CYP2C9 and CYP2C19: Deep Mutational Scanning and Functional Characterization of Genomic Missense Variants.

Single nucleotide variants in the open reading frames (ORFs) of pharmacogenes are important causes of interindividual variability in drug response. The functional characterization of variants of unknown significance within ORFs remains a major challenge for pharmacogenomics. Deep mutational scanning (DMS) is a high-throughput technique that makes it possible to analyze the functional effect of hundreds of variants in a parallel and scalable fashion.

Pharmacogenomic Next-Generation DNA Sequencing: Lessons from the Identification and Functional Characterization of Variants of Unknown Significance in and .

and are highly polymorphic pharmacogenes; however, clinically actionable genetic variability in drug metabolism due to these genes has been limited to a few common alleles. The identification and functional characterization of less-common open reading frame sequence variation might help to individualize therapy with drugs that are substrates for the enzymes encoded by these genes. The present study identified seven uncharacterized variants each in and using next-generation sequence data for 1013 subjects, and functionally characterized the encoded proteins.

Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic Interaction Between SLC38A7 and ALPPL2.

Anastrozole is a widely prescribed aromatase inhibitor for the therapy of estrogen receptor positive (ER+) breast cancer. We performed a genome-wide association study (GWAS) for plasma anastrozole concentrations in 687 postmenopausal women with ER+ breast cancer. The top single-nucleotide polymorphism (SNP) signal mapped across SLC38A7 (rs11648166, P = 2.

A phase 1 study of eribulin mesylate (E7389), a novel microtubule-targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Children's Oncology Group Phase 1 Consortium study (ADVL1314).

Background: Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose-limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors.

Methods: Eribulin was administered intravenously on days 1 and 8 in 21-day cycles.