by ecancer reporter Clare Sansom

The completion of the Human Genome Project in 2003 was a landmark in biology that was arguably as important as the discovery of the double helical structure of DNA almost exactly half a century earlier.

That first human genome sequence took over ten years and cost several billion dollars to obtain.

In the last decade, however, DNA sequencing technology has advanced so dramatically that it is now possible to sequence a human-sized genome – about three billion base pairs – in minutes to hours and at a cost of about a thousand dollars.

With large-scale sequencing now relatively cheap and accessible, it is possible to sequence and compare the genomes of many individuals.

A number of “mega-genome sequencing” projects have been set up in recent years, focusing either on specific populations such as the 50,000 inhabitants of the Faeroe Islands, or on one or more diseases.

The UK’s 100,000 Genomes Project was, at least at its launch late in 2012, the most ambitious of these programmes.

As its name implies, this project aims to sequence the complete genomes of 100,000 NHS patients over a time-scale of four years.

The UK’s Department of Health set up a wholly-owned company, Genomics England, to carry out this massive project.

Although the project started in England and the first patients selected to participate live there, patients from Wales, Northern Ireland and – whatever the result of the independence referendum – Scotland are expected to contribute DNA samples.

Genomics England has four aims, set out on its website:

• To bring benefit to patients
• To create an ethical and transparent programme based on [patient] consent
• To enable new scientific and medical discoveries
• To kick-start the development of a genomics industry in the UK.

The overall project has three initial clinical foci; cancer is one of these, and the others are rare diseases (the majority of which have a genetic origin) and some infectious diseases.

The cancer programme will involve sequencing at least one sample of the tumour and one sample of normal DNA from each patient selected.

Three working groups were set up early on to establish priorities and to plan the project implementation: these covered, respectively, science, ethics and data management.

The science working group, chaired by Professor David Lomas of University College London, recommended subgroups within the three selected therapeutic areas where genomic technology was likely to be of immediate benefit to patients.

Four priority areas were chosen for cancer: lung cancer, paediatric cancers, cancers of unknown primary and rare cancer syndromes, with the greatest emphasis placed on the first two.

Initiatives such as Cancer Research UK’s Stratified Medicine Programme are already under way to sequence hundreds of known “cancer genes” in patients with these and other tumour types.

Whole genome sequencing, although slower and more expensive than this targeted approach, complements it and is likely to lead to an even deeper understanding of the genetics of each cancer and how tumours differ between patients and over time.

Lung cancer is the second most commonly occurring cancer in the UK and the leading cause of cancer death, and there are few effective treatments available.

These tumours also present a particular challenge for sequencing because relatively few patients are diagnosed at a stage where they are eligible for surgery, and it is difficult to obtain samples of non-resectable tumours that are large enough for DNA analysis.

The working group recognised that tumours removed through surgery would form the backbone of this part of the project, but urged scientists to look also at methods of obtaining tissue samples from patients with non-resectable disease.

The group also recommended that at least two samples of each lung tumour be taken for analysis, so that the heterogeneity of these tumours – which is known to be high – could be explored.

Patients with other solid tumour types, many of whom are better served by current therapies than lung cancer patients, are likely to benefit indirectly from the results of this comprehensive analysis of lung tumours.

Paediatric cancers are rare, but cancer is still the leading cause of death in childhood, with over 200 children under 15 dying from the diseases each year in the UK.

Survival rates for most paediatric cancers have greatly increased in recent years, but these cancers can have severe long-term consequences: survivors of childhood cancer are at much greater risk of death from subsequent cancers or cardiovascular events than age-matched controls.

At least some of this excess mortality is caused by long-term side effects from the powerful drugs that were used to treat the original disease.

With only 1600 new cases arising each year it should be possible for almost all children diagnosed with cancer in the UK between 2014 and 2017 to be included in the project.

Analysing the genetic lesions that give rise to their tumours can be expected to lead to more targeted treatments with lower toxicity that would have less severe long-term effects.

Eventually, it should also be possible to predict which patients will be most at risk from drug toxicity and design treatment plans accordingly.

About 3% of cancer cases are diagnosed as “cancer of unknown primary”, where the tumour appears to be metastatic but the original site is unknown.

It is important to identify the likely origin of these tumours in order to select the most effective treatment.

The working group suggested that comprehensive genomic analysis is likely to prove quicker, easier and cheaper than the complex set of tests that is currently used.

The final priority in the cancer area covers both rare cancers and clusters of cases in families where there are no known mutations that increase susceptibility.

There is currently no system in the UK for collating records from patients in these categories for analysis, and the 100,000 Genomes Project provides an ideal opportunity to set one up.

Sequencing the genomes of these patients could help identify the genetic lesions involved in rare cancers and new familial “cancer genes”.

The ethics working group, chaired by Michael Parker, Professor of Bioethics at the University of Oxford, set out guidelines and principles for maintaining the highest degree of research ethics and thus, hopefully, maintaining the support and confidence of the patients involved and the general public.

Parker and his colleagues identified three major ethical challenges for the project, summed up very briefly as the need for free and informed patient consent; the release of information not directly relating to the patients’ original conditions; and issues relating to data use in research, including storage and anonymity.

All visitors to the Genomics England website are being encouraged to complete a survey covering the same range of issues.

Issues relating to the management of the enormous volume of data that will be generated by this project were discussed in a third working group, chaired by Professor Dame Janet Thornton, director of the European Bioinformatics Institute (EBI) in Hinxton, Cambridgeshire.

The raw data from each cancer patient, including the sequences of both tumour and normal genomes, has been estimated to occupy about 300 Gb of storage.

The group proposed an operational framework for the project with a single coordination centre within the NHS and linked to a nationwide network of sequencing, annotation and clinical centres.

Completed annotated datasets will be made available to researchers in both academia and industry.

Now, a year after the project was launched, it is still in its pilot phase, with the first DNA samples being collected and sequenced.

On 1 August 2014, however, Prime Minister David Cameron announced a major investment in infrastructure that will allow it to move up a gear.

The US-based genomics company Illumina has formed a partnership with Genomics England and will invest around £162 million over the next three years in sequencing technology and services.

The Wellcome Trust will also be making a significant investment in a sequencing hub at Hinxton, site of both the EBI and the Sanger Institute where approximately a third of the original human genome was sequenced.

Launched a decade after the publication of that first genome, the 100,000 Genomes Project can be expected to yield great dividends for life sciences research as well as for patients – including cancer patients – worldwide.