Whole-genome sequencing-based profiling of CYP2D6 structural variants in Japanese patients with solid tumors.

Abstract

Cytochrome P450 2D6 (CYP2D6), a key enzyme involved in the metabolism of a wide range of pharmaceuticals, exhibits extensive genetic variants, including copy number variations (CNVs) and structural alterations. Hybrid alleles formed between CYP2D6 and its highly homologous pseudogene CYP2D7 frequently result in reduced or absent enzymatic activity and show marked interethnic variability. However, accurate characterization of CNVs and hybrid structures in the Japanese population remains technically challenging. In this study, we performed a comprehensive analysis of CYP2D6 genetic and structural variants in 1,287 Japanese patients with solid tumors using whole-genome sequencing (WGS). CNVs and diplotypes were inferred using Sequenza and Aldy, visually inspected with Integrative Genomics Viewer (IGV), and validated using quantitative PCR and Sanger sequencing. A total of 68 distinct diplotypes were identified. The most frequent diplotype was *1/36+*10 (0.2176), followed by *1/*1 (0.1919), *1/*2 (0.0940), *1/*10 (0.0653), *2/*36+*10 (0.0645), and *36/*36+*10 (0.0513). Complete gene deletion (*5/*5) was detected in three cases, and heterozygous deletion (*5/-) in 86 cases. Given that functional annotations for CYP2D6 alleles are well established, WGS-based comprehensive detection represents a practical and scalable strategy for pharmacogenomic profiling. This approach is expected to support optimized drug selection and advance personalized medicine.