Published Online:December 11, 2013
Genomic sequencing is rapidly increasing its value as a clinical tool in the diagnosis and treatment of many diseases, including cancer. In his presentation, Justin M. Balko, PharmD, PhD, assistant professor, department of medicine, Vanderbilt University, provided a background on the current state of next-generation genomic sequencing (NGS) and discussed the potential role that pharmacists play as this science continues to evolve.
Dr Balko noted that the human genome consists of about 6 billion bases (A, T, C, G) comprising approximately 20,000 genes and 1.5% of base pairs code for protein. Almost everything that a living cell does is encoded in the DNA, including enzymatic processes, and DNA sequences (genotype) can alter expression level and directly or indirectly affect the functionality (phenotype) of a protein.
What make us unique as individuals, from a DNA point of view, are single nucleotide polymorphisms (SNPs), which occur in about 1 of 1000 bases. SNPs can affect the way a gene is turned on or off, or to what degree a gene is expressed, altering the functionality of the enzyme (eg, CYP450 variant alleles) or causing proteins to be nonfunctional.
Illustrating the advances in DNA sequencing, Dr Balko mentioned that the Human Genome Project completed the first mapping in 2001, involving 23 institutions over 13 years at a total cost of $3 billion. Current technology allows mapping of an individual’s genome in a single laboratory over 2 days at a cost of $5000. NGS is the term that refers to this current level of technology that allows for massively parallel sequencing. The original technique was named “Sanger sequencing,” after its creator.
Many different variations of NGS technologies are available through different companies; however, most NGS technologies are only available for research purposes. Some NGS technologies may be available through commercial reference laboratories, and facilities with Clinical Laboratory Improvement Amendments certification have met quality standards set by the Centers for Medicare & Medicaid Services.
Sequencing by NGS can provide information specific to germline DNA (eg, SNPs, heritable disease alleles), tumor DNA (eg, somatic mutations, gene amplifications, gene fusions), and bacterial or viral genomes (assisting with microbe identification, and antibiotic or therapeutic resistance markers). DNA sequencing can provide information regarding what diseases a patient may be at risk for, how he or she might respond to certain medications, and even what dose may be required to achieve efficacy or avoid toxicity, Dr Balko said.
Dr Balko noted that pharmacists have an opportunity to facilitate the role of NGS through an increased understanding of the genetic basis for disease and how it affects pharmacologic treatment choices. He provided examples in oncology, including a growing list of molecularly targeted inhibitors (ie, kinase inhibitors) that are commonly approved for cancers with distinct genetic alterations such as:
Epidermal growth factor receptor exon 19 or 21 mutations (erlotinib; lung cancer)
Anaplastic lymphoma kinase fusions (crizotinib; lung cancer)
HER2 amplifications ([ado]trastuzumab or lapatinib; breast cancer)
BRAF/NRAS mutations (vemurafenib; melanoma)
In addition, Dr Balko mentioned that pharmacists could also provide perspective on the use and value of NGS. Since the testing is costly, and benefits have not been explicitly validated by clinical trials, there is a need for treatment options to be weighed and patients to be directed to appropriate treatments or into clinical trials—an ideal role for pharmacists.
It was also noted that there are many barriers to NGS, such as cost, reproducibility, trust, and privacy. However, pharmacists are in a unique position to stay abreast of the impact of NGS and the powerful information coming from this evolving field of medicine, Dr Balko said. Doing so may lead to more personalized care and better outcomes.
For additional information, the following sites were identified: