Whole-exome sequencing reveals defective CYP3A4 variants predictive of paclitaxel dose-limiting neuropathy

• Published in: Clinical cancer research Vol. 21; no. 2; pp. 322 - 328
• Main Authors: Apellániz-Ruiz, María, Lee, Mi-Young, Sánchez-Barroso, Lara, Gutiérrez-Gutiérrez, Gerardo, Calvo, Isabel, García-Estévez, Laura, Sereno, María, García-Donás, Jesús, Castelo, Beatriz, Guerra, Eva, Leandro-García, Luis J, Cascón, Alberto, Johansson, Inger, Robledo, Mercedes, Ingelman-Sundberg, Magnus, Rodríguez-Antona, Cristina
• Format: Journal Article
• Language: English
• Published: United States 15.01.2015
• Subjects: Adult; Aged; Amino Acid Sequence; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - therapeutic use; Base Sequence; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Enzyme Stability; Exome; Female; HEK293 Cells; Humans; Medicin och hälsovetenskap; Middle Aged; Molecular Sequence Data; Paclitaxel - adverse effects; Paclitaxel - therapeutic use; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - genetics; Sequence Analysis, DNA
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.ccr-14-1758

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 whole-exome sequencing (WES) study to identify genetic susceptibility variants associated with paclitaxel neuropathy. 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. WES revealed 2 patients with rare CYP3A4 variants, a premature stop codon (CYP3A4*20 allele) and a novel missense variant (CYP3A4*25, p.P389S) causing reduced enzyme expression. Screening for CYP3A4 variants in the independent cohort revealed three additional CYP3A4*20 carriers, and two patients with missense variants exhibiting diminished enzyme activity (CYP3A4*8 and the novel CYP3A4*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 = 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 = 5.9 × 10(-5)). 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.