What is DNA Sequencing?
DNA sequencing refers to a range of techniques that analyze sections of the genome to single-nucleotide resolution. The traditional Sanger method is still popular in clinical applications, but high-throughput next generation sequencing (NGS) techniques are on the rise. NGS enables whole-genome, whole-exome, transcriptome, and targeted sequencing with relative ease.
Pros and Cons of Next-generation Sequencing (NGS)
The key reason for choosing NGS for clinical diagnostics is its combination of high throughput, speed, and resolution. Like microarrays, NGS assays can efficiently analyze the entire genome or exome, or focus on a specified number of targeted locations in the genome.
NGS’s single-nucleotide resolution also enables it to detect even the smallest possible mutations (SNPs) without necessarily requiring knowledge of the mutation in advance. As the technology improves, the combined detection of SNP and larger abnormalities is becoming easier, providing an all-in-one solution for detecting multiple types of mutations.
One of the challenges that NGS faces in the clinic is that it doesn’t yet have the long and proven track record or familiarity of other technologies. However, this is changing rapidly, with continuing innovation and decreases in the cost-per-base.
NGS technology also requires a fair bit of expertise to run assays and interpret data, but this too is changing. Recent progress on guidelines from the US Food and Drug Administration [i] and “game-changing” FDA cancer panel approvals [ii] are removing these barriers and leading to increased investment and clinical adoption.
Key Clinical Applications of NGS
In December 2018, Genomics England announced that they had reached the main goal of their ambitious “100 000 Genomes Project”—to sequence 100 000 genomes [iii]. The results are already making an impact on the lives of people with cancer and a range of other diseases.
The aims of Genomics England aren’t unique. All over the world, huge NGS initiatives and collaborations are launching or ongoing—all aiming to advance our understanding of genomics and improve patients’ lives through the power of DNA sequencing.
Here, we’ve picked out some of the DNA sequencing initiatives, where today’s scientists work together to change outcomes for patients tomorrow. Who are they, and what are trying to achieve?
100,000 Ways to Improve Molecular Diagnostics
One of the key aims of the 100 000 Genomes Project is to provide diagnostic tools for patients with rare diseases: those that have been difficult to diagnose in the past [iv]. These patients have often gone through ‘diagnostic odysseys’ as doctors struggled to uncover a cause for their condition.
Launched in 2013, the 100 000 genomes project didn’t just look at DNA containing harmful mutations, it also created healthy reference genomes. Cancer patients, for example, had both their healthy and tumor DNA sequenced. For inherited diseases, the project used parental genomes for comparison.
Genomics England expects to present the final results to the UK’s National Health Service (NHS) in 2019. But early results from this NGS initiative have already identified causative mutations in patients with previously undiagnosed conditions, enabling more targeted treatments and often ending years of uncertainty.
Setting the Standard for Cancer Diagnostics
As the use of clinical NGS expands and the number of available genetic tests increases, there’s an emerging need for improved standardization and regulatory oversight.
One collaboration that’s working on addressing this issue in the field of cancer sequencing is the Actionable Genome Consortium [v]. Its central goal is to work towards a clearer definition of an ‘actionable cancer genome’. It aims to set out clear standards that define tumors (and their treatments) by genetic makeup.
The collaboration began in 2014 and involves sequencing giant Illumina and four major US cancer centers [vi]: the Dana-Farber Cancer Institute, the Fred Hutchinson Cancer Research Center, the MD Anderson Cancer Center, and the Memorial Sloan Kettering Cancer Center.
The added value of this collaboration is that these major cancer centers have large, multidisciplinary cancer boards. Their know-how can help other clinicians working in cancer diagnostics assess the clinical significance of complex NGS data.
This collaboration is also already having an impact on the way organizations develop new sequencing panels [vii].
Assessing the Broader Impact of Clinical NGS
When it comes to gathering clinical sequencing data, the central paradigm is often “more is better.” But this quest for retrieving more and more information about our genomes overlooks a concern that many people have in our society: does more information always improve well-being?
This concern is one of the aspects of sequencing that the BabySeq project is investigating. BabySeq is a randomized clinical trial, in which scientists are sequencing the genomes of around 150 babies [i] in the treatment group and comparing to a control group where no sequencing takes place.
The aim of this approach is to investigate the broader impact of whole genome sequencing on the well-being of both babies and their parents. Alongside data on the babies’ health and the care they receive, the research also considers answers received from questionnaires given to parents about how access to their child’s genetic information affects their family life.
Researchers hope to use this information to gain an insight into the effects of DNA sequencing that might otherwise be overlooked with a purely clinical approach.
The biggest market for NGS is currently in reproductive health, more specifically non-invasive prenatal testing (NIPT)1, where it’s gradually replacing array-based techniques such as array comparative genomic hybridization (aCGH). NIPT provides a safer alternative to invasive tests as it analyzes fetal cell-free DNA (cfDNA) from the mother’s circulation, making detection of genetic disorders such as Down syndrome easier.
Use of NGS is also growing in oncology, Mendelian diseases, complex diseases, and infectious diseases. Clinical scientists can use NGS assays either for diagnosis or for decisions on treatment by studying both small mutations (e.g. SNPs and indels) and larger abnormalities (e.g. CNV) at the same time.
Refinement of cancer diagnoses is a particular growth area for NGS. As treatments become more personalized, there’s a need for classifying cancers in terms of their underlying mutations to help direct treatment options in the clinic. NGS plays a key role in this trend towards precision medicine, helping to minimize the human and financial costs of ineffective cancer treatments.
These are a few examples of NGS initiatives where clinical research using sequencing is telling us about more than just the mutations we have in our genes. Read our white paper for more information on current trends and applications of clinical NGS.
The Future of NGS
Out of the four key molecular diagnostics techniques (qPCR, FISH, microarrays, and NGS), NGS has the highest growth rate.2 This is likely because of its potential and ability to provide comprehensive data on a whole range of abnormalities.
The speed at which NGS will grow in different clinical markets will probably depend on pushing sequencing costs down further, as well as developments in the regulatory landscape. As clinical scientists get more familiar with the possibilities with NGS, they can also contribute to higher growth through demand.
1. BCC Research (2017) Next-generation Sequencing: Emerging Clinical Applications and Global Markets
2. BCC Research (2017) Next-generation Sequencing: Emerging Clinical Applications and Global Markets
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