Genomics-Informed Pathology

Nevertheless, the rate of uptake of new technologies by the field of pathology has traditionally been slow, resulting in delayed advancements. Our understanding of infectious disease and ability to conduct diagnostics using the compound microscope came nearly 150 years after its invention. Today, nearly 80 years after the invention of the electron microscope, disagreement remains about its full value in diagnostic practice. Digital imaging took nearly 10 years to become standard practice in medical pathology, despite being established in virtually all other branches of the hospital, and polymerase chain reaction (PCR) technologies took approximately 5 years to take hold, again despite widespread adoption in medical research. By the time these critical tools percolated into the standard practice of hospital pathology, they were no longer new, and were in some cases already being replaced by alternative strategies and competing technologies.

Today a game-changing technological innovation has emerged that the field of pathology must not ignore: next-generation sequencing of entire human genomes. In contrast to the gradual unfolding of other inventions that have sharpened the clinical impact of pathology, both the quality and speed of genomic sequencing technologies are rocketing upward. The fastest technologies can sequence an entire human genome, 3 billion bases, in hours, and corresponding costs have dropped from $30,000 to $4,000 within about a year. The much-heralded $1,000 genome is within grasp.

Pathologists must meet the challenge of genomic personalization

Because it has the potential to reshape health care and make personalized medicine a ubiquitous reality, pathologists cannot afford to ignore the sequencing revolution. “Revolution” is not too strong a word; this is not incremental change. The use of whole-genome analysis can, should, and will replace many current standard pathology practices of diagnosis and prognosis on which proper therapy and disease management rely.

To ensure that pathologists do not miss this historical moment, we have begun to establish a national agenda for the future of pathology in personalized medicine, highlighting key areas that must be addressed in order for pathology to play a leading role in the clinical application of whole-genome analysis. First, we must define guidelines that establish when a genetic variation (or set thereof) can be used to support clinical decisions, including assessment of risk, diagnosis, prognosis, and treatment plan. Second, a clinical interpretation system, which involves close coupling between clinicians and biomedical informatics specialists, must be designed to generate medical impact reports from sequencing data and whole-genome analysis. Proper clinical interpretation requires integration of numerous layers of information that pathologists are trained in, but the analysis of genomics data adds a volume of scale and complexity that requires a new kind of sophistication and knowledge. Finally, a training program aimed at producing a new breed of “genomic pathologist” through novel, national education programs must be put in place.

This is pathology’s time to seize the opportunity and march in step with the technological innovations of modern human genomics.

Pathology needs to gain control of the effort to establish a certified, clinical-grade database of genetic variations related to different disease states and susceptibility by enlisting the help of new professionals in genomic medicine who are trained in genomic technology, analytics, and interpretation. Current databases of this sort have been built through an ad hoc process designed to support research activities but have not focused specifically on what type and degree of clinical action can be derived from genomic variants.

We have to train our future doctors to understand the fundamentals of the pipeline from whole-genome sequencing to clinical annotation and to be able to interpret medical impact reports that contain genomically informed diagnoses. Pathology programs have to embrace the innovation of next-generation genomics by establishing resident training programs that provide all the skills necessary to interpret and act on whole-genome data. This is already beginning to happen. In the United States, a national committee has been formed, including members of the Program Directors Section (PRODS) of the Association of Pathology Chairs and other key stakeholders, to disseminate model curricula and support their widespread implementation. We are moving fast toward definitions of the core competencies in genomics and personalized medicine, and it is likely that within 2 years it will be required that all residents in pathology demonstrate proficiency in these areas.

This is pathology’s time to seize the opportunity and march in step with the technological innovations of modern human genomics. Getting there will require a national revamp of hospital pathology to ensure that modern genomic practices are deeply integrated with all other clinical tests in patient care, and regulated by stringent standards. In short, we must embed high-powered computational analysis of human genomes and their correlation with clinical assessment directly into the pipeline of standard-care testing and treatment. This may be the only way to guarantee that the “$1,000 genome” achieves its potential to make personalized medicine a widespread reality.

Dennis P. Wall is an associate professor and Director of Computational Biology at Harvard Medical School. Peter J. Tonellato, a professor and Director of the Laboratory for Personalized Medicine at Harvard Medical School, is also a professor at University of Wisconsin-Milwaukee. This article is adapted from an F1000 Medicine Reports, DOI:10.3410/M4-14 (open access at f1000.com/reports/m/4/14/).