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Open Access 01-12-2017 | Research article

N-glycosylation of serum proteins for the assessment of patients with IgD multiple myeloma

Authors: Jie Chen, Meng Fang, Xiaoling Chen, Changhong Yi, Jun Ji, Cheng Cheng, Mengmeng Wang, Xing Gu, Quansheng Sun, Chunfang Gao

Published in: BMC Cancer | Issue 1/2017

Abstract

Background

Because glycosylation is one of the most common post-translational modifications of proteins and because changes in glycosylation have been shown to have a significant correlation with the development of many cancer types, we investigated the serum N-glycome used to diagnose, stage and evaluate the pathological outcomes in IgD multiple myeloma.

Methods

Serum samples were available for 20 patients with IgD multiple myeloma, 41 patients with light chain multiple myeloma and 42 healthy control subjects. Serum N-glycans were released and analysed using DNA sequencer-assisted fluorophore-assisted capillary electrophoresis.

Results

Characteristic changes were revealed in the serum N-glycome of IgD myeloma. In particular, three N-glycans (NG1(6)A2F, Peak3; NG1(3)A2F, Peak4; NA2FB, Peak7) showed increased clinical value. The best area under the ROC curve of NG1(6)A2F to diagnose IgD myeloma was 0.981, with a 95.0% sensitivity and 95.2% specificity, and that of NG1(3)A2F was 0.936, with a 95.0% sensitivity and 78.6% specificity. The best area under the ROC curve of NA2FB/NG1(3)A2F to differentially diagnose IgD myeloma versus light chain myeloma was 0.744, with a 95.3% sensitivity and 50.0% specificity. The level of NG1(3)A2F was correlated with the international staging system, while the higher abundance of NA2FB presented in IgD myeloma was predictive of a shorter progression-free survival.

Conclusions

The advent of serum N-glycan signatures may play a role in the diagnosis, staging and prognosis of IgD myeloma and will serve as the foundation for a precision medicine approach to this rare subtype of multiple myeloma.

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Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, Fonseca R, Rajkumar SV, Offord JR, Larson DR, Plevak ME, Therneau TM, Greipp PR. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clinic Proc. 2003;78(1):21–33.CrossRef

Bladé J, Lust JA, Kyle RA. Immunoglobulin D multiple myeloma: presenting features, response to therapy, and survival in a series of 53 cases. J Clin Oncol. 1994;12(11):2398–404.CrossRefPubMed

Jancelewicz Z, Takatsuki K, Sugai S, Pruzanski W. IgD multiple myeloma. Review of 133 cases. Arch Intern Med. 1975;135(1):87–93.CrossRefPubMed

Morris C, Drake M, Apperley J, Iacobelli S, van Biezen A, Bjorkstrand B, Goldschmidt H, Harousseau JL, Morgan G, de Witte T, Niederwieser D, Gahrton G. Efficacy and outcome of autologous transplantation in rare myelomas. Haematologica. 2010;95(12):2126–33.CrossRefPubMedPubMedCentral

Jenkins N, Curling E. Glycosylation of recombinant proteins: problems and prospects. Enzym Microb Technol. 1994;16(5):354–64.CrossRef

Callewaert N, Van Vlierberghe H, Van Hecke A, Laroy W, Delanghe J, Contreras R. Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nat Med. 2004;10(4):429–34.CrossRefPubMed

An HJ, Miyamoto S, Lancaster KS, Kirmiz C, Li B, Lam KS, Leiserowitz GS, Lebrilla CB. Profiling of glycans in serum for the discovery of potential biomarkers for ovarian cancer. J Proteome Res. 2006;5(7):1626–35.CrossRefPubMed

Saldova R, Fan Y, Fitzpatrick JM, Watson RW, Rudd PM. Core fucosylation and alpha2-3 sialylation in serum N-glycome is significantly increased in prostate cancer comparing to benign prostate hyperplasia. Glycobiology. 2011;21(2):195–205.CrossRefPubMed

Arnold JN, Saldova R, Galligan MC, Murphy TB, Mimura-Kimura Y, Telford JE, Godwin AK, Rudd PM. Novel glycan biomarkers for the detection of lung cancer. J Proteome Res. 2011;10(4):1755–64.CrossRefPubMed

10.

Mittermayr S, Lê GN, Clarke C, Millán Martín S, Larkin AM, O'Gorman P, Bones J. Polyclonal immunoglobulin G N-glycosylation in the pathogenesis of plasma cell disorders. J Proteome Res. 2017;16(2):748–62.CrossRefPubMed

11.

Kovacs Z, Simon A, Szabo Z, Nagy Z, Varoczy L, Pal I, Csanky E, Guttman A. Capillary electrophoresis analysis of N-glycosylation changes of serum paraproteins in multiple myeloma. Electrophoresis. 2017;38(17):2115–23.CrossRefPubMed

12.

Laroy W, Contreras R, Callewaert N. Glycome mapping on DNA sequencing equipment. Nat Protoc. 2006;1(1):397–405.CrossRefPubMed

13.

Moreaux J, Sprynski AC, Dillon SR, Mahtouk K, Jourdan M, Ythier A, Moine P, Robert N, Jourdan E, Rossi JF, Klein BAPRIL. TACI interact with syndecan-1 on the surface of multiple myeloma cells to form an essential survival loop. Eur J Haematol. 2009;83(2):119–29.CrossRefPubMed

14.

Mahtouk K, Hose D, Rème T, De Vos J, Jourdan M, Moreaux J, Fiol G, Raab M, Jourdan E, Grau V, Moos M, Goldschmidt H, Baudard M, Rossi JF, Cremer FW, Klein B. Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells. Oncogene. 2005;24(21):3512–24.CrossRefPubMedPubMedCentral

15.

Mahtouk K, Cremer FW, Rème T, Jourdan M, Baudard M, Moreaux J, Requirand G, Fiol G, De Vos J, Moos M, Quittet P, Goldschmidt H, Rossi JF, Hose D, Klein B. Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma. Oncogene. 2006;25(54):7180–91.CrossRefPubMedPubMedCentral

16.

Sprynski AC, Hose D, Caillot L, Réme T, Shaughnessy JD Jr, Barlogie B, Seckinger A, Moreaux J, Hundemer M, Jourdan M, Meissner T, Jauch A, Mahtouk K, Kassambara A, Bertsch U, Rossi JF, Goldschmidt H, Klein B. The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor. Blood. 2009;113(19):4614–26.CrossRefPubMedPubMedCentral

17.

Derksen PW, Keehnen RM, Evers LM, van Oers MH, Spaargaren M, Pals ST. Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes met signaling in multiple myeloma. Blood. 2002;99(4):1405–10.CrossRefPubMed

18.

Yang Y, MacLeod V, Dai Y, Khotskaya-Sample Y, Shriver Z, Venkataraman G, Sasisekharan R, Naggi A, Torri G, Casu B, Vlodavsky I, Suva LJ, Epstein J, Yaccoby S, Shaughnessy JD Jr, Barlogie B, Sanderson RD. The syndecan-1 heparan sulfate proteoglycan is a viable target for myeloma therapy. Blood 2007;110(6):2041–2048.

19.

Chen J, Fang M, Zhao YP, Yi CH, Ji J, Cheng C, Wang MM, Gu X, Sun QS, Chen XL, Gao CF. Serum N-Glycans: a new diagnostic biomarker for light chain multiple myeloma. PLoS One. 2015;10(6):e0127022.CrossRefPubMedPubMedCentral

20.

Kuliszkiewicz-Janus M, Zimny A, Sokolska V, Saşiadek M, Kuliczkowski K, Immunoglobulin D. Myeloma--problems with diagnosing and staging (own experience and literature review). Leuk Lymphoma. 2005;46(7):1029–37.CrossRefPubMed

21.

Pandey S, Kyle RA. Unusual myelomas: a review of IgD and IgE variants. Oncology (Williston Park). 2013;27(8):798–803.

22.

International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the international myeloma working group. Br J Haematol. 2003;121(5):749–57.CrossRef

23.

Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23(1):3–9.CrossRefPubMed

24.

Fang M, Zhao YP, Zhou FG, LG L, Qi P, Wang H, Zhou K, Sun SH, Chen CY, Gao CF. N-Glycan based models improve diagnostic efficacies in hepatitis B virus-related hepatocellular carcinoma. Int J Cancer. 2010;127(1):148–59.CrossRefPubMed

25.

Liu XE, Desmyter L, Gao CF, Laroy W, Dewaele S, Vanhooren V, Wang L, Zhuang H, Callewaert N, Libert C, Contreras R, Chen C. N-Glycomic changes in hepatocellular carcinoma patients with liver cirrhosis induced by hepatitis B virus. Hepatology. 2007;46(5):1426–35.CrossRefPubMed

26.

Bunz SC, Rapp E, Neusüss C. Capillary electrophoresis/mass spectrometry of APTS-labeled glycans for the identification of unknown glycan species in capillary electrophoresis/laser-induced fluorescence systems. Anal Chem. 2013;85(21):10218–24.CrossRefPubMed

27.

Testa R, Vanhooren V, Bonfigli AR, Boemi M, Olivieri F, Ceriello A, Genovese S, Spazzafumo L, Borelli V, Bacalini MG, Salvioli S, Garagnani P, Dewaele S, Libert C, Franceschi C. N-Glycomic changes in serum proteins in type 2 diabetes mellitus correlate with complications and with metabolic syndrome parameters. PLoS One. 2015;10(3):e0119983.CrossRefPubMedPubMedCentral

28.

Apweiler R, Hermjakob H, Sharon N. On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim Biophys Acta. 1999;1473(1):4–8.CrossRefPubMed

29.

Hakomori S. Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens. Adv Cancer Res. 1989;52:257–331.CrossRefPubMed

30.

Kannagi R, Izawa M, Koike T, Miyazaki K, Kimura N. Carbohydrate-mediated cell adhesion in cancer metastasis and angiogenesis. Cancer Sci. 2004;95(5):377–84.CrossRefPubMed

31.

Partridge EA, Le Roy C, Di Guglielmo GM, Pawling J, Cheung P, Granovsky M, Nabi IR, Wrana JL, Dennis JW. Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science. 2004;306(5693):120–4.CrossRefPubMed

32.

Lau KS, Partridge EA, Grigorian A, Silvescu CI, Reinhold VN, Demetriou M, Dennis JW. Complex N-Glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell. 2007;129(1):123–34.CrossRefPubMed

33.

Dennis JW, Granovsky M, Warren CE. Glycoprotein glycosylation and cancer progression. Biochim Biophys Acta. 1999;1473(1):21–34.CrossRefPubMed

34.

Saldova R, Asadi Shehni A, Haakensen VD, Steinfeld I, Hilliard M, Kifer I, Helland A, Yakhini Z, Børresen-Dale AL, Rudd PM. Association of N-glycosylation with breast carcinoma and systemic features using high-resolution quantitative UPLC. J Proteome Res. 2014;13(5):2314–27.CrossRefPubMed

35.

Zhao YP, XY X, Fang M, Wang H, You Q, Yi CH, Ji J, Gu X, Zhou PT, Cheng C, Gao CF. Decreased core-fucosylation contributes to malignancy in gastric cancer. PLoS One. 2014;9(4):e94536.CrossRefPubMedPubMedCentral

36.

Yarema KJ, Bertozzi CR. Characterizing glycosylation pathways. Genome Biol. 2001;2(5):REVIEWS0004.CrossRefPubMedPubMedCentral

37.

Glavey SV, Manier S, Natoni A, Sacco A, Moschetta M, Reagan MR, Murillo LS, Sahin I, Wu P, Mishima Y, Zhang Y, Zhang W, Zhang Y, Morgan G, Joshi L, Roccaro AM, Ghobrial IM, O'Dwyer ME. The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma. Blood. 2014;124(11):1765–76.CrossRefPubMedPubMedCentral

38.

Li W, Niu Y, Xiong DC, Cao X, Ye XS. Highly substituted Cyclopentane-CMP conjugates as potent Sialyltransferase inhibitors. J Med Chem. 2015;58(20):7972–90.CrossRefPubMed

39.

Chen JY, Tang YA, Huang SM, Juan HF, LW W, Sun YC, Wang SC, KW W, Balraj G, Chang TT, Li WS, Cheng HC, Wang YCA. Novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways. Cancer Res. 2011;71(2):473–83.CrossRefPubMed

40.

Rillahan CD, Antonopoulos A, Lefort CT, Sonon R, Azadi P, Ley K, Dell A, Haslam SM, Paulson JC. Global metabolic inhibitors of sialyl- and fucosyltransferases remodel the glycome. Nat Chem Biol. 2012;8(7):661–8.CrossRefPubMedPubMedCentral

41.

Rogentine GN Jr, Rowe DS, Bradley J, Waldmann TA, Fahey JL. Metabolism of human immunoglobulin D (IgD). J Clin Invest 1966;45(9):1467–1478.

42.

Vladutiu AO, Immunoglobulin D. Properties, measurement, and clinical relevance. Clin Diagn Lab Immunol. 2000;7(2):131–40.PubMedPubMedCentral

43.

Arnaud P, Dechavanne M, Creyssel R. Metabolism of human monoclonal immunoglobulin D. A study in two patients with monoclonal IgD gammapathy. Biomedicine. 1974;21(2):77–81.PubMed

44.

Arnold JN, Radcliffe CM, Wormald MR, Royle L, Harvey DJ, Crispin M, Dwek RA, Sim RB, Rudd PM. The glycosylation of human serum IgD and IgE and the accessibility of identified oligomannose structures for interaction with mannan-binding lectin. J Immunol. 2004;173(11):6831–40.CrossRefPubMed

Title: N-glycosylation of serum proteins for the assessment of patients with IgD multiple myeloma
Authors: Jie Chen
Meng Fang
Xiaoling Chen
Changhong Yi
Jun Ji
Cheng Cheng
Mengmeng Wang
Xing Gu
Quansheng Sun
Chunfang Gao
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-017-3891-3

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