Concordance between CYP2D6 genotypes obtained from tumor-derived and germline DNA

Abstract

Formalin-fixed, paraffin-embedded tumors (FFPETs) are a valuable source of DNA for genotype association studies and are often the only germline DNA resource from cancer clinical trials. The anti-estrogen tamoxifen is metabolized into endoxifen by CYP2D6, leading to the hypothesis that patients with certain CYP2D6 genotypes may not receive benefit because of their inability to activate the drug. Studies testing this hypothesis using FFPETs have provided conflicting results. It has been postulated that CYP2D6 genotype determined using FFPET may not be accurate because of somatic tumor alterations. In this study, we determined the concordance between CYP2D6 genotypes generated using 3 tissue sources (FFPETs; formalin-fixed, paraffin-embedded unaffected lymph nodes [FFPELNs]; and whole blood cells [WBCs]) from 122 breast cancer patients. Compared with WBCs, FFPET and FFPELN genotypes were highly concordant (>94%), as were the predicted CYP2D6 metabolic phenotypes (>97%). We conclude that CYP2D6 genotypes obtained from FFPETs accurately represent the patient's CYP2D6 metabolic phenotype.

Figure 1.

Concordance and agreement of CYP2D6 scores and predicted phenotypes of 122 breast cancer patients’ matched DNA samples from white blood cells (WBCs), formalin-fixed, paraffin-embedded tumors (FFPETs), and formalin-fixed, paraffin-embedded unaffected lymph nodes (FFPELNs). Genotypes could not be determined for one FFPET and five FFPELNs because of low DNA quality/concentration and for one FFPELN for unknown reasons. Concordance and agreement exclude the one nondetermined (ND) FFPET and five/six ND FFPELN samples without adequate DNA quality/concentration for genotyping. EM = extensive metabolizer; IM = intermediate metabolizer; PM = poor metabolizer.