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Frequency of undetected CYP2D6 hybrid genes in clinical samples: impact on phenotype prediction.

ABSTRACT: Cytochrome P450 2D6 (CYP2D6) is highly polymorphic. CYP2D6-2D7 hybrid genes can be present in samples containing CYP2D6*4 and CYP2D6*10 alleles. CYP2D7-2D6 hybrid genes can be present in samples with duplication signals and in samples with homozygous genotyping results. The frequency of hybrid genes in clinical samples is unknown. We evaluated 1390 samples for undetected hybrid genes by polymerase chain reaction (PCR) amplification, PCR fragment analysis, TaqMan copy number assays, DNA sequencing, and allele-specific primer extension assay. Of 508 CYP2D6*4-containing samples, 109 (21.5%) harbored CYP2D6*68 + *4-like, whereas 9 (1.8%) harbored CYP2D6*4N + *4-like. Of 209 CYP2D6*10-containing samples, 44 (21.1%) were found to have CYP2D6*36 + *10. Of 332 homozygous samples, 4 (1.2%) harbored a single CYP2D7-2D6 hybrid, and of 341 samples with duplication signals, 25 (7.3%) harbored an undetected CYP2D7-2D6 hybrid. Phenotype before and after accurate genotyping was predicted using a method in clinical use. The presence of hybrid genes had no effect on the phenotype prediction of CYP2D6*4- and CYP2D6*10-containing samples. Four of four (100%) homozygous samples containing a CYP2D7-2D6 gene had a change in predicted phenotype, and 23 of 25 (92%) samples with a duplication signal and a CYP2D7-2D6 gene had a change in predicted phenotype. Four novel genes were identified (CYP2D6*13A1 variants 1 and 2, CYP2D6*13G1, and CYP2D6*13G2), and two novel hybrid tandem structures consisting of CYP2D6*13B + *68×2 + *4-like and CYP2D6*13A1 variant 2 + *1×N were observed.

SUBMITTER: Black JL

PROVIDER: S-EPMC3250050 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Frequency of undetected CYP2D6 hybrid genes in clinical samples: impact on phenotype prediction.

Black John Logan JL Walker Denise L DL O'Kane Dennis J DJ Harmandayan Maria M

Drug metabolism and disposition: the biological fate of chemicals 20111017 1

Cytochrome P450 2D6 (CYP2D6) is highly polymorphic. CYP2D6-2D7 hybrid genes can be present in samples containing CYP2D6*4 and CYP2D6*10 alleles. CYP2D7-2D6 hybrid genes can be present in samples with duplication signals and in samples with homozygous genotyping results. The frequency of hybrid genes in clinical samples is unknown. We evaluated 1390 samples for undetected hybrid genes by polymerase chain reaction (PCR) amplification, PCR fragment analysis, TaqMan copy number assays, DNA sequencin ...[more]

PMID: 22004686

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Project description:BackgroundClinical endpoint prediction remains challenging for health providers. Although predictors such as age, gender, and disease staging are of considerable predictive value, the accuracy often ranges between 60 and 80%. An accurate prognosis assessment is required for making effective clinical decisions.MethodsWe proposed an extended prognostic model based on clinical covariates with adjustment for additional variables that were radio-graphically induced, termed imaging biomarkers. Eight imaging biomarkers were introduced and investigated in a cohort of 68 non-small cell lung cancer subjects with tumor internal characteristic. The subjects comprised of 40 males and 28 females with mean age at 68.7 years. The imaging biomarkers used to quantify the solid component and non-solid component of a tumor. The extended model comprises of additional frameworks that correlate these markers to the survival ends through uni- and multi-variable analysis to determine the most informative predictors, before combining them with existing clinical predictors. Performance was compared between traditional and extended approaches using Receiver Operating Characteristic (ROC) curves, Area under the ROC curves (AUC), Kaplan-Meier (KM) curves, Cox Proportional Hazard, and log-rank tests (p-value).ResultsThe proposed hybrid model exhibited an impressive boosting pattern over the traditional approach of prognostic modelling in the survival prediction (AUC ranging from 77 to 97%). Four developed imaging markers were found to be significant in distinguishing between subjects having more and less dense components: (P = 0.002-0.006). The correlation to survival analysis revealed that patients with denser composition of tumor (solid dominant) lived 1.6-2.2 years longer (mean survival) and 0.5-2.0 years longer (median survival), than those with less dense composition (non-solid dominant).ConclusionThe present study provides crucial evidence that there is an added value for incorporating additional image-based predictors while predicting clinical endpoints. Though the hypotheses were confirmed in a customized case study, we believe the proposed model is easily adapted to various clinical cases, such as predictions of complications, treatment response, and disease evolution.

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Frequency of undetected CYP2D6 hybrid genes in clinical samples: impact on phenotype prediction.

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Frequency of undetected CYP2D6 hybrid genes in clinical samples: impact on phenotype prediction.

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