Journal Article

DKFZ-2023-00080

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Cross-ancestry GWAS defines the extended CYP2D6 locus as the principal genetic determinant of endoxifen plasma concentrations.

Khor, C. C. ; Winter, S. ; Sutiman, N. ; Mürdter, T. E. ; Chen, S. ; Lim, J. S. L. ; Li, Z. ; Li, J. ; Sim, K. S. ; Ganchev, B. ; Eccles, D. ; Eccles, B. ; Tapper, W. ; Zgheib, N. K. ; Tfayli, A. ; Ng, R. C. H. ; Yap, Y. S. ; Lim, E. ; Wong, M. ; Wong, N. S. ; Ang, P. C. S. ; Dent, R. ; Tremmel, R. ; Klein, K. ; Schaeffeler, E. ; Zhou, Y. ; Lauschke, V. M. ; Eichelbaum, M. ; Schwab, M. ; Brauch, H. B.DKFZ* ; Chowbay, B. ; Schroth, W.

2023
Wiley-Blackwell Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/cpt.2846

Abstract: The therapeutic efficacy of tamoxifen is predominantly mediated by its active metabolites 4-hydroxy-tamoxifen and endoxifen, whose formation is catalyzed by the polymorphic cytochrome P450 CYP2D6. Yet, known CYP2D6 polymorphisms only partially determine metabolite concentrations in vivo. We performed the first cross-ancestry genome-wide association study with well-characterized patients of European, Middle-Eastern and Asian descent (N=497) to identify genetic factors impacting active and parent metabolite formation. Genome-wide significant variants were functionally evaluated in an independent liver cohort (N=149) and in silico. Metabolite prediction models were validated in two independent European breast cancer cohorts (N=287, N=189). Within a single 1-Mb region of chromosome 22q13 encompassing the CYP2D6 gene, 589 variants were significantly associated with tamoxifen metabolite concentrations, particularly endoxifen and MR endoxifen/N-desmethyltamoxifen (minimal P =5.4E-35 and 2.5E-65, respectively). Previously suggested other loci were not confirmed. Functional analyses revealed 66% of associated, mostly intergenic variants to be significantly correlated with hepatic CYP2D6 activity or expression (rho=0.35 to -0.52), and six hotspot regions in the extended 22q13 locus impacting gene regulatory function. Machine learning models based on hotspot variants (N=12) plus CYP2D6 activity score (AS) increased the explained variability (~9%) compared to AS alone, explaining up to 49% (median R2 ) and 72% of the variability in endoxifen and MR endoxifen/N-desmethyltamoxifen, respectively. Our findings suggest that the extended CYP2D6 locus at 22q13 is the principal genetic determinant of endoxifen plasma concentration. Long-distance haplotypes connecting CYP2D6 with adjacent regulatory sites and non-genetic factors may account for the unexplained portion of variability.

Note: 2023 Mar;113(3):712-723

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Contributing Institute(s):

1. DKTK TU zentral (TU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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