Whole exome sequencing detects variants of genes that mediate response to anticancer drugs.
Certain interindividual differences affecting the efficacy of drug treatment and adverse drug reactions are caused by genetic variants, and their phenotypic effects differ among ethnic groups. In this study, we used whole exome sequencing (WES) systematically to identify germline mutations that influence the activities of drug-metabolizing enzymes, as well as that of a transporter. We analyzed DNA isolated from blood samples from 2,042 Japanese patients with diverse cancers. We identified sequence variants of CYP2B6 (rs3745274), CYP2C9 (rs1057910), CYP2C19 (rs4986893), CYP2C19 (rs4244285), TPMT (rs1142345), NAT2 (rs1799930), NAT2 (rs1799931), UGT1A1 (rs4148323), COMT (rs4680), ABCB1 (rs1045642), and CDA (rs60369023). Wider application of WES will help to determine the effects of mutations on the activities of proteins encoded by drug response genes, and the information gained will accelerate the development of personalized therapies for patients with cancer. Moreover, this knowledge may provide clues for preventing cancer before the onset of symptoms.
Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute.
Sumiko
S
Ohnami
Takeshi
T
Nagashima
Kenichi
K
Urakami
Yuji
Y
Shimoda
Fukumi
F
Kamada
Junko
J
Saito
Akane
A
Naruoka
Masakuni
M
Serizawa
Yoko
Y
Masuda
Shumpei
S
Ohnami
Masatoshi
M
Kusuhara
Ken
K
Yamaguchi
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics; D003564:Cytidine Deaminase / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D059472:Exome; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014166:Transferases / Q000235:genetics; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D003577:Cytochrome P-450 Enzyme System; D014166:Transferases; D003564:Cytidine Deaminase