liu.seSearch for publications in DiVA
Change search
ReferencesLink to record
Permanent link

Direct link
Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy
Spanish National Cancer Research Centre, Spain .
Spanish National Cancer Research Centre, Spain .
Spanish National Cancer Research Centre, Spain .
Karolinska University Hospital, Sweden .
Show others and affiliations
2013 (English)In: Journal of Medical Genetics, ISSN 1468-6244, E-ISSN 1468-6244, Vol. 50, no 9, 599-605 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BMJ Publishing Group , 2013. Vol. 50, no 9, 599-605 p.
Keyword [en]
Genetics, Genome-wide, Molecular genetics, Peripheral nerve disease, Oncology
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-97438DOI: 10.1136/jmedgenet-2012-101466ISI: 000323450200005OAI: diva2:647891

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|

Available from: 2013-09-12 Created: 2013-09-12 Last updated: 2015-03-27

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Åvall-Lundqvist, ElisabethGreen, Henrik
By organisation
Division of Clinical SciencesFaculty of Health SciencesDepartment of OncologyDivision of Drug Research
In the same journal
Journal of Medical Genetics
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 55 hits
ReferencesLink to record
Permanent link

Direct link