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Sökning: WFRF:(Robledo Mercedes) > (2010-2014) > Genome-wide associa...

  • Leandro-Garcia, Luis J.Spanish National Cancer Research Centre, Spain (författare)

Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy

  • Artikel/kapitelEngelska2013

Förlag, utgivningsår, omfång ...

  • 2013-06-17
  • BMJ Publishing Group Ltd,2013
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:liu-97438
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-97438URI
  • https://doi.org/10.1136/jmedgenet-2012-101466DOI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-128467URI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:127250659URI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Funding Agencies|Spanish Ministry of Science and Innovation|SAF2006-01139SAF2009-08307|Spanish Ministry of Economy and Competiveness|SAF2012-35779|Swedish Cancer Society||Swedish Research Council||Fondkistan||Stiftelsen Sigurd och Elsa Goljes Minne and Markus Borgstroms stiftelse||Cancer Research Funds of Radiumhemmet||FIS fellowship|FI08/00375|
  • QC 20130912
  • Background Peripheral neuropathy is the dose limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat solid tumours. This toxicity exhibits great inter-individual variability of unknown origin. The present study aimed to identify genetic variants associated with paclitaxel induced neuropathy via a whole genome approach. less thanbrgreater than less thanbrgreater thanMethods A genome-wide association study (GWAS) was performed in 144 white European patients uniformly treated with paclitaxel/carboplatin and for whom detailed data on neuropathy was available. Per allele single nucleotide polymorphism (SNP) associations were assessed by Cox regression, modelling the cumulative dose of paclitaxel up to the development of grade 2 sensory neuropathy. less thanbrgreater than less thanbrgreater thanResults The strongest evidence of association was observed for the ephrin type A receptor 4 (EPHA4) locus (rs17348202, p=1.0x10(-6)), and EPHA6 and EPHA5 were among the top 25 and 50 hits (rs301927, p=3.4x10(-5) and rs1159057, p=6.8x10(-5)), respectively. A meta-analysis of EPHA5-rs7349683, the top marker for paclitaxel induced neuropathy in a previous GWAS (r(2)=0.79 with rs1159057), gave a hazard ratio (HR) estimate of 1.68 (p=1.4x10(-9)). Meta-analysis of the second hit of this GWAS, XKR4-rs4737264, gave a HR of 1.71 (p=3.1x10(-8)). Imputed SNPs at LIMK2 locus were also strongly associated with this toxicity (HR=2.78, p=2.0x10(-7)). less thanbrgreater than less thanbrgreater thanConclusions This study provides independent support of EPHA5-rs7349683 and XKR4-rs4737264 as the first markers of risk of paclitaxel induced neuropathy. In addition, it suggests that other EPHA genes also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualised paclitaxel chemotherapy.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Inglada-Perez, LuciaSpanish National Cancer Research Centre, Spain (författare)
  • Pita, GuillermoSpanish National Cancer Research Centre, Spain (författare)
  • Hjerpe, ElisabetKarolinska Institutet (författare)
  • Leskelae, SusannaSpanish National Cancer Research Centre, Spain (författare)
  • Jara, CarlosFdn Hospital Alcorcon, Spain (författare)
  • Mielgo, XabierFdn Hospital Alcorcon, Spain (författare)
  • Gonzalez-Neira, AnnaSpanish National Cancer Research Centre, Spain (författare)
  • Robledo, MercedesSpanish National Cancer Research Centre, Spain (författare)
  • Åvall-Lundqvist, ElisabethKarolinska Institutet,Linköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet,Region Östergötland, Onkologiska kliniken US,Karolinska University Hospital, Sweden(Swepub:liu)eliav51 (författare)
  • Green, HenrikKTH,Linköpings universitet,Avdelningen för läkemedelsforskning,Hälsouniversitetet,Genteknologi,Science for Life Laboratory, SciLifeLab(Swepub:kth)u11x12gx (författare)
  • Rodriguez-Antona, CristinaSpanish National Cancer Research Centre, Spain (författare)
  • Karolinska InstitutetSpanish National Cancer Research Centre, Spain (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Journal of Medical Genetics: BMJ Publishing Group Ltd50:9, s. 599-6050022-25931468-6244

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