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Targeted sequencing...
Targeted sequencing reveals low-frequency variants in EPHA genes as markers of paclitaxel-induced peripheral neuropathy.
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- Apellániz-Ruiz, Maria (författare)
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain
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- Tejero, Héctor (författare)
- Translational Bioinformatics Unit, Spanish National Cancer Research Centre, Madrid, Spain
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- Inglada-Pérez, Lucía (författare)
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain. ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain
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- Sánchez-Barroso, Lara (författare)
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain
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- Gutiérrez-Gutiérrez, Gerardo (författare)
- Neurology Section, Hospital Universitario Infanta Sofía, Madrid, Spain
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- Calvo, Isabel (författare)
- Medical Oncology Department, Hospital Montepríncipe, Madrid, Spain. Medical Oncology Department, Centro Integral Oncológico Clara Campal, Madrid, Spain
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- Castelo, Beatriz (författare)
- Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain
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- Redondo, Andrés (författare)
- Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain
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- García-Donás, Jesus (författare)
- Gynecological and Genitourinary Tumors Programme, Centro Integral Oncológico Clara Campal, Madrid, Spain
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- Romero-Laorden, Nuria (författare)
- Gynecological and Genitourinary Tumors Programme, Centro Integral Oncológico Clara Campal, Madrid, Spain
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- Sereno, Maria (författare)
- Medical Oncology Department, Hospital Universitario Infanta Sofía, Madrid, Spain
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- Merino, María (författare)
- Medical Oncology Department, Hospital Universitario Infanta Sofía, Madrid, Spain
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- Currás-Freixes, Maria (författare)
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain
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- Montero-Conde, Cristina (författare)
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain
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- Mancikova, Veronika (författare)
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain
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- Åvall-Lundqvist, Elisabeth, 1957- (författare)
- Karolinska Institutet,Linköpings universitet,Avdelningen för Kirurgi, Ortopedi och Onkologi,Medicinska fakulteten,Region Östergötland, Onkologiska kliniken US
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- Green, Henrik (författare)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden
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- Al-Shahrour, Fatima (författare)
- Translational Bioinformatics Unit, Spanish National Cancer Research Centre, Madrid, Spain
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- Cascon, Alberto (författare)
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain. ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain
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- Robledo, Mercedes (författare)
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain
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- Rodriguez-Antona, Cristina (författare)
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain.ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain
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(creator_code:org_t)
- American Association of Cancer Research, 2017
- 2017
- Engelska.
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Ingår i: Clinical Cancer Research. - : American Association of Cancer Research. - 1078-0432 .- 1557-3265. ; 23:5, s. 1227-1235
- Relaterad länk:
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https://liu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine (hsv//eng)
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Apellániz-Ruiz, ...
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Tejero, Héctor
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Inglada-Pérez, L ...
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Sánchez-Barroso, ...
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Gutiérrez-Gutiér ...
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Calvo, Isabel
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Castelo, Beatriz
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Redondo, Andrés
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García-Donás, Je ...
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Romero-Laorden, ...
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Sereno, Maria
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Merino, María
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Currás-Freixes, ...
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Montero-Conde, C ...
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Mancikova, Veron ...
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Åvall-Lundqvist, ...
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Green, Henrik
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Al-Shahrour, Fat ...
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Cascon, Alberto
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Robledo, Mercede ...
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Rodriguez-Antona ...
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MEDICIN OCH HÄLS ...
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Clinical Cancer ...
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Linköpings universitet
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Karolinska Institutet