Next-generation sequencing in pharmacogenomics – fit for clinical decision support?

ABSTRACT

Introduction

The technological advances of sequencing methods during the past 20 years have fuelled the generation of large amounts of sequencing data that comprise common variations, as well as millions of rare and personal variants that would not be identified by conventional genotyping. While comprehensive sequencing is technically feasible, its clinical utility for guiding personalized treatment decisions remains controversial.

Areas covered

We discuss the opportunities and challenges of comprehensive sequencing compared to targeted genotyping for pharmacogenomic applications. Current pharmacogenomic sequencing panels are heterogeneous and clinical actionability of the included genes is not a major focus. We provide a current overview and critical discussion of how current studies utilize sequencing data either retrospectively from biobanks, databases or repurposed diagnostic sequencing, or prospectively using pharmacogenomic sequencing.

Expert opinion

While sequencing-based pharmacogenomics has provided important insights into genetic variations underlying the safety and efficacy of a multitude pharmacological treatments, important hurdles for the clinical implementation of pharmacogenomic sequencing remain. We identify gaps in the interpretation of pharmacogenetic variants, technical challenges pertaining to complex loci and variant phasing, as well as unclear cost-effectiveness and incomplete reimbursement. It is critical to address these challenges in order to realize the promising prospects of pharmacogenomic sequencing.

KEYWORDS:

• Variant effect prediction
• gene-drug associations
• targeted sequencing
• genomic medicine
• precision medicine

Article highlights

• Sequencing shows benefits over genotyping regarding genomic information provided and utility over time. Lack of guidance with regard to the interpretation of rare and novel variants as well as unclear cost-effectiveness remain the main challenges for its broader clinical use.

• Current pharmacogenomic targeted sequencing panels are used primarily for research applications and differ drastically in scope and composition.

• Actionability is not major design criterion for the inclusion of genes in most pharmacogenomic sequencing panels.

• NGS data from clinical projects, biobanks and sequencing databases provide ample resources for large-scale pharmacogenomic variation profiling and rare variant analysis.

• Sequencing instead of genotyping is becoming increasingly prevalent for the investigation of extreme phenotypes and drug response predictions.

Declaration of interest

VM Lauschke is co-founder, CEO and shareholder of HepaPredict AB. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The laboratory received funding from the Swedish Research Council [grant numbers 2019-01837 and 2021-02801], the Knut and Alice Wallenberg Foundation [Grant VC-2021-0026], Cancerfonden [Grant 23-0763PT] and the Robert Bosch Foundation, Stuttgart, Germany.