (members 6 and 19L) reached a nominal significance level. The association between genetically predicted decreased fibrinogen levels may be related to roles of fibrinogen other than blood clotting. be related to its nonhemostatic role. It is plausible that a causal relationship with monocyte concentration could be explained by selection of a light chain–producing clone during progression of monoclonal gammopathy of unknown significance toward AL amyloidosis. Because TNFRSF proteins have key functions in lymphocyte biology, it is entirely plausible that they offer a potential link to AL amyloidosis pathophysiology. Our study provides insight into AL amyloidosis etiology, suggesting high circulating levels of monocytes and TNFRSF proteins as risk factors.
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... Many MM risk loci were found in several study. Integration of gene expression, epigenetic profiling and in situ Hi-C data suggested altered B-cell differentiation, dysregulation of autophagy/apoptosis, and cell cycle signaling as shared perturbed mechanistic pathways [44]. Patients with DM have an increase in insulin-like growth factor (IGF)-I [45]. ...
Influence of diabetes mellitus on the biochemical parameters and outcomes of multiple myeloma
Article
Full-text available
Objective The incidence of MM in most registries remains stable or showing only a slightly increase. However, prevalence of MM is increasing due to the increase in overall survival in the last two decades. The aim of this study was to observe changes in biochemical parameters during the diagnosis and treatment of MM. Methods A retrospective analysis was made of the biochemical indicators, survival time, and related adverse events of 196 patients with MM. Results Of the 196 patients with MM, 26 were diagnosed with DM (DM-MM group) at the first diagnosis, 31 with steroid-induced diabetes mellitus (SID-MM group) during treatment, and 139 without DM (MM group). There was no significant difference between the three groups in the mean age of onset, sex ratio, incidence of hypercalcemia, renal dysfunction, anemia, abnormal lactate dehydrogenase, and median value of D-dimer and fibrinogen during diagnosis and treatment. There was no significant difference in survival time between the SID-MM and MM groups, but there was a significant difference between the DM-MM and MM groups. Conclusion There was no significant difference between the three groups in the incidence of hypercalcemia, anemia, and renal function impairment. The survival time of patients with DM was shorter than that of patients without DM.
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... p = 0.86). Further, when rs195314 was examined in a GWAS of MM including 4403 MM cases and 7265 controls [10], the OR was 1.02 (95% CI: 0.82-1.24, p = 0.5). ...
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... In addition, four single-nucleotide polymorphisms (SNPs), not related to MM, were significantly found [18]. It was reported that the cyclin D1 locus appeared as a more prominent driver for AL amyloidosis patients compared to MM and MGUS patients and it could offer possible new therapeutic targets [19]. ...
Daratumumab in the Treatment of Light-Chain (AL) Amyloidosis
Article
Full-text available
  • Mar 2021
Systemic light-chain (AL) amyloidosis is caused by a small B cell, most commonly a plasma cell (PC), clone that produces toxic light chains (LC) that cause organ dysfunction and deposits in tissues. Due to the production of amyloidogenic, misfolded LC, AL PCs display peculiar biologic features. The small, indolent plasma cell clone is an ideal target for anti-CD38 immunotherapy. A recent phase III randomized study showed that in newly diagnosed patients, the addition of daratumumab to the standard of care increased the rate and depth of the hematologic response and granted more frequent organ responses. In the relapsed/refractory setting, daratumumab alone or as part of combination regimens gave very promising results. It is likely that daratumumab-based regimens will become new standards of care in AL amyloidosis. Another anti-CD38 monoclonal antibody, isatuximab, is at an earlier stage of development as a treatment for AL amyloidosis. The ability to target CD38 on the amyloid PC offers new powerful tools to treat AL amyloidosis. Future studies should define the preferable agents to combine with daratumumab upfront and in the rescue setting and assess the role of maintenance. In this review, we summarize the rationale for using anti-CD38 antibodies in the treatment of AL amyloidosis.
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... Light chain (AL) amyloidosis is caused by a small B-cell clone, more commonly a plasma cell (PC) clone with shared genetic features with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, producing light chains (LCs) that form amyloid deposits and exert toxicity on target organs [1][2][3] . ...
Minimal residual disease negativity by next-generation flow cytometry is associated with improved organ response in AL amyloidosis
Article
Full-text available
  • Feb 2021
Light chain (AL) amyloidosis is caused by a small B-cell clone producing light chains that form amyloid deposits and cause organ dysfunction. Chemotherapy aims at suppressing the production of the toxic light chain (LC) and restore organ function. However, even complete hematologic response (CR), defined as negative serum and urine immunofixation and normalized free LC ratio, does not always translate into organ response. Next-generation flow (NGF) cytometry is used to detect minimal residual disease (MRD) in multiple myeloma. We evaluated MRD by NGF in 92 AL amyloidosis patients in CR. Fifty-four percent had persistent MRD (median 0.03% abnormal plasma cells). There were no differences in baseline clinical variables in patients with or without detectable MRD. Undetectable MRD was associated with higher rates of renal (90% vs 62%, p = 0.006) and cardiac response (95% vs 75%, p = 0.023). Hematologic progression was more frequent in MRD positive (0 vs 25% at 1 year, p = 0.001). Altogether, NGF can detect MRD in approximately half the AL amyloidosis patients in CR, and persistent MRD can explain persistent organ dysfunction. Thus, this study supports testing MRD in CR patients, especially if not accompanied by organ response. In case MRD persists, further treatment could be considered, carefully balancing residual organ damage, patient frailty, and possible toxicity.
View
It's Worth the Weight: Obesity and the Transition from Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma
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Full-text available
  • Jul 2023
The overweight/obesity epidemic is a serious public health concern that affects over 40% of adults globally and increases the risk of numerous chronic diseases such as type II diabetes, heart disease, and various cancers1,2. Multiple myeloma (MM) is a lymphohematopoietic cancer that is caused by the uncontrolled clonal expansion of plasma cells. Recent studies have shown that obesity is a risk factor not only for MM3, but also for monoclonal gammopathy of undetermined significance (MGUS)4, a precursor disease state of MM. Obesity may furthermore promote the transition of MGUS to MM5,6. Thus, this review will summarize the epidemiological evidence regarding the role of obesity in MM and MGUS, discuss the biologic mechanisms that drive these disease processes, and detail the obesity-targeted pharmacologic and lifestyle interventions that may reduce the risk of MGUS to MM progression.
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A genetic risk score of alleles related to MGUS interacts with socioeconomic position in a population-based cohort
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Full-text available
  • Mar 2022
Environmental, genetic, and social factors are suggested to jointly influence monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma. Aim of this study was to investigate interactions between MGUS-related genetic variants and socioeconomic position (SEP) indicators education and income on MGUS in a population-based study. Two different MGUS-related genetic risk allele sum scores (GRS) were calculated based on recent genome-wide meta-analyses. Odds Ratios (OR) were estimated in 4329 participants including 238 MGUS cases to assess associations and multiplicative interaction. The relative excess risk due to interaction (RERI) was calculated to assess additive interaction. Both GRSs were associated with MGUS. A multiplicative interaction between one GRS and education was observed with genetic effects of OR 1.34 (95% CI 1.11–1.62) per risk allele in the highest and OR 1.06 (95% CI 0.86–1.31) in the lowest education group. A RERI of 0.10 (95% CI 0.05–0.14) also indicated additive interaction. Further, additive GRS by income interaction (RERI 0.07; 95% CI 0.01–0.13) for the same GRS was also indicated. Results indicate interaction between MGUS-related genetic risk and SEP. Non-genetic MGUS risk factors more common in higher education groups may influence the expression of MGUS-related genetic variants.
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Epidemiology, genetics and treatment of multiple myeloma and precursor diseases
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Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of plasma cells. The incidence of MM worldwide is increasing with greater than 140 000 people being diagnosed with MM per year. Whereas 5‐year survival after a diagnosis of MM has improved from 28% in 1975 to 56% in 2012, the disease remains essentially incurable. In this review, we summarize our current understanding of MM including its epidemiology, genetics and biology. We will also provide an overview of MM management that has led to improvements in survival, including recent changes to diagnosis and therapies. Areas of unmet need include the management of patients with high‐risk MM, those with reduced performance status and those refractory to standard therapies. Ongoing research into the biology and early detection of MM as well as the development of novel therapies, such as immunotherapies, has the potential to influence MM practice in the future.
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Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma
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  • Mar 2019
Inherited genetic susceptibility to multiple myeloma has been investigated in a number of studies. Although 23 individual risk loci have been identified, much of the genetic heritability remains unknown. Here we carried out genome-wide interaction analyses on two European cohorts accounting for 3,999 cases and 7,266 controls and characterized genetic susceptibility to multiple myeloma with subsequent meta-analysis that discovered 16 unique interacting loci. These risk loci along with previously known variants explain 17% of the heritability in liability scale. The genes associated with the interacting loci were found to be enriched in transforming growth factor beta signaling and circadian rhythm regulation pathways suggesting immunoglobulin trait modulation, T H 17 cell differentiation and bone morphogenesis as mechanistic links between the predisposition markers and intrinsic multiple myeloma biology. Further tissue/cell-type enrichment analysis associated the discovered genes with hemic-immune system tissue types and immune-related cell types indicating overall involvement in immune response.
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Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
Article
Full-text available
  • Dec 2018
Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.
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ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia
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  • May 2017
Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor. While Asxl2 was required for normal haematopoietic stem cell self-renewal, Asxl2 loss promoted AML1-ETO leukemogenesis. Moreover, ASXL2 target genes strongly overlapped with those of RUNX1 and AML1-ETO and ASXL2 loss was associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. These data reveal that Asxl2 is a critical regulator of haematopoiesis and mediates transcriptional effects that promote leukemogenesis driven by AML1-ETO.
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Multiple myeloma risk variant at 7p15.3 creates an IRF4-binding site and interferes with CDCA7L expression
Article
Full-text available
  • Nov 2016
Genome-wide association studies have identified several risk loci for multiple myeloma (MM); however, the mechanisms by which they influence MM are unknown. Here by using genetic association data and functional characterization, we demonstrate that rs4487645 G>T, the most highly associated variant (P = 5.30 × 10−25), resides in an enhancer element 47 kb upstream of the transcription start site of c-Myc-interacting CDCA7L. The G-risk allele, associated with increased CDCA7L expression (P=1.95 × 10−36), increases IRF4 binding and the enhancer interacts with the CDCA7L promoter. We show that suppression of CDCA7L limits MM proliferation through apoptosis, and increased CDCA7L expression is associated with adverse patient survival. These findings implicate IRF4-mediated CDCA7L expression in MM biology and indicate how germline variation might confer susceptibility to MM.
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Search for familial clustering of multiple myeloma with any cancer
Article
Full-text available
  • Oct 2015
Multiple myeloma (MM) is a disease of immunoglobulin producing plasma cells which reside mainly in the bone marrow. Family members of MM patients are at a risk of MM but whether other malignancies are in excess in family members is not established and is the aim of this study. MM patients (24,137) were identified from the Swedish Cancer Registry from years 1958-2012. Relative risks (RRs) were calculated for MM defined by any cancer diagnosed in first degree relatives and compared to individuals whose relatives had no cancer. MM was reliably associated with relative's colorectal, breast and prostate cancers, non-thyroid endocrine tumors, leukemia and cancer of unknown primary; additionally MM was associated with subsites of bone and connective tissue tumors and of non-Hodgkin lymphoma, including lymphoplasmacytic lymphoma/Waldenström macroglobulinema (RR 3.47). MM showed a strong association (RR 1.91) in colorectal cancer families, possibly as part of an unidentified syndrome. All the associations of MM with discordant cancers are novel suggesting that MM shares genetic susceptibility with many cancers. The associations of MM bone and connective tissue tumors were supported by at least two independent results. Whether the results signal bone-related biology shared by MM and these tumors deserves further study.Leukemia accepted article preview online, 09 October 2015. doi:10.1038/leu.2015.279.
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Identification of sequence variants influencing immunoglobulin levels
Article
  • Jun 2017
  • Nat Genet
Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10(-55), β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10(-8), β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.
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Genome-wide association study of immunoglobulin light chain amyloidosis in three patient cohorts: Comparison to myeloma
Article
  • Dec 2016
Immunoglobulin light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibers derived from immunoglobulin light chain. AL amyloidosis and multiple myeloma (MM) originate from monoclonal gammopathy of undetermined significance. We wanted to characterize germline susceptibility to AL amyloidosis using a genome-wide association study (GWAS) on 1229 AL amyloidosis patients from Germany, UK and Italy, and 7526 healthy local controls. For comparison with MM, recent GWAS data on 3790 cases were used. For AL amyloidosis, single nucleotide polymorphisms (SNPs) at 10 loci showed evidence of an association at P<10⁻⁵ with homogeneity of results from the 3 sample sets; some of these were previously documented to influence MM risk, including the SNP at the IRF4 binding site. In AL amyloidosis, rs9344 at the splice site of cyclin D1, promoting translocation (11;14), reached the highest significance, P=7.80 × 10⁻¹¹; the SNP was only marginally significant in MM. SNP rs79419269 close to gene SMARCD3 involved in chromatin remodeling was also significant (P=5.2 × 10⁻⁸). These data provide evidence for common genetic susceptibility to AL amyloidosis and MM. Cyclin D1 is a more prominent driver in AL amyloidosis than in MM, but the links to aggregation of light chains need to be demonstrated.
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Increased Serum Free Light Chains Precede the Presentation of Immunoglobulin Light Chain Amyloidosis
Article
  • Jul 2014
Purpose: Patients with immunoglobulin light chain amyloidosis (AL amyloidosis) generally present with advanced organ dysfunction and have a high risk of early death. We sought to characterize monoclonal immunoglobulin (M-Ig) light chains before clinical presentation of AL amyloidosis. Patients and methods: We obtained prediagnostic sera from 20 cases with AL amyloidosis and 20 healthy controls matched for age, sex, race, and age of serum sample from the Department of Defense Serum Repository. Serum protein electrophoresis with immunofixation and serum free light chain (FLC) analysis were performed on all samples. Results: An M-Ig was detected in 100% of cases and 0% of controls (P < .001). The M-Ig was present in 100%, 80%, and 42% of cases at less than 4 years, 4 to 11 years, and more than 11 years before diagnosis, respectively. The median FLC differential (FLC-diff) was higher in cases compared with controls at all time periods, less than 4 years (174.8 v 0.3 mg/L; P < .001), 4 to 11 years (65.1 v 2.2 mg/L; P < .001), and more than 11 years (4.5 v 0.4 mg/L; P = .03) before diagnosis. The FLC-diff was greater than 23 mg/L in 85% of cases and 0% of controls (P < .001). The FLC-diff level increased more than 10% per year in 84% of cases compared with 16% of controls (P < .001). Conclusion: Increase of FLCs, including within the accepted normal range, precedes the development of AL amyloidosis for many years.
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Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk
Article
  • Aug 2013
  • Nat Genet
To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 × 10(-14)), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 × 10(-11)), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 × 10(-9)) and 22q13.1 (rs877529, CBX7, P = 7.63 × 10(-16)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition.
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