Whole-genome sequencing: a step closer to personalized medicine.

THE PAST 60 YEARS HAVE WITNESSED REMARKABLE progress in genetics and genomics from the description of the DNA double helix by Watson and Crick to the release of the first draft sequence of the human genome in 2001 and the successful completion of the human genome project in 2003. From that time, there has been increasing hope and expectation that, as soon as the cost of sequencing the whole genome could become affordable, the promise of personalized medicine would be fulfilled. No field of medicine has benefited more from advances in genomics and the application of genetic testing than oncology. These advances have had a substantial influence on cancer risk assessment, determination of prognosis, and choice of treatment. Clinical applications of novel genetic tools include sequencing and analysis of germline genomic rearrangements at key cancer genes like BRCA1, BRCA2, and TP53; mismatch repair genes such as MLH1, MSH2, MSH6, and PMS2; development and widespread use of clinical karyotyping for hematologic malignancies; analysis of ERBB2 overexpression in breast cancer; KRAS gene mutations in colorectal cancer—and even gene expression analysis in breast cancer as a form of molecular pathology. In many cases, these genetic data have not only prognostic value but also important therapeutic implications for the patient. With the advent of more comprehensive, genomewide analyses of large tumor sets by projects like the Cancer Genome Atlas, the number of clinically relevant molecular tests is expected to continue to increase. Yet even these tests of commonly mutated cancer genes have limits and will always lack sensitivity to atypical mutations or gene expression patterns. The complexities of any individual’s cancer genome, and the treatment implications therein, are unlikely to be defined by single genes. For this reason, the latest advances in genomic technology have excited so many in the field. Over the past few years, high-throughput, short-read DNA sequencers have revolutionized the field of genomics and have accelerated the pace of discovery in cancer research. The new technologies simultaneously read millions of short, 50to 200-nucleotide DNA sequences from a pool of randomized genomic fragments in a single experiment. The process, which would have taken months with older technologies, is finished in a few days. Prior to the completion of the Human Genome Project, these short reads would have been difficult to interpret, as their genomic origin would have been unknown. However, the human reference sequence is now used to computationally map these sequences to the genome and to identify polymorphisms and novel mutations in a patient’s DNA. The ability to sequence an individual’s entire genome as well as the patient’s tumor genome is now a feasible enterprise at a cost and speed that was unthinkable even 5 years ago. In less than 3 years, DNA sequencing costs have decreased by more than 100-fold. The rate of improvement exceeds the advancement in computational power over the same time period, which predicts an oncoming wave of genomic data. Today, sequencing a tumor genome is still expensive and requires an infrastructure that is incompatible with a clinical setting, but the trend suggests that we are a lot closer to cost-effective, clinical genomics than most physicians realize. Two articles in this issue of JAMA are remarkable examples of the power that these genomic data hold for patients with a diagnosis of cancer. In one report, Link and colleagues, from Washington University, St Jude Children’s Research Hospital, and University of Chicago, performed whole-genome sequencing on skin and leukemic cells from a woman with suspected cancer susceptibility syndrome based on the early onset of several primary tumors. The patient had breast cancer at age 37 years, had ovarian cancer at age 39 years with recurrence at age 42 years, and developed treatment-related acute myeloid leukemia (t-AML) 6 months later. Genetic testing for mutations of the BRCA1 and BRCA2 genes was unrevealing, and in keeping with guidelines for assessment of high risk for familial cancer, no additional targeted genetic testing was obtained. However, whole-genome DNA sequencing showed that the patient was heterozygous for a novel deletion of 3 exons of the TP53 gene and that the intact copy of TP53 had been