Significant new developments in long-read sequencing at Genomics England

  • Novel nanopore sequencing technology used to sequence long reads of over 100 cancer tumours from 100,000 Genomes Project
  • Findings show benefits of long-read sequencing where structural changes in genome can be spotted more easily
  • Study is proof-of-concept for Genomics England to build analytical pipeline, with appropriate procurement, for long-read sequencing to be used alongside existing short-read sequencing technology to support clinical decisions

Using cutting-edge analytics, the cancer team at Genomics England have analysed a first batch of over 100 whole genome sequences generated by novel technology from tumour samples from the 100,000 Genomes Project. This proof-of-concept utilised Oxford Nanopore Technologies sequencing – which can analyse very long regions of DNA – and if successful, in the future could sit alongside existing Illumina short-read technology to advance precision medicine for patients with cancer in the NHS. Using both technologies together would ensure that clinicians have an arsenal of diagnostic tools to enable them to build a better, broader picture of lots of different cancers and, importantly, to guide patient care.

Structural variants (SVs), such as oncogenic fusions, can drive the changes in genes that become cancerous in many ways. Despite their clinical importance, the identification of SVs in cancer genomes remains challenging, as they are often very large. During this proof-of-concept, the quality of the sequencing that the team achieved opened significant potential of resolving complex SVs and discovering new chromosomal abnormalities in previously un-interpretated regions of the genome, thanks to the long nanopore reads being able to span large and complex regions. The clinically relevant fusions and other rearrangements that the cancer team has identified from long-read data are essential prognostic markers in patients with acute leukaemia and could support clinical management decisions, such as the need for a bone marrow transplantation or a change in a patient’s current treatment. This is a huge milestone as these discoveries show the relevance of using long-read sequencing, and complementing existing short-read sequencing, for clinical use in cancer care.

To our knowledge, this is the largest publicly available collection, globally, of cancer clinical samples to date to have been whole genome sequenced using long-read technology. The collection of over 100 genomes includes multiple cancer types (acute leukaemia, several different sarcoma types and ovarian cancer) with a broad range of genomic rearrangements and mutational signatures. Marrying this collection with short-read technology and other molecular testing data, and by bringing together world leaders in nanopore long-read sequencing, ensures that Genomics England are paving the way for building a state-of-the-art analytical pipeline, with appropriate procurement processes in place to do so. With these collaborations in place, we expect to be able to find new signatures of genomic instability that can be associated with improved patient prognosis or response to treatment. In addition, real world data in the Genomics England research environment will support this effort.

An often-difficult aspect of analysing a blood cancer sample, from a patient, is ensuring that there is enough uncontaminated DNA to compare with the cancer sample – this allows the identification of gene variants that could be causing the cancer. Another significant outcome that the team has shown is that saliva was proven to provide sufficient quality DNA for analysis, thus ensuring SVs can be identified in blood cancers. Saliva has been explored before but is seen as a controversial source of DNA due to the potential for microbial contamination and DNA fragmentation.

Of the study, Genomics England’s Scientific Director for Cancer Dr. Alona Sosinsky, said:

We’ve seen very encouraging outcomes from our first glance at genomic data generated with nanopore technology. That gives us confidence and opens the door for developing clinical applications for this cutting-edge technology. Through the network of clinical colleagues, academic collaborators and pharma partners, we’ve already identified potential clinical trials where nanopore sequencing can provide unique opportunities for stratifying patients for personalised treatments. Our next step is to ensure that we have an analytical pipeline that utilises these opportunities that nanopore technology is providing. Our unique and growing collection of data attracts world leaders in algorithm development to support us in this endeavour.

Minister for Innovation, Lord Kamall, said:

Genomics is changing the future of healthcare – from improving diagnosis and more targeted treatments, to making healthcare systems more efficient.

This innovative research once again demonstrates the UK’s leadership in trialling cutting-edge technology to help improve the diagnosis and treatment of cancer, and successfully collaborate with industry experts beyond the pandemic, including Oxford Nanopore.

The UK continues to be at the forefront in genomics expertise using brand new techniques to find more precise ways to diagnose and improve the way we treat illness.

Clinically, nanopore long-read sequencing is still in the discovery phase, and more implementation research and evaluation is needed before it can be used widely across the NHS.  However this emerging technology does have the potential to be an important transformational technology in genomic medicine. While we further explore long-read sequencing technology for use particularly in cancer care, the NHS Genomic Medicine Service will continue to provide access for eligible patients to whole genome sequencing using existing, clinically proven short-read technology delivered through its network of seven Genomic Laboratory Hubs and our partners at Illumina.

Watch our new video below for more information about nanopore long-read sequencing and what we are doing with it at Genomics England.

Additional information

Short-read sequencing and long-read sequencing: Find out more about these technologies on PHG Foundation’s website.

Oncogenic fusions: A fusion gene is a hybrid gene formed of two previously separate genes, and when these fusions happen, the resulting hybrid gene can be drivers in the development of cancer.

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