Volume 4 Issue 1
Jun.  2020
Turn off MathJax
Article Contents
Yan Cheng, Fumou Sun, Xing Cui, Siegfried Janz. Genetic predisposition to multiple myeloma[J]. Blood&Genomics, 2020, 4(1): 9-18. doi: 10.46701/BG2020012020103
Citation: Yan Cheng, Fumou Sun, Xing Cui, Siegfried Janz. Genetic predisposition to multiple myeloma[J]. Blood&Genomics, 2020, 4(1): 9-18. doi: 10.46701/BG2020012020103

Genetic predisposition to multiple myeloma

doi: 10.46701/BG2020012020103
More Information
  • Corresponding author: Siegfried Janz, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee 53226, WI, USA. TEL: +1- 414-955-5784, E-mail: sjanz@mcw.edu
  • Received Date: 2020-02-29
  • Accepted Date: 2020-04-21
  • Rev Recd Date: 2020-04-08
  • Available Online: 2021-07-01
  • Publish Date: 2020-06-30
  • Genetic myeloma risk research relied on genome-wide association studies to identify 24 common but low-impact germline predisposition alleles that account for an estimated one eighth of the heritable myeloma risk in Caucasians. Next-generation sequencing, particularly whole-exome sequencing, uncovered a handful of rare but high-impact myeloma risk loci that convey intriguing clues about etiology. The recent discovery of NCOA1 as a myeloma susceptibility gene in Han Chinese has set the stage for the more complete elucidation of the genetic myeloma risk across ethnic barriers. Validating individual myeloma risk loci at the functional level and integrating predisposition genes in genetic networks and biological pathways are important research tasks going forward. Candidate pathways that are currently emerging include plasma cell development, autophagy, telomere maintenance, and cell cycle regulation. An outstanding knowledge gap in the area of gene-environment interaction concerns the possibility that tumor-promoting effects of myeloma susceptibility alleles depend on specific environmental or occupational exposures. An implicit promise of myeloma risk research is the detection of new molecular targets for myeloma treatments and preventions. A related outcome is new biomarkers for patient stratification, prognostication, and development of individualized treatment plans.

     

  • Abbreviations: GWAS, genome-wide association study; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; NGS, next-generation sequencing; OR, odds ratio; RAF, relative allele frequency; RR, relative risk; TWAS, transcriptome-wide association study; WES, whole exome sequencing
    The authors declared no conflict of interests.
  • loading
  • [1]
    Kristinsson SY, Bjorkholm M, Goldin LR, et al. Patterns of hematologic malignancies and solid tumors among 37, 838 first-degree relatives of 13, 896 patients with multiple myeloma in Sweden[J]. Int J Cancer, 2009, 125(9): 2147-50. doi: 10.1002/ijc.24514
    [2]
    Morgan GJ, Johnson DC, Weinhold N, et al. Inherited genetic susceptibility to multiple myeloma[J]. Leukemia, 2014, 28(3): 518-24. doi: 10.1038/leu.2013.344
    [3]
    Broderick P, Chubb D, Johnson DC, et al. Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk[J]. Nat Genet, 2011, 44(1): 58-61.
    [4]
    Martino A, Campa D, Jamroziak K, et al. Impact of polymorphic variation at 7p15.3, 3p22.1 and 2p23.3 loci on risk of multiple myeloma[J]. Br J Haematol, 2012, 158(6): 805-9. doi: 10.1111/j.1365-2141.2012.09244.x
    [5]
    Weinhold N, Johnson DC, Chubb D, et al. The CCND1 c. 870G > A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma[J]. Nat Genet, 2013, 45(5): 522-5. doi: 10.1038/ng.2583
    [6]
    Chubb D, Weinhold N, Broderick P, et al. Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk[J]. Nat Genet, 2013, 45(10): 1221-5. doi: 10.1038/ng.2733
    [7]
    Mitchell JS, Li N, Weinhold N, et al. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma[J]. Nat Commun, 2016, 7: 12050. doi: 10.1038/ncomms12050
    [8]
    Went M, Sud A, Forsti A, et al. Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma[J]. Nat Commun, 2018, 9(1): 3707. doi: 10.1038/s41467-018-04989-w
    [9]
    Pertesi M, Went M, Hansson M, et al. Genetic predisposition for multiple myeloma[J]. Leukemia, 2020, 34(3): 697-708. doi: 10.1038/s41375-019-0703-6
    [10]
    Ziv E, Dean E, Hu D, et al. Genome-wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients[J]. Nat Commun, 2015, 6: 7539. doi: 10.1038/ncomms8539
    [11]
    Rajkumar SV, Merlini G, San Miguel JF. Haematological cancer: Redefining myeloma[J]. Nat Rev Clin Oncol, 2012, 9(9): 494-6. doi: 10.1038/nrclinonc.2012.128
    [12]
    Weinhold N, Johnson DC, Rawstron AC, et al. Inherited genetic susceptibility to monoclonal gammopathy of unknown significance[J]. Blood, 2014, 123(16): 2513-7; quiz 2593. doi: 10.1182/blood-2013-10-532283
    [13]
    Thomsen H, Campo C, Weinhold N, et al. Genomewide association study on monoclonal gammopathy of unknown significance (MGUS)[J]. Eur J Haematol, 2017, 99(1): 70-9. doi: 10.1111/ejh.12892
    [14]
    Chattopadhyay S, Thomsen H, Weinhold N, et al. Eight novel loci implicate shared genetic etiology in multiple myeloma, AL amyloidosis, and monoclonal gammopathy of unknown significance[J]. Leukemia, 2020, 34(4): 1187-91. doi: 10.1038/s41375-019-0619-1
    [15]
    Chattopadhyay S, Thomsen H, da Silva Filho MI, et al. Enrichment of B cell receptor signaling and epidermal growth factor receptor pathways in monoclonal gammopathy of undetermined significance: a genome-wide genetic interaction study[J]. Mol Med, 2018, 24(1): 30. doi: 10.1186/s10020-018-0031-8
    [16]
    Peng M, Zhao G, Yang F, et al. NCOA1 is a novel susceptibility gene for multiple myeloma in the Chinese population: A case-control study[J]. PLoS One, 2017, 12(3): e0173298. doi: 10.1371/journal.pone.0173298
    [17]
    Butrym A, Lacina P, Rybka J, et al. Cereblon and IRF4 variants affect risk and response to treatment in multiple myeloma[J]. Arch Immunol Ther Exp (Warsz), 2016, 64(Suppl 1): 151-6. http://europepmc.org/articles/PMC5334380/
    [18]
    Lacina P, Butrym A, Mazur G, et al. BSG and MCT1 genetic variants influence survival in multiple myeloma patients[J]. Genes (Basel), 2018, 9(5): 226. doi: 10.3390/genes9050226
    [19]
    Shah V, Boyd KD, Houlston RS, et al. Constitutional mutation in CDKN2A is associated with long term survivorship in multiple myeloma: a case report[J]. BMC Cancer, 2017, 17(1): 718. doi: 10.1186/s12885-017-3715-5
    [20]
    Campa D, Martino A, Macauda A, et al. Genetic polymorphisms in genes of class switch recombination and multiple myeloma risk and survival: an IMMEnSE study[J]. Leuk Lymphoma, 2019, 60(7): 1803-11. doi: 10.1080/10428194.2018.1551536
    [21]
    Waller RG, Darlington TM, Wei X, et al. Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk[J]. PLoS Genet, 2018, 14(2): e1007111. doi: 10.1371/journal.pgen.1007111
    [22]
    Bolli N, Barcella M, Salvi E, et al. Next-generation sequencing of a family with a high penetrance of monoclonal gammopathies for the identification of candidate risk alleles[J]. Cancer, 2017, 123(19): 3701-8. doi: 10.1002/cncr.30777
    [23]
    Wei X, Calvo-Vidal MN, Chen S, et al. Germline lysine-specific demethylase 1 (LSD1/KDM1A) mutations confer susceptibility to multiple myeloma[J]. Cancer Res, 2018, 78(10): 2747-59. doi: 10.1158/0008-5472.CAN-17-1900
    [24]
    Scales M, Chubb D, Dobbins SE, et al. Search for rare protein altering variants influencing susceptibility to multiple myeloma[J]. Oncotarget, 2017, 8(22): 36203-10. doi: 10.18632/oncotarget.15874
    [25]
    Grass S, Preuss KD, Ahlgrimm M, et al. Association of a dominantly inherited hyperphosphorylated paraprotein target with sporadic and familial multiple myeloma and monoclonal gammopathy of undetermined significance: a case-control study[J]. Lancet Oncol, 2009, 10(10): 950-6. doi: 10.1016/S1470-2045(09)70234-7
    [26]
    Grass S, Preuss KD, Thome S, et al. Paraproteins of familial MGUS/multiple myeloma target family-typical antigens: hyperphosphorylation of autoantigens is a consistent finding in familial and sporadic MGUS/MM[J]. Blood, 2011, 118(3): 635-7. doi: 10.1182/blood-2011-01-331454
    [27]
    Preuss KD, Fadle N, Regitz E, et al. Inactivation of protein-phosphatase 2A causing hyperphosphorylation of autoantigenic paraprotein targets in MGUS/MM is due to an exchange of its regulatory subunits[J]. Int J Cancer, 2014, 135(9): 2046-53. doi: 10.1002/ijc.28864
    [28]
    Nair S, Sng J, Boddupalli CS, et al. Antigen-mediated regulation in monoclonal gammopathies and myeloma[J]. JCI Insight, 2018, 3(8): 98259 doi: 10.1172/jci.insight.98259
    [29]
    Beksac M, Gragert L, Fingerson S, et al. HLA polymorphism and risk of multiple myeloma[J]. Leukemia, 2016, 30(11): 2260-4. doi: 10.1038/leu.2016.199
    [30]
    Greenberg AJ, Vachon CM, Rajkumar SV. Disparities in the prevalence, pathogenesis and progression of monoclonal gammopathy of undetermined significance and multiple myeloma between blacks and whites[J]. Leukemia, 2012, 26(4): 609-14. doi: 10.1038/leu.2011.368
    [31]
    Costa LJ, Brill IK, Omel J, et al. Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States[J]. Blood Adv, 2017, 1(4): 282-7. doi: 10.1182/bloodadvances.2016002493
    [32]
    Waxman AJ, Mink PJ, Devesa SS, et al. Racial disparities in incidence and outcome in multiple myeloma: a population-based study[J]. Blood, 2010, 116(25): 5501-6. doi: 10.1182/blood-2010-07-298760
    [33]
    Baughn LB, Pearce K, Larson D, et al. Differences in genomic abnormalities among African individuals with monoclonal gammopathies using calculated ancestry[J]. Blood Cancer J, 2018, 8(10): 96. doi: 10.1038/s41408-018-0132-1
    [34]
    Rand KA, Song C, Dean E, et al. A meta-analysis of multiple myeloma risk regions in African and European ancestry populations identifies putatively functional loci[J]. Cancer Epidemiol Biomarkers Prev, 2016, 25(12): 1609-18. doi: 10.1158/1055-9965.EPI-15-1193
    [35]
    Erickson SW, Raj VR, Stephens OW, et al. Genome-wide scan identifies variant in 2q12.3 associated with risk for multiple myeloma[J]. Blood, 2014, 124(12): 2001-3. doi: 10.1182/blood-2014-07-586701
    [36]
    Weinhold N, Meissner T, Johnson DC, et al. The 7p15.3 (rs4487645) association for multiple myeloma shows strong allele-specific regulation of the MYC-interacting gene CDCA7L in malignant plasma cells[J]. Haematologica, 2015, 100(3): e110-3. doi: 10.3324/haematol.2014.118786
    [37]
    Li N, Johnson DC, Weinhold N, et al. Multiple myeloma risk variant at 7p15.3 creates an IRF4-binding site and interferes with CDCA7L expression[J]. Nat Commun, 2016, 7: 13656. doi: 10.1038/ncomms13656
    [38]
    Du Z, Weinhold N, Song GC, et al. A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry[J]. Blood Adv, 2020, 4(1): 181-90. doi: 10.1182/bloodadvances.2019000491
    [39]
    Manojlovic Z, Christofferson A, Liang WS, et al. Comprehensive molecular profiling of 718 multiple myelomas reveals significant differences in mutation frequencies between African and European descent cases[J]. PLoS Genet, 2017, 13(11): e1007087. doi: 10.1371/journal.pgen.1007087
    [40]
    Acquaviva J, Chen X, Ren R. IRF-4 functions as a tumor suppressor in early B-cell development[J]. Blood, 2008, 112(9): 3798-806. doi: 10.1182/blood-2007-10-117838
    [41]
    Iida S, Rao PH, Butler M, et al. Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma[J]. Nat Genet, 1997, 17(2): 226-30. doi: 10.1038/ng1097-226
    [42]
    Heintel D, Zojer N, Schreder M, et al. Expression of MUM1/IRF4 mRNA as a prognostic marker in patients with multiple myeloma[J]. Leukemia, 2008, 22(2): 441-5. doi: 10.1038/sj.leu.2404895
    [43]
    Fanzo JC, Yang W, Jang SY, et al. Loss of IRF-4-binding protein leads to the spontaneous development of systemic autoimmunity[J]. J Clin Invest, 2006, 116(3): 703-14. doi: 10.1172/JCI24096
    [44]
    Shaffer AL, Emre NC, Lamy L, et al. IRF4 addiction in multiple myeloma[J]. Nature, 2008, 454(7201): 226-31. doi: 10.1038/nature07064
    [45]
    Walker BA, Boyle EM, Wardell CP, et al. Mutational spectrum, copy number changes, and outcome: Results of a sequencing study of patients with newly diagnosed myeloma[J]. J Clin Oncol, 2015, 33(33): 3911-20. doi: 10.1200/JCO.2014.59.1503
    [46]
    Zhu YX, Braggio E, Shi CX, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide[J]. Blood, 2011, 118(18): 4771-9. doi: 10.1182/blood-2011-05-356063
    [47]
    Zhu YX, Braggio E, Shi CX, et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma[J]. Blood, 2014, 124(4): 536-45. doi: 10.1182/blood-2014-02-557819
    [48]
    Greenberg AJ, Walters DK, Kumar SK, et al. Responsiveness of cytogenetically discrete human myeloma cell lines to lenalidomide: lack of correlation with cereblon and interferon regulatory factor 4 expression levels[J]. Eur J Haematol, 2013, 91(6): 504-13. doi: 10.1111/ejh.12192
    [49]
    Schuster SR, Kortuem KM, Zhu YX, et al. The clinical significance of cereblon expression in multiple myeloma[J]. Leuk Res, 2014, 38(1): 23-8. doi: 10.1016/j.leukres.2013.08.015
    [50]
    Lopez-Girona A, Heintel D, Zhang LH, et al. Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response[J]. Br J Haematol, 2011, 154(3): 325-36. doi: 10.1111/j.1365-2141.2011.08689.x
    [51]
    Blocka J, Durie BGM, Huhn S, et al. Familial cancer: how to successfully recruit families for germline mutations studies? Multiple myeloma as an example[J]. Clin Lymphoma Myeloma Leuk, 2019, 19(10): 635-44 e2. doi: 10.1016/j.clml.2019.06.012
    [52]
    Liu J, Liu W, Mi L, et al. Incidence and mortality of multiple myeloma in China, 2006-2016: an analysis of the Global Burden of Disease Study 2016[J]. J Hematol Oncol, 2019, 12(1): 136. doi: 10.1186/s13045-019-0807-5
    [53]
    Ali M, Ajore R, Wihlborg AK, et al. The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression[J]. Nat Commun, 2018, 9(1): 1649. doi: 10.1038/s41467-018-04082-2
    [54]
    Li N, Johnson DC, Weinhold N, et al. Genetic predisposition to multiple myeloma at 5q15 is mediated by an ELL2 enhancer polymorphism[J]. Cell Rep, 2017, 20(11): 2556-64. doi: 10.1016/j.celrep.2017.08.062
    [55]
    Shearer JJ, Beane Freeman LE, Liu D, et al. Longitudinal investigation of haematological alterations among permethrin-exposed pesticide applicators in the Biomarkers of Exposure and Effect in Agriculture study[J]. Occup Environ Med, 2019, 76(7): 467-70. doi: 10.1136/oemed-2018-105559
    [56]
    Tual S, Busson A, Boulanger M, et al. Occupational exposure to pesticides and multiple myeloma in the AGRICAN cohort[J]. Cancer Causes Control, 2019, 30(11): 1243-50. doi: 10.1007/s10552-019-01230-x
    [57]
    Lincz LF, Scorgie FE, Robertson R, et al. Genetic variations in benzene metabolism and susceptibility to multiple myeloma[J]. Leukemia Res, 2007, 31(6): 759-63. doi: 10.1016/j.leukres.2006.07.012
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(1)  / Tables(3)

    Article Metrics

    Article views (22) PDF downloads(0) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return