Developments in genomics and molecular diagnosis: A snapshot

Bioinformatics technology has launched a revolution in DNA sequencing. Genetics experts are highlighting a range of genomics research by metagenomic analysis, genetic expressions in certain cancers and in infectious disease, according to a series of studies published in the April edition of the Journal of the American Medical Association.

Molecular cytogenetic analysis provides information about genetic duplications and deletions for hundreds of thousands of nucleotides at finer resolutions than the light microscope, notes Bruce R. Korf, MD, PhD, from the department of genetics at University of Alabama at Birmingham, and colleagues, who published a review of the current state of molecular cancer diagnosis.

The authors described the cost of genomic analysis as “plummeting,” making it far easier to diagnose, assess risk and develop new treatments according to patients’ own genetic information and needs.

“Diagnostic testing for single gene disorders can be done by targeted analysis for specific mutations, by sequencing a specific gene to scan for mutations, or by analyzing multiple genes in which mutation may lead to a similar phenotype,” wrote Korf et al. “The advent of massively parallel next-generation sequencing facilitates the analysis of multiple genes and now is being used to sequence the coding regions of the genome (the exome) for clinical testing.”

Exome sequencing calls for bioinformatics analyses to single out a genetic variant that signals a particular pathology. Cancer therapies, risk assessment and patient prognosis can be informed by genomic and exomic sequencing. The authors suggested many possibilities for clinical expansion, and provided an overview of 17 pharmacogenetic associations that could be tested to improve patient management, including HER2 and ER/PR genetic expression for breast cancer patients in line for targeted therapy and a wide range of other disease applications from HIV to rheumatoid arthritis and bipolar disorder.

“For individuals with rare genetic disorders, the possibility of a definitive diagnosis has never been greater, the precision of diagnostic testing is likely to continue to increase and the cost to decrease,” wrote the researchers. “Molecular genetic and genomic testing to guide treatment of common conditions will increasingly be incorporated into day-to-day medical practice. Pharmacogenetic tests are likely to be incorporated into electronic prescribing systems with testing and dosing recommendations built in.”

Anne R. Cappola, MD, from the division of endocrinology, diabetes and metabolism at Perelman School of Medicine, University of Pennsylvania in Philadelphia, and colleagues, remarked on the effect of the gene BRAF V600E, which has been shown to mediate pathology of aggressive papillary thyroid cancers (PTC). “This provides a strong biological rationale for current trials of targeted tyrosine kinase inhibitor therapy for BRAF V600E-positive PTC patients with advanced disease,” wrote the authors. BRAF V600E has been implicated in a majority of mortalities for PTC, which ordinarily has a good prognosis. Still another genetic study concluded that the gene may not be as predictive of mortality as previously thought.

“This is particularly relevant when considering that 45 percent of PTC tumors are BRAF V600E-positive, and implies that additional tumor or genomic factors may influence tumor aggressiveness,” they added.

The world of infectious disease microbiology is experiencing a boon of sequencing research for a host of different viruses and bacteria, yet experts say much more needs to be done in light of previous and potential outbreaks. 

“Targeted sequencing of phylogenetically informative microbial genes, such as the bacterial 165 rRNA gene, directly from clinical specimens, has had a modest but increasing influence on the practice of clinical microbiology,” noted David A. Relman, MD, from the department of medicine, microbiology and immunology at Stanford University School of Medicine in Stanford, Calif. “Whole genome sequencing of viruses and bacteria has substantively increased outbreak investigations and strain tracking. Yet the rapid identification and characterization of microbial agents in routine cases of infectious disease is a major and increasing unmet need, made even more pressing by the alarming increase in antimicrobial resistance and the dwindling availability of effective antimicrobial agents.”