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The importance of a sub-region on chromosome 19q13.3 for prognosis of multiple myeloma patients after high-dose treatment and stem cell support: a linkage disequilibrium mapping in RAI and CD3EAP

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Abstract

The gene RAI was originally described as an inhibitor of RelA/p65 subunit of nuclear factor κB (NF–κB). Here, we analyse the association between genetic variation in the genes RAI and CD3EAP and outcome of 348 myeloma patients treated with high-dose treatment (HDT), 146 patients treated with interferon-α (INF-α) as maintenance treatment, 177 patients treated with thalidomide, and 74 patients treated with bortezomib at relapse and address if the effects of polymorphisms in CD3EAP and RAI are modified by a functional polymorphism in NFКB1. By linkage disequilibrium mapping, we found that variant alleles of several polymorphisms in a sub-region of 19q13.3 spanning the regions RAI-intron1-1 to RAI intron1-3 and the region exon1 to exon3–6 in CD3EAP were associated with prolonged time-to-treatment failure (TTF; p = 0.003) and overall survival (OS; p = 0.02). Haplotype analyses revealed that none of the haplotypes were more strongly associated to TTF or OS than the two strongly linked SNPs, RAI-intron1-1 (rs4572514) and CD3EAP G-21A (rs967591). The association of RAI-intron1-1 and CD3EAP G-21A with TTF was independent of NFKB1-94 ins/del, but homozygous ins-allele carriers which were also variant allele carriers of RAI-intron1-1 or CD3EAP G-21A had the longest OS. Among patients treated with INF-α or thalidomide, no effect was seen in relation to genotype. Our results indicate that polymorphism in RAI and CD3EAP are associated with outcome of myeloma patients treated with HDT. Combination analyses with the functional polymorphism in NFKB1 suggest that a possibly functional effect of RAI or CD3EAP could be related to NF–κB availability.

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Abbreviations

MM:

multiple myeloma

OS:

overall survival

TTF:

time-to-treatment failure

HDT:

high-dose treatment

SNP:

single-nucleotide polymorphism

LD:

linkage disequilibrium

CI:

confidence interval

RR:

relative risk

ERCC1 :

excision-repair cross-complementing 1

ERCC2 :

excision-repair cross-complementing 2

RAI :

RelA associated inhibitor (also named PPP1R13L protein phosphatase 1, regulatory (inhibitor) subunit 13 like and iASPP)

CD3EAP :

CD3e molecule epsilon-associated protein (also named ASE1 anti-sense to ERCC1)

NER:

nucleotide excision repair

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Acknowledgement

We thank Bettina Hansen and Lars Bentzen for expert technical assistance. Participants from the Nordic Myeloma Study Group (NMSG) are thanked. This work was supported by The Research Fund at Region Sjaelland.

Author information

Authors and Affiliations

  1. Department of Oncology and Haematology, Roskilde Hospital, Copenhagen University, DK-4000, Roskilde, Denmark

    Annette J. Vangsted

  2. Department of Haematology, University Hospital of Copenhagen at Herlev, DK-2730, Herlev, Denmark

    Tobias Wirenfeldt Klausen

  3. Department of Haematology, University Hospital of Copenhagen at Rigshospitalet, DK-2100, Copenhagen, Denmark

    Peter Gimsing

  4. Department of Haematology, Odense University Hospital, DK-5000, Odense, Denmark

    Niels Abildgaard

  5. Department of Haematology, Aarhus University Hospital, DK-8000, Aarhus, Denmark

    Niels F. Andersen

  6. Department of Haematology, Aalborg University Hospital, DK-9100, Aalborg, Denmark

    Henrik Gregersen

  7. Institute of Human Genetics, University of Aarhus, DK-8000, Aarhus C, Denmark

    Bjørn Andersen Nexø

  8. National Food Institute, Technical University of Denmark, DK-2860, Copenhagen, Denmark

    Ulla Birgitte Vogel

  9. National Research Centre for the Working Environment, DK-2100, Copenhagen, Denmark

    Ulla Birgitte Vogel

  10. Department of Oncology and Haematology Roskilde Hospital, Copenhagen University, Køgevej 9-13, 4000, Roskilde, Denmark

    Annette J. Vangsted

Authors
  1. Annette J. Vangsted
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  2. Tobias Wirenfeldt Klausen
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  3. Peter Gimsing
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  4. Niels Abildgaard
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  5. Niels F. Andersen
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  6. Henrik Gregersen
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  7. Bjørn Andersen Nexø
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  8. Ulla Birgitte Vogel
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Corresponding author

Correspondence to Annette J. Vangsted.

Electronic supplementary material

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ESM 1

(DOC 46 kb)

ESM 2

The genotype frequency of SNPs in the genes XPD, RAI, CD3EAP and ERCC1 located in the sub-region 19q13.3 (DOC 76 kb)

ESM 3

Characteristics of the patient population subdivided by the polymorphisms. (DOC 48 kb)

ESM 4

Supplement. Combination analysis of NFKB1-94ins/del, CD3EAP G-21A and RAI-intron1-1 (DOC 41 kb)

ESM 5

Linkage disequilibrium among 33 SNPs in the genes ERCC2, RAI and ERCC1. Plot of relative D’/LOD scores between the 33 SNPs from 348 Caucasian multiple myeloma patients produced by the programme Haplo-view (http://www.broad.mit.eud/mpg/haploview). Blue arrows: SNPs represented in haplotype analysis including RAI, ASE1 and ERCC1. Red arrows: SNPs represented in haplotype analysis in the gene CD3EAP (PPT 234 kb)

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Vangsted, A.J., Klausen, T.W., Gimsing, P. et al. The importance of a sub-region on chromosome 19q13.3 for prognosis of multiple myeloma patients after high-dose treatment and stem cell support: a linkage disequilibrium mapping in RAI and CD3EAP . Ann Hematol 90, 675–684 (2011). https://doi.org/10.1007/s00277-010-1105-z

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  • DOI: https://doi.org/10.1007/s00277-010-1105-z

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