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Targeted sequencing reveals low-frequency variants in EPHA genes as markers of paclitaxel-induced peripheral neuropathy.
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
Translational Bioinformatics Unit, Spanish National Cancer Research Centre, Madrid, Spain.
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain. ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.
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2017 (engelsk)Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, nr 5, s. 1227-1235Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

PURPOSE: Neuropathy is the dose limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for inter-individual differences remain unexplained. In this study we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes.

EXPERIMENTAL DESIGN: We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics and 30 Charcot-Marie-Tooth genes, in 228 cancer patients with no/low neuropathy or high grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/ gene-based analyses were used to compare variant frequencies among neuropathy groups and Cox regression models were used to analyze neuropathy evolution along treatment.

RESULTS: Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low frequency non-synonymous variants in EPHA6 were present exclusively in patients with high neuropathy and all affected the ligand binding domain. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency non-synonymous variant carriers (HR=14.60, 95%CI=2.33-91.62, P=0.0042) and an independent cohort confirmed an increased neuropathy risk (HR=2.07, 95%CI=1.14-3.77, P=0.017). Combining the series gave an estimated 2.50-fold higher risk of neuropathy (95%CI=1.46-4.31; P=9.1x10(-4)).

CONCLUSION: This first study sequencing EPHA genes revealed that low frequency variants in EPHA6, EPHA5 and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHAs neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs.

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American Association of Cancer Research , 2017. Vol. 23, nr 5, s. 1227-1235
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Identifikatorer
URN: urn:nbn:se:liu:diva-133683DOI: 10.1158/1078-0432.CCR-16-0694ISI: 000396015600014PubMedID: 27582484Scopus ID: 2-s2.0-85014608950OAI: oai:DiVA.org:liu-133683DiVA, id: diva2:1062614
Merknad

Funding agencies: Spanish Ministry of Economy and Competiveness [SAF2015-64850-R]; Severo Ochoa Excellence Programme [SEV-2011-0191]; Fundacion AECC; Swedish Cancer Society; Swedish Research Council; LiU Cancer

Tilgjengelig fra: 2017-01-07 Laget: 2017-01-07 Sist oppdatert: 2018-04-17bibliografisk kontrollert

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