Genomic pathology: challenges for implementation.

Currently, the practice of pathology is undergoing a transition in which the focus is on individual molecular tests for specific predictive biomarkers for various types of cancers. This current model is predominantly based on single tests for 1 or more biomarkers to predict possible response to 1 or more distinct targeted therapies for a cancer. However, an even more powerful technology looms on the horizon and is expected to eventually replace individual tests as the standard for personalized health care. During the past several years, the ability to map or sequence the entire genome of a cancer in a matter of minutes for a reasonable cost has become an increasingly realistic goal that could make this technology available for routine use in the evaluation of patients’ cancers. Known as whole genome sequencing or analysis or mapping, this global approach would provide a tremendous wealth of information—essentially disclosing the full picture of possible therapeutic targets for a patient’s tumor—in contrast to limited testing for a few separate genes, which might or might not prove of value as targets in a given case. Today, one might test a sample of a pulmonary adenocarcinoma for epidermal growth factor receptor (EGFR) mutations. Most likely the test would be mutational analysis of the EGFR gene, and, in up to 10% of Western patients, one might find an EGFR mutation that is potentially responsive to anti-EGFR therapy. As part of an algorithm, one might next test for ALK fusion genes using fluorescent in situ hybridization, and, in about 3% to 7% of adenocarcinomas, one might find ALK fusion genes that are potentially responsive to anti-ALK therapy. And so on, for a restricted number of genes. Once the roster of candidate biomarkers has been exhausted, one is left with adenocarcinomas that do not have any of the potential therapeutic targets and, for all cases, one does not know what other targets may be undiscovered in the vast majority of the genome that has not been examined. In contrast, by mapping the same adenocarcinoma’s entire genome, one can examine not only for EGFR mutations and ALK fusion genes at the same time, but also for other somatic changes throughout the genome, including previously unsuspected new genes, loci, and pathways. This would provide a more complete picture of all possible therapeutic targets with one test. Of course, the utility of whole genome sequencing is not limited to the therapy of cancer. This technology also has applications for infectious diseases, inherited diseases, and other types of diseases, so that its impact is expected to be felt across the entire spectrum of human disease. Indeed, some have speculated that every person may have his or her genome sequenced at birth to provide a baseline for future prediction/prevention, diagnosis, and treatment throughout the person’s lifetime. The reason that whole genome sequencing was not previously used for routine clinical practice was the large amount of time and the exorbitant cost of such testing. When the Human Genome Project finished sequencing the first entire human genome in 2003, the project took 13 years and cost nearly $2.7 billion. Not surprisingly, commercial companies have developed new generations of genome sequencing machines that today allow whole genome sequencing at a fraction of the time and cost of earlier sequencers. Companies now talk of sequencing the entire human genome in less than 15 minutes for a cost of $100 per genome. It is the ability to deliver this powerful technology in real time at a practical cost that has led to the expectation that this technology may one day replace the plethora of individual tests now performed in laboratories. Besides clinically acceptable turnaround time and affordable cost, this technology must be suitable for the analysis of routine formalin-fixed, paraffin-embedded specimens. It seems inevitable that this technology will become routine clinical practice in the future. The pathologist practicing today or in training today will want to know how soon to expect this technology and, of course, what steps he or she should be taking to address it. The answers are complex and challenging. Regarding the latter question, calls to action have recently been published, including, but not limited to, the proceedings of the meeting at the Banbury Conference Center on genome-era pathology and a call for a third track in genomic pathology by James M. Musser, MD, PhD, chair of The Methodist Hospital Department of Pathology and Laboratory Medicine, published in the Archives of Pathology & Accepted for publication April 13, 2011. From the Department of Pathology, Methodist Hospital, Houston, Texas (Dr Cagle); the Department of Pathology, University of Pittsburgh Medical Center–Presbyterian Hospital, Pittsburgh, Pennsylvania (Dr Dacic); and the Department of Pathology, University of Texas Health Science Center at Tyler (Dr Allen). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Philip T. Cagle, MD, Department of Pathology, The Methodist Hospital, 6565 Fannin St, Main Bldg, Room 227, Houston, TX 77030 (e-mail: pcagle@tmhs.org). Editorial