No abstract

Purpose: Paclitaxel, a widely used chemotherapeutic drug, can cause peripheral neuropathies leading to dose reductions and treatment suspensions and decreasing the quality of life of patients. It has been suggested that genetic variants altering paclitaxel pharmacokinetics increase neuropathy risk, but the major causes of interindividual differences in susceptibility to paclitaxel toxicity remain unexplained. We carried out a wholeexome sequencing (WES) study to identify genetic susceptibility variants associated with paclitaxel neuropathy.Experimental Design: Blood samples from 8 patients with severe paclitaxel-induced peripheral neuropathy were selected for WES. An independent cohort of 228 cancer patients with complete paclitaxel neuropathy data was used for variant screening by DHPLC and association analysis. HEK293 cells were used for heterologous expression and characterization of two novel CYP3A4 enzymes.Results: WES revealed 2 patients with rare CYP3A4 variants, a premature stop codon (CYP3A4 Ã 20 allele) and a novel missense variant (CYP3A4 Ã 25, p.P389S) causing reduced enzyme expression. Screening for CYP3A4 variants in the independent cohort revealed three additional CYP3A4 Ã 20 carriers, and two patients with missense variants exhibiting diminished enzyme activity (CYP3A4 Ã 8 and the novel CYP3A4 Ã 27 allele, p.L475V). Relative to CYP3A4 wild-type patients, those carrying CYP3A4 defective variants had more severe neuropathy (2-and 1.3-fold higher risk of neuropathy for loss-of-function and missense variants, respectively, P ¼ 0.045) and higher probability of neuropathy-induced paclitaxel treatment modifications (7-and 3-fold higher risk for loss-of-function and missense variants, respectively, P ¼ 5.9 Â 10 À5 ).Conclusion: This is the first description of a genetic marker associated with paclitaxel treatment modifications caused by neuropathy. CYP3A4 defective variants may provide a basis for paclitaxel treatment individualization.

Purpose-Recently, we observed that telomeres of BRCA1/2 mutation carriers were shorter than those of controls or sporadic breast cancer patients, suggesting that mutations in these genes might be responsible for this event. Given the contradictory results reported in the literature, we tested whether other parameters, such as chemotherapy, could be modifying telomere-length.Methods-We performed a cross-sectional study measuring leukocyte telomere-length of 266 sporadic breasts cancer patients treated with first-line chemotherapy, with a median follow up of 240 days.Additionally, we performed both cross-sectional and longitudinal studies in a series of 236 familial breast cancer patients that included affected and non-affected BRCA1/2 mutation carriers. We Ethical standards:The authors declare that this work complies with current Spanish laws. Conflict of interest:The authors declare that they have no conflicts of interest. Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts have measured in leukocytes from peripheral blood: The telomere-length, percentage of short telomeres (<3Kb), telomerase activity levels and the annual telomere shortening speed.Results-In sporadic cases we found that chemotherapy exerts a transient telomere shortening effect (around 2 years) that varies depending on the drug combination.In familial cases, only patients receiving treatment were associated with telomere shortening but they recovered normal telomere-length after a period of two years.Conclusion-Chemotherapy affects telomere-length and should be considered in the studies that correlate telomere-length with disease susceptibility.

Translational RelevancePaclitaxel treatment frequently cause peripheral neuropathy, an adverse event that can limit treatment course and lead to permanent symptoms drastically decreasing quality of life. Our group has contributed to the identification and validation of common polymorphisms in EPHA genes associated with paclitaxel neuropathy, but a large part of the inter-individual variation in neuropathy remains unexplained. We hypothesized that low-frequency variants with strong effects may contribute to the neuropathy variability in patients. By performing targeted exon sequencing of candidate genes we found for the first time that patients carrying low-frequency non-synonymous coding variants in EPHA5/6/8 contribute to paclitaxelinduced neuropathy susceptibility. Furthermore, these genes might also be relevant neuropathy markers for other neurotoxic drugs due to the involvement of Eph receptors in neuronal functions. 4ABSTRACT 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. 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, 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.