Henrik Green | Linköping University (original) (raw)

Papers by Henrik Green

Forensic Science International

Journal of Analytical Toxicology

Oxycodone is an opioid with strong analgesic effects widely used to treat acute and chronic pain.... more Oxycodone is an opioid with strong analgesic effects widely used to treat acute and chronic pain. Interpretation of oxycodone concentrations in postmortem cases is complicated due to tolerance and overlapping concentrations for fatal and non-fatal levels. In this study, our aim was to develop and validate a method for oxycodone and its three metabolites: noroxycodone, oxymorphone, and noroxymorphone in postmortem femoral blood. Our goal was to define reference concentrations for intoxications and non-intoxications, and investigate metabolic ratios in different causes of death. A rapid LC–MS-MS method using protein precipitated postmortem blood was developed. LLOQ was 0.005 μg/g blood for all analytes, ULOQ was 1.0 μg/g for oxycodone and noroxycodone, and 0.25 μg/g for oxymorphone and noroxymorphone. The method displayed high precision (3.3–7.7%) and low bias (−0.3–12%). In total, 192 cases were analysed and concentrations ranged from 0.005–13 μg/g for oxycodone, 0.005–2.0 μg/g for n...

Background In recent years treatment options for advanced pancreatic cancer has markedly improved... more Background In recent years treatment options for advanced pancreatic cancer has markedly improved, and a combination regimen of gemcitabine and nab-paclitaxel is now considered standard of care in Sweden and elsewhere. Nevertheless, a majority of patients do not respond to treatment. In order to guide the individual patient to the most beneficial therapeutic strategy, simple and easily available prognostic and predictive markers are needed.Methods The potential prognostic value of a range of blood/serum parameters, patient-, and tumour characteristics was explored in a retrospective cohort of 75 patients treated with gemcitabine/nab-paclitaxel (Gem/NabP) for advanced pancreatic ductal adenocarcinoma (PDA) in the South Eastern Region of Sweden. Primary outcome was overall survival while progression free survival was the key secondary outcome.Result Univariable Cox regression analysis revealed that high baseline serum albumin (> 37 g/L) and high age (>65) were positive prognosti...

The Pharmacogenomics Journal

Drug Testing and Analysis

Metabolomics can be defined as the scientific field aiming at characterizing all low-weight molec... more Metabolomics can be defined as the scientific field aiming at characterizing all low-weight molecules (so-called metabolites) in a biological system. At the time of death, the level and type of metabolites present will most likely reflect the events leading up to death.In this proof of concept study, we investigated the potential of post-mortem metabolomics by identifying post-mortem biomarkers, correlated these identified biomarkers with those reported in clinical metabolomics studies, and finally validated the models predictability of unknown autopsy cases. In this post-mortem metabolomics setting, ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry data from 404 post-mortem samples, including pneumonia cases and control cases, were processed using XCMS (R). Potential biomarkers were evaluated using principal component analysis and orthogonal partial least squares-discriminant analysis. Biomarkers were putatively annotated using an inhouse database and the online databases METLIN and HMDB. The results showed that clear group separation was observed between pneumonia cases and control cases. The metabolites responsible for group separation belonged to a broad set of biological classes, such as amino acids, carnitines, lipids, nicotinamides, nucleotides, and steroids. Many of these metabolites have been reported as important in clinical manifestation of pneumonia. For the unknown autopsy cases, the sensitivity and specificity were 86 and 84%, respectively. This study successfully investigated the robustness and usability of post-mortem metabolomics in death investigations. The identified post-mortem biomarkers correlated well with biomarkers reported and identified through clinical research.

Genes

Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will al... more Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested “gene-negative” for familial predominantly pediatric CM, in hopes of finding a causative gene variant. Methods: 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with “gene-negative” results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel. Results: The mean age at clinical pre...

Genes

Treatments that include gemcitabine and carboplatin induce dose-limiting myelosuppression. The un... more Treatments that include gemcitabine and carboplatin induce dose-limiting myelosuppression. The understanding of how human bone marrow is affected on a transcriptional level leading to the development of myelosuppression is required for the implementation of personalized treatments in the future. In this study, we treated human hematopoietic stem and progenitor cells (HSPCs) harvested from a patient with chronic myelogenous leukemia (CML) with gemcitabine/carboplatin. Thereafter, scRNA-seq was performed to distinguish transcriptional effects induced by gemcitabine/carboplatin. Gene expression was calculated and evaluated among cells within and between samples compared to untreated cells. Cell cycle analysis showed that the treatments effectively decrease cell proliferation, indicated by the proportion of cells in the G2M-phase dropping from 35% in untreated cells to 14.3% in treated cells. Clustering and t-SNE showed that cells within samples and between treated and untreated samples...

Drug Testing and Analysis

DNA immunoprecipitation sequencing (DIP-seq) is a common enrichment method for profiling DNA modi... more DNA immunoprecipitation sequencing (DIP-seq) is a common enrichment method for profiling DNA modifications in mammalian genomes. However, DIP-seq profiles often exhibit significant variation between independent studies of the same genome and from profiles obtained by alternative methods. Here we show that these differences are primarily due to intrinsic affinity of IgG for short unmodified DNA repeats. This pervasive experimental error accounts for 50 – 99% of regions identified as ‘enriched’ for DNA modifications in DIP-seq data. Correction of this error profoundly alters DNA modification profiles for numerous cell types, including mouse embryonic stem cells, and subsequently reveals novel associations between DNA modifications, chromatin modifications and biological processes. We propose new methodological guidelines that minimize the impact of these errors on future DIP-seq experiments and allow new insights to be made from the wealth of existing DIP-seq data.

International Journal of Legal Medicine

Cancer chemotherapy and pharmacology, 2018

Despite therapeutic advances, patients with multiple myeloma (MM) continue to experience disease ... more Despite therapeutic advances, patients with multiple myeloma (MM) continue to experience disease relapse and treatment resistance. The gene ABCB1 encodes the drug transporter P-glycoprotein, which confers resistance through drug extrusion across the cell membrane. Lenalidomide (Len) is excreted mainly via the kidneys, and, given the expression of P-gp in the renal tubuli, single-nucleotide polymorphisms (SNPs) in the ABCB1 gene may influence Len plasma concentrations and, subsequently, the outcome of treatment. We, therefore, investigated the influence of ABCB1 genetic variants on Len treatment outcomes and adverse events (AEs). Ninety patients with relapsed or refractory MM, who received the second-line Len plus dexamethasone in the Rev II trial, were genotyped for the ABCB1 SNPs 1199G>A (Ser400Asn, rs2229109), 1236C>T (silent, rs1128503), 2677G>T/A (Ala893Ser, rs2032582), and 3435C>T (silent, rs1045642) using pyrosequencing, and correlations to response parameters, out...

The AAPS Journal

New fentanyl analogs have recently emerged as new psychoactive substances and have caused numerou... more New fentanyl analogs have recently emerged as new psychoactive substances and have caused numerous fatalities worldwide. To determine if the new analogs follow the same metabolic pathways elucidated for fentanyl and known fentanyl analogs, we performed in vitro and in vivo metabolite identification studies for acetylfentanyl, acrylfentanyl, 4-fluoroisobutyrylfentanyl and furanylfentanyl. All compounds were incubated at 10 µM with pooled human hepatocytes for up to 5 h. For each compound, four or five authentic human urine samples from autopsy cases with and without enzymatic hydrolysis were analyzed. Data acquisition was performed in data-dependent acquisition mode during liquid-chromatography high-resolution mass spectrometry analyses. Data was analyzed 1) manually based on predicted biotransformations and 2) with MetaSense software using data-driven search algorithms. Acetylfentanyl, acrylfentanyl and 4-fluoroisobutyrylfentanyl were predominantly metabolized by Ndealkylation, cleaving off the phenethyl moiety, monohydroxylation at the ethyl linker and piperidine ring as well as hydroxylation/methoxylation at the phenyl ring. In contrast, furanylfentanyl's major metabolites were generated by amide hydrolysis and dihydrodiol formation while the nor-metabolite was minor or not detected in case samples at all. In general, in vitro results matched the in vivo findings well, showing identical biotransformations in each system. Phase II conjugation was observed, particularly for acetylfentanyl. Based on our results, we suggest the following specific and abundant metabolites as analytical targets in urine: a hydroxymethoxy and monohydroxylated metabolite for acetylfentanyl; a monohydroxy and dihydroxy metabolite for acrylfentanyl; two monohydroxy metabolites and a hydroxymethoxy metabolite for 4-fluoro-isobutyrylfentanyl and a dihydrodiol metabolite and the amide hydrolysis metabolite for furanylfentanyl.

Tetrahedron Letters, 2017

Studies on the metabolism of bioactive substances containing the adamantyl moiety have shown that... more Studies on the metabolism of bioactive substances containing the adamantyl moiety have shown that hydroxylation is likely to occur at a tertiary carbon of adamantane. Herein, we report the synthesis and identification of one major metabolite of AKB-48, a new illicit psychoactive substance with a hydroxyl group at a secondary carbon of the adamantyl ring.

The AAPS journal, Jan 13, 2017

Meclonazepam is a benzodiazepine patented in 1977 to treat parasitic worms, which recently appear... more Meclonazepam is a benzodiazepine patented in 1977 to treat parasitic worms, which recently appeared as a designer benzodiazepine and drug of abuse. The aim of this study was to identify metabolites suitable as biomarkers of drug intake in urine using high-resolution mass spectrometry, authentic urine samples, and different model systems including human liver microsomes, cryopreserved hepatocytes, and a mice model. The main metabolites of meclonazepam found in human urine were amino-meclonazepam and acetamido-meclonazepam; also, minor peaks for meclonazepam were observed in three of four urine samples. These observations are consistent with meclonazepam having a metabolism similar to that of other nitro containing benzodiazepines such as clonazepam, flunitrazepam, and nitrazepam. Both metabolites were produced by the hepatocytes and in the mice model, but the human liver microsomes were only capable of producing minor amounts of the amino metabolite. However, under nitrogen, the amou...

Forensic science international, Jan 5, 2016

Flubromazolam is a triazolam benzodiazepine that recently emerged as a new psychoactive substance... more Flubromazolam is a triazolam benzodiazepine that recently emerged as a new psychoactive substance. Since metabolism data are scarce and good analytical targets besides the parent are unknown, we investigated flubromazolam metabolism in vitro and in vivo. 10μmol/L flubromazolam was incubated with human liver microsomes for 1h and with cryopreserved human hepatocytes for 5h. Mice were administered 0.5 or 1.0mg flubromazolam/kg body weight intraperitoneally, urine was collected for 24h. All samples, together with six authentic forensic human case specimens, were analyzed (with or without hydrolysis, in case it was urine) by UHPLC-HRMS on an Acquity HSS T3 column with an Agilent 6550 QTOF. Data mining was performed manually and with MassMetasite software (Molecular Discovery). A total of nine metabolites were found, all generated by hydroxylation and/or glucuronidation. Besides O-glucuronidation, flubromazolam formed an N(+)-glucuronide. Flubromazolam was not metabolized extensively in ...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 31, 2016

Neuropathy is the dose limiting toxicity of paclitaxel and a major cause for decreased quality of... more 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. 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. Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced ...

Clinical Cancer Research, 2007

Forensic Science International

Journal of Analytical Toxicology

Oxycodone is an opioid with strong analgesic effects widely used to treat acute and chronic pain.... more Oxycodone is an opioid with strong analgesic effects widely used to treat acute and chronic pain. Interpretation of oxycodone concentrations in postmortem cases is complicated due to tolerance and overlapping concentrations for fatal and non-fatal levels. In this study, our aim was to develop and validate a method for oxycodone and its three metabolites: noroxycodone, oxymorphone, and noroxymorphone in postmortem femoral blood. Our goal was to define reference concentrations for intoxications and non-intoxications, and investigate metabolic ratios in different causes of death. A rapid LC–MS-MS method using protein precipitated postmortem blood was developed. LLOQ was 0.005 μg/g blood for all analytes, ULOQ was 1.0 μg/g for oxycodone and noroxycodone, and 0.25 μg/g for oxymorphone and noroxymorphone. The method displayed high precision (3.3–7.7%) and low bias (−0.3–12%). In total, 192 cases were analysed and concentrations ranged from 0.005–13 μg/g for oxycodone, 0.005–2.0 μg/g for n...

Background In recent years treatment options for advanced pancreatic cancer has markedly improved... more Background In recent years treatment options for advanced pancreatic cancer has markedly improved, and a combination regimen of gemcitabine and nab-paclitaxel is now considered standard of care in Sweden and elsewhere. Nevertheless, a majority of patients do not respond to treatment. In order to guide the individual patient to the most beneficial therapeutic strategy, simple and easily available prognostic and predictive markers are needed.Methods The potential prognostic value of a range of blood/serum parameters, patient-, and tumour characteristics was explored in a retrospective cohort of 75 patients treated with gemcitabine/nab-paclitaxel (Gem/NabP) for advanced pancreatic ductal adenocarcinoma (PDA) in the South Eastern Region of Sweden. Primary outcome was overall survival while progression free survival was the key secondary outcome.Result Univariable Cox regression analysis revealed that high baseline serum albumin (> 37 g/L) and high age (>65) were positive prognosti...

The Pharmacogenomics Journal

Drug Testing and Analysis

Metabolomics can be defined as the scientific field aiming at characterizing all low-weight molec... more Metabolomics can be defined as the scientific field aiming at characterizing all low-weight molecules (so-called metabolites) in a biological system. At the time of death, the level and type of metabolites present will most likely reflect the events leading up to death.In this proof of concept study, we investigated the potential of post-mortem metabolomics by identifying post-mortem biomarkers, correlated these identified biomarkers with those reported in clinical metabolomics studies, and finally validated the models predictability of unknown autopsy cases. In this post-mortem metabolomics setting, ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry data from 404 post-mortem samples, including pneumonia cases and control cases, were processed using XCMS (R). Potential biomarkers were evaluated using principal component analysis and orthogonal partial least squares-discriminant analysis. Biomarkers were putatively annotated using an inhouse database and the online databases METLIN and HMDB. The results showed that clear group separation was observed between pneumonia cases and control cases. The metabolites responsible for group separation belonged to a broad set of biological classes, such as amino acids, carnitines, lipids, nicotinamides, nucleotides, and steroids. Many of these metabolites have been reported as important in clinical manifestation of pneumonia. For the unknown autopsy cases, the sensitivity and specificity were 86 and 84%, respectively. This study successfully investigated the robustness and usability of post-mortem metabolomics in death investigations. The identified post-mortem biomarkers correlated well with biomarkers reported and identified through clinical research.

Genes

Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will al... more Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested “gene-negative” for familial predominantly pediatric CM, in hopes of finding a causative gene variant. Methods: 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with “gene-negative” results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel. Results: The mean age at clinical pre...

Genes

Treatments that include gemcitabine and carboplatin induce dose-limiting myelosuppression. The un... more Treatments that include gemcitabine and carboplatin induce dose-limiting myelosuppression. The understanding of how human bone marrow is affected on a transcriptional level leading to the development of myelosuppression is required for the implementation of personalized treatments in the future. In this study, we treated human hematopoietic stem and progenitor cells (HSPCs) harvested from a patient with chronic myelogenous leukemia (CML) with gemcitabine/carboplatin. Thereafter, scRNA-seq was performed to distinguish transcriptional effects induced by gemcitabine/carboplatin. Gene expression was calculated and evaluated among cells within and between samples compared to untreated cells. Cell cycle analysis showed that the treatments effectively decrease cell proliferation, indicated by the proportion of cells in the G2M-phase dropping from 35% in untreated cells to 14.3% in treated cells. Clustering and t-SNE showed that cells within samples and between treated and untreated samples...

Drug Testing and Analysis

DNA immunoprecipitation sequencing (DIP-seq) is a common enrichment method for profiling DNA modi... more DNA immunoprecipitation sequencing (DIP-seq) is a common enrichment method for profiling DNA modifications in mammalian genomes. However, DIP-seq profiles often exhibit significant variation between independent studies of the same genome and from profiles obtained by alternative methods. Here we show that these differences are primarily due to intrinsic affinity of IgG for short unmodified DNA repeats. This pervasive experimental error accounts for 50 – 99% of regions identified as ‘enriched’ for DNA modifications in DIP-seq data. Correction of this error profoundly alters DNA modification profiles for numerous cell types, including mouse embryonic stem cells, and subsequently reveals novel associations between DNA modifications, chromatin modifications and biological processes. We propose new methodological guidelines that minimize the impact of these errors on future DIP-seq experiments and allow new insights to be made from the wealth of existing DIP-seq data.

International Journal of Legal Medicine

Cancer chemotherapy and pharmacology, 2018

Despite therapeutic advances, patients with multiple myeloma (MM) continue to experience disease ... more Despite therapeutic advances, patients with multiple myeloma (MM) continue to experience disease relapse and treatment resistance. The gene ABCB1 encodes the drug transporter P-glycoprotein, which confers resistance through drug extrusion across the cell membrane. Lenalidomide (Len) is excreted mainly via the kidneys, and, given the expression of P-gp in the renal tubuli, single-nucleotide polymorphisms (SNPs) in the ABCB1 gene may influence Len plasma concentrations and, subsequently, the outcome of treatment. We, therefore, investigated the influence of ABCB1 genetic variants on Len treatment outcomes and adverse events (AEs). Ninety patients with relapsed or refractory MM, who received the second-line Len plus dexamethasone in the Rev II trial, were genotyped for the ABCB1 SNPs 1199G>A (Ser400Asn, rs2229109), 1236C>T (silent, rs1128503), 2677G>T/A (Ala893Ser, rs2032582), and 3435C>T (silent, rs1045642) using pyrosequencing, and correlations to response parameters, out...

The AAPS Journal

New fentanyl analogs have recently emerged as new psychoactive substances and have caused numerou... more New fentanyl analogs have recently emerged as new psychoactive substances and have caused numerous fatalities worldwide. To determine if the new analogs follow the same metabolic pathways elucidated for fentanyl and known fentanyl analogs, we performed in vitro and in vivo metabolite identification studies for acetylfentanyl, acrylfentanyl, 4-fluoroisobutyrylfentanyl and furanylfentanyl. All compounds were incubated at 10 µM with pooled human hepatocytes for up to 5 h. For each compound, four or five authentic human urine samples from autopsy cases with and without enzymatic hydrolysis were analyzed. Data acquisition was performed in data-dependent acquisition mode during liquid-chromatography high-resolution mass spectrometry analyses. Data was analyzed 1) manually based on predicted biotransformations and 2) with MetaSense software using data-driven search algorithms. Acetylfentanyl, acrylfentanyl and 4-fluoroisobutyrylfentanyl were predominantly metabolized by Ndealkylation, cleaving off the phenethyl moiety, monohydroxylation at the ethyl linker and piperidine ring as well as hydroxylation/methoxylation at the phenyl ring. In contrast, furanylfentanyl's major metabolites were generated by amide hydrolysis and dihydrodiol formation while the nor-metabolite was minor or not detected in case samples at all. In general, in vitro results matched the in vivo findings well, showing identical biotransformations in each system. Phase II conjugation was observed, particularly for acetylfentanyl. Based on our results, we suggest the following specific and abundant metabolites as analytical targets in urine: a hydroxymethoxy and monohydroxylated metabolite for acetylfentanyl; a monohydroxy and dihydroxy metabolite for acrylfentanyl; two monohydroxy metabolites and a hydroxymethoxy metabolite for 4-fluoro-isobutyrylfentanyl and a dihydrodiol metabolite and the amide hydrolysis metabolite for furanylfentanyl.

Tetrahedron Letters, 2017

Studies on the metabolism of bioactive substances containing the adamantyl moiety have shown that... more Studies on the metabolism of bioactive substances containing the adamantyl moiety have shown that hydroxylation is likely to occur at a tertiary carbon of adamantane. Herein, we report the synthesis and identification of one major metabolite of AKB-48, a new illicit psychoactive substance with a hydroxyl group at a secondary carbon of the adamantyl ring.

The AAPS journal, Jan 13, 2017

Meclonazepam is a benzodiazepine patented in 1977 to treat parasitic worms, which recently appear... more Meclonazepam is a benzodiazepine patented in 1977 to treat parasitic worms, which recently appeared as a designer benzodiazepine and drug of abuse. The aim of this study was to identify metabolites suitable as biomarkers of drug intake in urine using high-resolution mass spectrometry, authentic urine samples, and different model systems including human liver microsomes, cryopreserved hepatocytes, and a mice model. The main metabolites of meclonazepam found in human urine were amino-meclonazepam and acetamido-meclonazepam; also, minor peaks for meclonazepam were observed in three of four urine samples. These observations are consistent with meclonazepam having a metabolism similar to that of other nitro containing benzodiazepines such as clonazepam, flunitrazepam, and nitrazepam. Both metabolites were produced by the hepatocytes and in the mice model, but the human liver microsomes were only capable of producing minor amounts of the amino metabolite. However, under nitrogen, the amou...

Forensic science international, Jan 5, 2016

Flubromazolam is a triazolam benzodiazepine that recently emerged as a new psychoactive substance... more Flubromazolam is a triazolam benzodiazepine that recently emerged as a new psychoactive substance. Since metabolism data are scarce and good analytical targets besides the parent are unknown, we investigated flubromazolam metabolism in vitro and in vivo. 10μmol/L flubromazolam was incubated with human liver microsomes for 1h and with cryopreserved human hepatocytes for 5h. Mice were administered 0.5 or 1.0mg flubromazolam/kg body weight intraperitoneally, urine was collected for 24h. All samples, together with six authentic forensic human case specimens, were analyzed (with or without hydrolysis, in case it was urine) by UHPLC-HRMS on an Acquity HSS T3 column with an Agilent 6550 QTOF. Data mining was performed manually and with MassMetasite software (Molecular Discovery). A total of nine metabolites were found, all generated by hydroxylation and/or glucuronidation. Besides O-glucuronidation, flubromazolam formed an N(+)-glucuronide. Flubromazolam was not metabolized extensively in ...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 31, 2016

Neuropathy is the dose limiting toxicity of paclitaxel and a major cause for decreased quality of... more 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. 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. Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced ...

Clinical Cancer Research, 2007