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  • Chattopadhyay, SubhayanGerman Cancer Research Centre,Heidelberg University (author)

Enrichment of B cell receptor signaling and epidermal growth factor receptor pathways in monoclonal gammopathy of undetermined significance : a genome-wide genetic interaction study

  • Article/chapterEnglish2018

Publisher, publication year, extent ...

  • 2018-06-11
  • Springer Science and Business Media LLC,2018

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:2d6c4e63-9a82-4dc0-abff-29615a036852
  • https://lup.lub.lu.se/record/2d6c4e63-9a82-4dc0-abff-29615a036852URI
  • https://doi.org/10.1186/s10020-018-0031-8DOI

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  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • BACKGROUND: Recent identification of 10 germline variants predisposing to monoclonal gammopathy of undetermined significance (MGUS) explicates genetic dependency of this asymptomatic precursor condition with multiple myeloma (MM). Yet much of genetic burden as well as functional links remain unexplained. We propose a workflow to expand the search for susceptibility loci with genome-wide interaction and for subsequent identification of genetic clusters and pathways.METHODS: Polygenic interaction analysis on 243 cases/1285 controls identified 14 paired risk loci belonging to unique chromosomal bands which were then replicated in two independent sets (case only study, 82 individuals; case/control study 236 cases/ 2484 controls). Further investigation on gene-set enrichment, regulatory pathway and genetic network was carried out with stand-alone in silico tools separately for both interaction and genome-wide association study-detected risk loci.RESULTS: Intronic-PREX1 (20q13.13), a reported locus predisposing to MM was confirmed to have contribution to excess MGUS risk in interaction with SETBP1, a well-established candidate predisposing to myeloid malignancies. Pathway enrichment showed B cell receptor signaling pathway (P < 5.3 × 10- 3) downstream to allograft rejection pathway (P < 5.6 × 10- 4) and autoimmune thyroid disease pathway (P < 9.3 × 10- 4) as well as epidermal growth factor receptor regulation pathway (P < 2.4 × 10- 2) to be differentially regulated. Oncogene ALK and CDH2 were also identified to be moderately interacting with rs10251201 and rs16966921, two previously reported risk loci for MGUS.CONCLUSIONS: We described novel pathways and variants potentially causal for MGUS. The methodology thus proposed to facilitate our search streamlines risk locus-based interaction, genetic network and pathway enrichment analyses.

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Added entries (persons, corporate bodies, meetings, titles ...)

  • Thomsen, HaukeGerman Cancer Research Centre(Swepub:lu)med-hth (author)
  • da Silva Filho, Miguel InacioGerman Cancer Research Centre(Swepub:lu)med-md_ (author)
  • Weinhold, NielsUniversity of Arkansas for Medical Sciences (author)
  • Hoffmann, PerUniversity of Basel (author)
  • Nöthen, Markus MUniversity of Bonn (author)
  • Marina, ArendtUniversity of Duisburg-Essen (author)
  • Jöckel, Karl-HeinzUniversity of Duisburg-Essen (author)
  • Schmidt, BörgeUniversity of Duisburg-Essen (author)
  • Pechlivanis, SonaliUniversity of Duisburg-Essen (author)
  • Langer, ChristianUniversity of Ulm (author)
  • Goldschmidt, HartmutNational Centre of Tumor Diseases (author)
  • Hemminki, KariLund University,Lunds universitet,Allmänmedicin och klinisk epidemiologi,Forskargrupper vid Lunds universitet,Family Medicine and Clinical Epidemiology,Lund University Research Groups,German Cancer Research Centre(Swepub:lu)med-khk (author)
  • Försti, AstaLund University,Lunds universitet,Allmänmedicin och klinisk epidemiologi,Forskargrupper vid Lunds universitet,Family Medicine and Clinical Epidemiology,Lund University Research Groups,German Cancer Research Centre(Swepub:lu)med-asf (author)
  • German Cancer Research CentreHeidelberg University (creator_code:org_t)

Related titles

  • In:Molecular Medicine: Springer Science and Business Media LLC24:11528-36581076-1551

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