Large National Sequencing Projects in Europe

Integration of genomic medicine into the care pathway

Genomic medicine is revolutionising the care pathway and therefore how the public health system is organised. Two editorial articles published in April 2018 issue of the Annals of Oncology underpin emergence of modernised genomics services in France and UK with explanation of sequencing and informatics infrastructure, a process of local transformation, and expansion in skills and new professional networks that have evolved through delivery of the projects.

The French Plan for Genomic Medicine 2025

The ‘French Model’ is based on 14 operating measures. The aim of such transformative, 10-year plan is to benefit from the specificities of French health care system and bring yet more closely together care, research, training and innovation in the service of healthcare and quality of life.  

The plan was commissioned by Prime Minister in 2015 and developed by Aviesan (the French National Alliance for Life Sciences and Health) in 2016. It aims to position France as an international leader in personalised and precision medicine, fully integrating genomic medicine into healthcare pathways and establishing a national genomic medicine industry that promotes innovation and economic growth.

Genome sequencing will be performed by 12 ultra-high-throughput services covering the whole country, two of which being launched in 2018. A national data analysis facility (CAD) will interpret and store data and interface with other national and international databases. A Reference Centre for Innovation, Assessment and Transfer (CRefIX), based at academic centres of excellence, is developing the procedures, tools and technologies to be deployed at the sequencing centres and CAD and will also be responsible for implementation, commissioning and workforce training. The CrefiX is already operational and has allowed the implementation of the first clinical projects. To overcome the technological and clinical obstacles and to address the regulatory framework encountered along the clinical pathway, four pilot projects on cancer (2400 patients with soft-tissue sarcoma or colon cancer), rare diseases, common diseases and a sample of the general population are commenced.

It is anticipated that France will be capable of sequencing 235 000 genomes per year by 2020, corresponding to 20 000 patients with rare diseases together with their families, and 50 000 high-priority patients with metastatic cancer or cancer refractory to treatment.

The Genomics England 100 000 Genomes Project

The programme was initiated in 2012 to develop infrastructure for routine high throughput tumour sequencing, in particular whole-genome sequencing (WGS) in order to establish a national research platform of molecular data with linkage to longitudinal clinical data and transform delivery of molecular testing in NHS clinical cancer care. 

Thirteen established centres were designated as NHS Genomics Medicine Centres (GMCs) and each links out to up to 18 local recruiting hospitals. Tissue collection and preparation, DNA extraction and quantitation are undertaken locally, followed by transfer of DNA to the central national biorepository. The WGS is delivered by Illumina at the new national 100 000 Genomes Sequencing Centre. Processed sequencing files are then passed back to Genomics England which by using standardised automated pipelines undertakes processing, calling, quality checking, prioritising, storing and presentation of the whole-genome analysis. Applying established knowledge-bases, the acquired somatic variants are tiered and annotated for potential diagnostic, predictive or prognostic actionability. Results are presented back to the clinical users at GMCs via decision-support tools. A supplementary analysis is also supplied, providing full analysis of tumour structural and copy number variation as well as other research content including pan-genomic analyses of tumour signatures and mutational burden. Results are reviewed at multidisciplinary Tumour Sequencing Boards, which have been set up in federated networks across each NHS GMC. National standards for reporting of somatic cancer variants, technical validation and return of pertinent and secondary germline findings have been established through an NHS England-led national working group.

Researchers can access de-identified genomic and linked clinical data within the secure research data environment via collaboration within a Genomics England Clinical Interpretation Partnership domain. Although currently immature, these will develop into rich longitudinal datasets through lifelong linkage to different national datasets.

Aside from long term national transformation of tissue collection pathways, other key challenges during initial rollout of project have included the high requirements for DNA, timescale of return of results and engagement of clinicians. Requirement for tumour-derived DNA has been reduced by >50%. A ‘fast-tracked’ sample pipeline has been established through which turnaround time from receipt of DNA to issuing of a WGS analysis has now been reduced to <18 working days.

From late 2018, delivery of all NHS clinical sequencing will be through a new NHS Genomic Medicine Service comprising a national centralised ISO-accredited infrastructure for clinical WGS developed by Genomics England and a consolidated network of NHS England Genomic Laboratory Regional Genetics Hubs.

A national testing directory is being established to advance consistency of testing indications and technologies.

In the initial phase, the main focus for NHS central commissioned WGS will be in rare disease; in the majority of tumour types panel testing will be indicated and how the number/complexity of actionable markers increases, there is expectation of ‘tipping’ successive tumour types over to WGS. 

References

Lethimonnier F, Levy Y. Genomic medicine France 2025. Annals of Oncology 2018; 29(4):783–784.

Turnbull C. Introducing whole-genome sequencing into routine cancer care: the Genomics England 100 000 Genomes Project. Annals of Oncology 2018; 29(4):784–787.