Introduction and Brief overview of NGS
An important technological advance in the practice of diagnostic and clinical medicine is next-generation sequencing (NGS). This technology is rapidly transforming clinical practice by providing a means to obtain both diagnostic and prognostic data with the same data. This transformation is made possible because of the cost-effective and rapid nature of NGS.
Next-generation sequencing is a massive parallel sequencing method allowing the sequencing of large numbers of different DNA fragments simultaneously in a single reaction. The amount of sequence information that previously took years to achieve with Sanger sequencing takes only weeks using NGS. Due to the speed and lower costs of obtaining sequence results, NGS is accessible to the clinical medicine arena.
Genomic information obtained via NGS provides significant benefits to clinical medical practice including the most accurate identification of biomarkers of disease, detecting inherited disorders, and identifying genetic factors that can help predict responses to therapies. This article will discuss the most rapidly emerging applications of NGS in clinical medical practice.
Clinical Applications of NGS
The power of NGS is harnessed for screening newborns for a number of genetic disorders. For example, Baker et al1 showed that NGS was used to accurately screen for cystic fibrosis in newborns. The higher sensitivity of NGS for carrier screening of recessive disorders allows the detection of mutations in more affected births, yet with lower costs2.
The noninvasive application of NGS to detect genetic conditions in the developing fetus is also emerging. Palomaki et al analyzed NGS test results for Down syndrome and euploid pregnancies and showed a 98% detection rate for Down syndrome 3. These advances provide confidence in the potential to use NGS as the standard for prenatal and other clinical screening efforts.
The genetic nature of cancer etiology makes NGS a beneficial tool in cancer diagnostics. The technology is already available to detect mutations (i.e., BRCA1) in those who are identified as having a higher risk of developing cancer-based on family history4. There are now commercially available multigene cancer biomarker panels for the assessment of cancer recurrence risk and to provide information that can be used to determine the best treatment approaches5.
Next-generation sequencing has been used to detect rare variants in patients with Mendelian disease phenotypes. This NGS application bolsters prognostic power and allows early treatment of secondary illnesses associated with a genetic disorder. Further, this approach can help indicate the treatment for underlying causes of clinical symptoms of these disorders. Worthey et al obtained NGS data that uncovered a variant in an infant predisposed to the development of hemophagocytosis. With this information, medical personnel were able to provide the child a beneficial bone marrow transplant6.
Infectious disease monitoring and diagnosis is also a growing area for the application of NGS. It is being used in some microbiology laboratories; however, additional decreases in cost and speed are necessary for NGS to be used routinely in infectious disease diagnostics. Also important for the increased application of NGS in infectious disease diagnostics is a better understanding of the genotype-phenotype relationships for pathogenic microorganisms7.
Response to individualized therapy can be achieved when armed with NGS data. As mentioned for the case of the child with Down syndrome, therapy can be tailored to a patient so that life-saving and specific treatment measures can be implemented. The information can potentially be used to avoid treatments that would be associated with adverse events in a particular patient that may not occur in another. Also, specific therapies with the highest potential for success can be chosen to reduce the agony and cost of inadequate treatment approaches.
Targeted therapies are available for some types of cancer and are based on NGS-derived data that uncover specific genetic variations detected in tumor cells. These include the use of Imatinib mesylate for chronic myeloid leukemia, Panitumumab for colorectal cancer, and Erlotinib for lung cancer5. Cancer chemotherapy decision-making also benefits from NGS data. Since resistance can develop to chemotherapeutic agents, a targeted therapeutic approach based on genomic data can be of much benefit in these cases.
Diagnostic and prognostic power for diseases and disorders is progressively enhanced with the application of NGS. Early detection and successful treatment of disease will increasingly become more common with improvements in and capacity for the analysis of the massively expanding NGS data. Next-generation sequencing has a beneficial role at all steps in the clinical disease management process. Not only higher survival rates are possible, but new advances in improving the quality of life of patients can be realized with the clinical benefits provided by NGS diagnostic and screening efforts.
- Baker MW, Atkins AE, Cordovado SK, Hendrix M, Earley MC, Farrell PM. Improving
newborn screening for cystic fibrosis using next-generation sequencing
technology: a technical feasibility study. Genet Med. 2016 Mar;18(3):231-8.
- Azimi M, Schmaus K, Greger V, Neitzel D, Rochelle R, Dinh T. Carrier screening
by next-generation sequencing: health benefits and cost effectiveness. Mol Genet
Genomic Med. 2016 Jan 29;4(3):292-302.
- Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, et al. (2011) DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 13(11):913-20.
- Meldrum C, Doyle MA, Tothill RW. Next-Generation Sequencing for Cancer Diagnostics: a Practical Perspective. The Clinical Biochemist Reviews. 2011;32(4):177-195.
- Gullapalli RR, Desai KV, Santana-Santos L, Kant JA, Becich MJ. Next generation
sequencing in clinical medicine: Challenges and lessons for pathology and
biomedical informatics. J Pathol Inform. 2012;3:40.
- Worthey EA, Mayer AN, Syverson GD, Helbling D, Bonacci BB, Decker B, et al. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med. 2011;13(3):255–62.
- Lefterova MI, Suarez CJ, Banaei N, Pinsky BA. Next-Generation Sequencing for
Infectious Disease Diagnosis and Management: A Report of the Association for
Molecular Pathology. J Mol Diagn. 2015 Nov;17(6):623-34.