Sequencing Structural Variants in Cancer for Precision Therapeutics

The identification of mutations that guide therapy selection for patients with cancer is now routine in many clinical centres. The majority of assays used for solid tumour profiling use DNA sequencing to interrogate somatic point mutations because they are relatively easy to identify and interpret. Many cancers, however, including high-grade serous ovarian, oesophageal, and small-cell lung cancer, are driven by somatic structural variants that are not measured by these assays. Therefore, there is currently an unmet need for clinical assays that can cheaply and rapidly profile structural variants in solid tumours. In this review we survey the landscape of ‘actionable’ structural variants in cancer and identify promising detection strategies based on massively-parallel sequencing.

TrendsLarge-scale tumour-sequencing studies have demonstrated that the majority of cancers are driven by either SNVs or SVs.There is currently a bias towards clinical sequencing of SNVs rather than SVs.The computational and analytical overhead associated with whole-genome sequencing is delaying clinical deployment, despite the $1000 genome now becoming a clinical reality.Low cost, shallow whole-genome sequencing is emerging as a promising clinical sequencing strategy for SV-driven tumours.Algorithmic advances are improving sequencing efficiency by extracting additional information from existing sequencing assays.