Genomic Profiling and Personalized Medicine

Vol. 17 •Issue 4 • Page 36
Genomic Profiling and Personalized Medicine

As genomic profiling finds success in research labs worldwide, the promise of its clinical applications could usher in a new era of individualized medical care—with molecular imaging as a key component.

Getting personal may be socially taboo, but when it comes to healthcare, the more revealing the information, the better. Enter genomic profiling, the simultaneous evaluation of every gene in a person’s body to identify genes associated with a certain disease or condition. Transforming care delivery, this approach to medicine will lead us to a future of predictive, personalized care.

In particular, genomic profiling will allow us to potentially assess the risk of developing ailments or symptoms, provide more accurate disease classification and identify biomarkers for early detection or even prevention of diseases—especially cancer. A better understanding of genomic profiling’s promise begins with a review of its profiling methods, clinical applications, research applications, molecular imaging’s role and obstacles to overcome.

Profiling Methods

Gene expression profiling at the RNA level is the most popular high-throughput strategy, as it directly assays gene activities by measuring their expression level. The approach’s biggest limitation is its requirement of snap-frozen tissues to preserve the state of gene expression levels.

Another genomic profiling strategy is measuring gene copy numbers at the DNA level. Although gene dosage may not directly correlate with gene expression level, the higher stability of DNA relative to RNA makes gene copy number profiling an attractive alternative to expression profiling because of its potential to use archival samples in the form of formalin-fixed, paraffin-embedded tissues available from all clinical pathology departments.1

Unlike DNA, significant degradation of RNA in formalin-fixed, paraffin-embedded tissues makes routine expression profiling with such tissues incompatible with the available high-throughput platforms for genomic profiling, including oligonucleotide arrays and bead arrays. Other emerging strategies include micro-RNA profiling and epigenetic profiling, both of which contribute additional complementary information to comprehensive genomic profiling.

A common paradigm of genomic profiling is generating microarray data using one of the commercial platforms and applying sophisticated computational and statistical data analyses to identify the molecular signatures that correlate with the clinical and biological parameters of interest. Another much-anticipated development is the use of high-throughput DNA sequencing to sequence the entire genome of each individual. This is the ultimate method of identifying all the genetic variants and mutations in each person.

Clinical Applications

The past few years have witnessed an explosion of clinical and research applications of genomic profiling in a variety of settings. By comparing genomic profiles between disease groups and control groups–or among different disease subtypes–we can identify molecular signatures as biomarkers to refine diagnosis and improve the accuracy of prognostication for personalized patient care. We can also exploit as potential therapeutic targets the candidate genes identified as part of the molecular signatures associated with different diseases. More recently, researchers have successfully employed genome-wide genotyping association studies using single nucleotide polymorphism (SNP) arrays to identify candidate genes associated with diseases; this may lead to new strategies for early detection and prevention.

A clinical application success story is the recent Food and Drug Administration approval of the first diagnostic genetic test, MammaPrint®, from the Molecular Profiling Institute Inc., Phoenix, and Agendia BV, Amsterdam, the Netherlands, for predicting the risk of relapse in patients with breast cancer.2 It examines the pattern of activities from 70 specific genes in breast cancers after they are surgically removed. Twenty-three percent of patients suggested to be at high risk (based on these gene signatures) had a recurrence within five years, compared with only 5 percent of patients with favorable gene signatures who had a relapse. While the results aren’t optimal, the FDA’s endorsement of genetic testing for a complex disease is a significant step toward the era of personalized medicine. Others are on the horizon. Celera Genomics, Rockville, MD, has developed a genetic test that can help predict whether a hepatitis C patient will eventually progress to liver cirrhosis.3

Research Applications

The fruition of clinical applications is not possible without extensive research efforts. Given the availability of genomic profiling data from patient specimens, one could also study the underlying mechanisms of disease. The molecular signatures derived from genomic profiles will provide important clues regarding the genes and pathways involved in the disease process. Based on this, we can generate genetically engineered animal models that mimic the genetic alterations in human. These models are invaluable for studying the underlying biology of a specific disease and for the preclinical testing of new drugs against it.

At the population level, genomic profiling that examines hundreds of thousands of genetic markers has enabled the so-called genome-wide association studies (GWAS) that can identify candidate genes and genetic variants associated with common diseases. By performing GWAS in a patient group vs. a control group, researchers have identified candidate genes and genetic variants in many common diseases, including breast cancer,4 prostate cancer5 and type 2 diabetes.6,7 These findings will significantly accelerate our understanding of the underlying genetic mechanisms of diseases. Genomic profiling technology undoubtedly has facilitated research advances by generating novel hypotheses and scientific approaches that will profoundly improve our health and quality of life.

Synergy With Molecular Imaging

While the medical field is harnessing various genomic profiling methods in both clinical and research applications, molecular imaging techniques offer an unparalleled opportunity to maximize the benefits of genomic profiling for personalized medicine. Noninvasive in vivo molecular imaging using nuclear, magnetic resonance imaging (MRI) and optical imaging techniques has the potential to validate genomic profiling findings in live tissues by either directly imaging specific molecules and pathway activity or indirectly via reporter gene activity. Applications of positron emission tomography (PET) and optical-based reporter imaging such as bioluminescence and fluorescence have been used to monitor the activity of foreign genes introduced into genetically engineered animal models. These applications demonstrate the role of foreign genes in causing diseases (similar to those in humans) and may follow the response to therapy designed to target the disease-causing genes.8

Basically, molecular imaging studies provide a spatial and temporal dimension to our understanding of oncogenesis and the progression and treatment of cancer. For example, investigators have adopted sampling of human glioblastoma multiforme for microarray analysis using MRI guidance to identify genomic profiles associated with high vascular permeability.9 Although many molecular imaging studies are limited to animal models, intense efforts are under way to translate these findings clinically. Once genomic profiling reveals that only a limited number of clinically relevant genes need following for each disease type, we could use molecular imaging in such clinical monitoring. Patients will also undergo molecular profiling by noninvasive imaging before receiving customized targeted therapy based on profiling results. Imaging will monitor therapy response as well.

Molecular imaging also impacts personalized patient care. Once biomarkers are associated with certain diseases, MRI, PET and ultrasound techniques may be used to monitor enzymes, receptors and other specific molecules associated with biological processes such as apoptosis, angiogenesis and thrombosis.10 Molecular imaging is being exploited in the treatment of cancer, inflammation and heart diseases by enabling early detection and monitoring disease progression throughout therapy.10


Before genomic profiling can realize its promise, we must overcome some challenges. First, the various existing technology platforms need standardization. We must validate clinically relevant profiles with independent datasets—preferably those from multi-institutional studies. In addition, the burgeoning industry of genomic technologies has resulted in a flurrying development of analytic software used by different investigators, leading to different outcomes and conclusions. This has created an obstacle for comparing or combining results among different datasets.

The recent burst of activities in the field also has exposed the severe shortage of well-trained bioinformaticians. It’s critical that we make a nationwide, concerted effort to establish training programs in bioinformatics in academic and research institutions at all levels.

Progress Continues

Advances in genomic profiling have tremendously accelerated our quest to fully understand the genetic makeup of individuals. This field gained real momentum with the deciphering of additional genomes of individuals, including the discovery of DNA by James Watson, PhD.11 Genomic profiling approaches clearly hold immense promise and have demonstrated the potentials to improve healthcare and disease prevention.

A number of exciting, ongoing projects are designed to reap the benefits of the Human Genome Project with the aid of genomic profiling technologies. One of the programs launched by the Centers for Disease Control and Prevention the Evaluation of Genomic Applications in Practice and Prevention–aims to implement and evaluate a systematic process to assess genomic profiling technologies slated for translation from research to clinical and health practice.12

Research advances in genomic profiling will spawn novel methods for refinement and prediction of diseases and their outcomes, patient stratification for personalized therapy and more reliable methods for early detection and possible disease prevention–impacting every facet of patient care.

Dr. Lau is an attending physician in the division of Hematology-Oncology at Texas Children’s Hospital; head of the Molecular Neuro-oncology Laboratory and the Cancer Genomics Program at the Texas Children’s Cancer Center and Hematology Service; and an associate professor at Baylor College of Medicine, all in Houston. Jian Wang, MS, is a PhD candidate in the program of Structural and Computational Biology and Molecular Biophysics at Baylor College of Medicine, Houston.

For a list of references, go to

Gene Targeting Takes Nobel Prize

Nobel laureates of 2007 were rewarded handsomely for their discoveries of “principles for introducing specific gene modifications in mice by the use of embryonic stem cells.” Mario R. Capecchi, PhD, Howard Hughes Medical Institute investigator and distinguished professor of Human Genetics and Biology at the University of Utah, Salt Lake City; Sir Martin J. Evans, FRS, DSc, director of the School of Biosciences and professor of Mammalian Genetics, Cardiff University, U.K.; and Oliver Smithies, DPhil, excellence professor of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, received their awards Dec. 10 in Stockholm, Sweden.

The trio has made a series of ground-breaking discoveries concerning embryonic stem cells and DNA recombination in mammals. Their discoveries led to gene targeting in mice—now being applied to virtually all areas of biomedicine from basic research to new therapy development. With this method, it’s possible to produce almost any type of DNA modification in the mouse genome, allowing scientists to establish the roles of individual genes in health and disease. Gene targeting has already produced more than 500 different mouse models of human disorders, including cancer, diabetes and cardiovascular and neurodegenerative diseases.

The first reports in which homologous recombination in embryonic stem cells were used to generate gene-targeted mice were published in 1989. Since then, gene targeting has developed into a highly versatile technology with the capability to introduce mutations that can be activated at specific time points—or in specific cells or organs–both during development and in the adult animal.