Is pharmacogenetic CYP2D6 testing useful?

BACKGROUND: Pharmacogenetic testing is used to uncover genetic causes for variations in drug response. Documentation of the method's usefulness in a clinical setting is scarce. The aim of the study was to systematically categorize the experience from routine CYP2D6 genotyping in a diagnostic laboratory. MATERIAL AND METHODS: All samples submitted to our laboratory for CYP2D6 genotyping in the period 29.06.98-28.12.09 were examined retrospectively. The samples were classified into three indication groups based on clinical information given in the request form. All samples, and a control group consisting of 100 healthy blood donors, were tested for the four most prevalent non-functional CYP2D6 alleles in the European population, and for ultrarapid metabolizer-associated duplications of the gene. RESULTS: 325 samples were included. The proportion of ultrarapid metabolizers was significantly higher in the patient group (4.0 %, p = 0.045) than in the control group (0 %), with the highest proportion among those patients that used a known CYP2D6 substrate. The percentage of poor metabolizers was not significantly higher in the patient group (8.3 %) than in the control group (6.0 %) (p = 0.528). INTERPRETATION: The CYP2D6 analysis could rarely explain the patients' side effects or lack of drug response, even though the study group was selected because of clinical problems due to drugs they were using. Two explanations may be that the indication(s) for genetic testing is not clearly defined and that the CYP2D6 genotype is only one of many factors that determine individual drug response.

Complete mutation screening and haplotype characterization of the BRCA1 gene in 61 familial breast cancer patients from Norway.

Mutations in the Breast-Cancer-1 (BRCA1) gene are the major cause of familial breast/ovarian cancer. Among familial breast cancer only, 15-20% have been suggested to have a deleterious mutation in BRCA1. A highly sensitive method (REF-SSCP) was applied to screen the open reading frame and the 5'UTRs of BRCA1 for mutations. The patient cohort comprised 61 unrelated moderate to high risk breast cancer patients from Western-Norway. Only one known deleterious BRCA1 mutation (c.816-817delGT) was found in two of the 61 patients (3.3%). Four haplotypes were established based on nine known single nucleotide polymorphisms. Two patients had a novel deletion (c.-33_-29delAAAAA) in the 5'UTR, and a novel amino acid substitution (L523W) was found in one patient. Size variations analysis in the 5'UTR was repeated in a cohort of 159 unrelated familial breast/ovarian cancer patients and 94 healthy blood donors. Two patients were identified with 5'UTR (c.-30 to -60) variations (CAAAA)5 and (CAAAA)7, instead of the (CAAAA)6-repeat. All of the identified 5'UTR size variations were localized between the start codon and the most stable secondary structures previously proposed for the exon 1b transcript. No such alterations were found among the healthy blood donors but association studies of the 5'UTR variations within the respective families were not conclusive.