Targeted sequencing reveals low-frequency variants in EPHA genes as markers of paclitaxel-induced peripheral neuropathy.

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Targeted sequencing reveals low-frequency variants in EPHA genes as markers of paclitaxel-induced peripheral neuropathy.

Apellániz-Ruiz, Maria (författare): Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain

Tejero, Héctor (författare): Translational Bioinformatics Unit, Spanish National Cancer Research Centre, Madrid, Spain

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

Gutiérrez-Gutiérrez, Gerardo (författare): Neurology Section, Hospital Universitario Infanta Sofía, Madrid, Spain

Calvo, Isabel (författare): Medical Oncology Department, Hospital Montepríncipe, Madrid, Spain. Medical Oncology Department, Centro Integral Oncológico Clara Campal, Madrid, Spain

Castelo, Beatriz (författare): Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain

Redondo, Andrés (författare): Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain

García-Donás, Jesus (författare): Gynecological and Genitourinary Tumors Programme, Centro Integral Oncológico Clara Campal, Madrid, Spain

Romero-Laorden, Nuria (författare): Gynecological and Genitourinary Tumors Programme, Centro Integral Oncológico Clara Campal, Madrid, Spain

Sereno, Maria (författare): Medical Oncology Department, Hospital Universitario Infanta Sofía, Madrid, Spain

Merino, María (författare): Medical Oncology Department, Hospital Universitario Infanta Sofía, Madrid, Spain

Currás-Freixes, Maria (författare): Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain

Montero-Conde, Cristina (författare): Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain

Mancikova, Veronika (författare): Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain

Åvall-Lundqvist, Elisabeth, 1957- (författare): Karolinska Institutet,Linköpings universitet,Avdelningen för Kirurgi, Ortopedi och Onkologi,Medicinska fakulteten,Region Östergötland, Onkologiska kliniken US

Green, Henrik (författare): Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden

Al-Shahrour, Fatima (författare): Translational Bioinformatics Unit, Spanish National Cancer Research Centre, Madrid, Spain

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

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

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.
Ingår i: Clinical Cancer Research. - : American Association of Cancer Research. - 1078-0432 .- 1557-3265. ; 23:5, s. 1227-1235

Relaterad länk:: https://liu.diva-por... (primary) (Raw object); visa fler...; https://urn.kb.se/re...; https://doi.org/10.1...; http://kipublication...; visa färre...

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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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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin

Artiklar i publikationen: Clinical Cancer ...

Av lärosätet: Linköpings universitet; Karolinska Institutet

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Targeted sequencing reveals low-frequency variants in EPHA genes as markers of paclitaxel-induced peripheral neuropathy.

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