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


METHODS
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*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)).


CONCLUSIONS
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.
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
María
M
Apellániz-Ruiz
Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Mi-Young
MY
Lee
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Lara
L
Sánchez-Barroso
Neurology Section, Hospital Universitario Infanta Sofía, Madrid, Spain.
Gerardo
G
Gutiérrez-Gutiérrez
Medical Oncology Department, Hospital Montepríncipe, Madrid, Spain. Medical Oncology Department, Centro Integral Oncológico Clara Campal, Madrid, Spain.
Isabel
I
Calvo
Medical Oncology Department, Centro Integral Oncológico Clara Campal, Madrid, Spain.
Laura
L
García-Estévez
Medical Oncology Department, Hospital Universitario Infanta Sofía, Madrid, Spain.
María
M
Sereno
Gynecological and Genitourinary Tumors Programme Centro Integral Oncologico Clara Campal CIOCC, Madrid, Spain.
Jesús
J
García-Donás
Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain.
Beatriz
B
Castelo
Medical Oncology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain.
Eva
E
Guerra
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Luis J
LJ
Leandro-García
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
Alberto
A
Cascón
Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Inger
I
Johansson
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
Mercedes
M
Robledo
Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Magnus
M
Ingelman-Sundberg
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain. crodriguez@cnio.es.
Cristina
C
Rodríguez-Antona
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000627:therapeutic use; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004795:Enzyme Stability; D059472:Exome; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D017239:Paclitaxel / Q000009:adverse effects* / Q000627:therapeutic use; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000235:genetics*; D017422:Sequence Analysis, DNA
D000972:Antineoplastic Agents, Phytogenic; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel