Bioinformatics research has developed rapid, increasingly specific, and cost-effective tools to analyze and interpret health information.
Next-generation sequencing (NGS) is one such tool. Also called massively parallel or deep sequencing, NGS is an advanced technique that can sequence the entire genome in a day, a tremendous leap forward from the Sanger technique, which took over a decade to do so.1
NGS can include exhaustive parallel sequencing of individual small nucleotide fragments, with the follow-up analysis requiring bioinformatics to reconnect the puzzle based on the reference human genome. The technology has the flexibility to sequence the entire genome or specific areas of interest, such as the whole-exome (22,000 genes) or individual genes.1
Applications of NGS
Sequencing panels such as OncoType DX, MammaPrint, and Prolaris have had a tremendous impact on clinical diagnosis, prognosis, and treatment decisions in oncology. NGS gene sequencing panels have also found their place in the National Comprehensive Cancer Network guidelines for patients with ovarian cancer.2
Need for Whole-Genome Sequencing
While whole-exome (the exome is the coding region of the genome) is currently the most popular method of sequencing, there is still a need for whole-genome sequencing funneled by the knowledge that the noncoding regions (introns) of the genome may have direct tumorigenic effects and can cause genomic instability. Individualized whole-genome sequencing offers the potential for personalized treatment and care management.1
Identifying specific mutations, developing drugs to target those mutations, and individualizing treatment can improve outcomes and simultaneously reduce some of the side effects associated with the use of cancer drugs.
Cost of Sequencing the Human Genome
The sequencing of the first human genome, concluded in 2003, required 13 years and cost a staggering $3 billion.3
The picture is very different today: Illumina boasts that the cost of sequencing a single genome is around $1000 and requires just days. These advances create an entirely new spectrum of opportunities to exploit.
The cost-efficiency boast has a caveat, though: the low price is applicable only for high-volume users that handle huge DNA databases, such as the Broad Institute and the Sanger Institute. Additionally, the up-front cost of the instruments is high, ranging from $50,000 to $750,000.3
Challenges With NGS
While scientists surmounted the entire gamut of technical challenges as NGS was being developed, several aspects of the technology remain disputed. These challenges include:
Data storage. Storage, in a compressed format, of the data generated by a single exome sequencing requires about 10 GB of disk space; at just 3 runs a month, that adds up to 1.4 TB of data. Data analysis requires additional disk space.
Statistical significance. Achieving statistical significance for the data may be challenging, with respect to finding as many samples to analyze and the associated cost. Collaboration may be key.
Data safety/privacy. Patient data may be difficult to keep secret. Safety of patients’ genetic information is a prime public concern— information from SNP arrays, exome, or whole-genome sequencing could find its way into wrong hands and be exploited.
Finding samples. Inter-institutional collaborations may assist with obtaining large numbers of good quality samples. High standards are required to be maintained for sequencing samples obtained by using public funds.
Functional validation. Genetic information by itself is difficult to sell or make a persuasive argument with, and requires credible support from phenotypic or functional data.
Translation to the clinic. While several sequencing panels are already being used in the clinic, exome/whole-genome sequencing panels may not be far behind— if challenges with Clinical Laboratory Improvement Amendments (CLIA) certification are overcome.4
Assuming that technical hurdles will be met, how will manufacturers and users ensure that NGS will be reimbursed by payers? Similar to the challenges faced by existing diagnostic panels, analytical validity and clinical utility will top the list of concerns that payers would have with NGS, particularly whole-genome sequencing. Another important concern will be whether the results from an NGS test are clinically actionable to necessitate medical intervention.