Molecular genetics of AML

In the past decade, a series of technological advances have revolutionized our ability to interrogate cancer genomes, culminating in whole-genome sequencing, which provides genome-wide coverage at a single base-pair resolution. To date, the tumor genome has been sequenced in nearly 40 cases of acute myeloid leukemia (AML). On average, each AML genome contains approximately 400 mutations, including 6-26 coding mutations. The majority of these mutations are 'background' mutations that were acquired during normal aging of hematopoietic stem cells. Though comprehensively identifying 'driver' mutations remains a challenge, a number of novel driver mutations in AML have been identified through whole-genome sequencing. The digital nature of next-generation sequencing has revealed clonal heterogeneity in the majority of AML at diagnosis. Importantly, in some cases, a minor subclone contributed to relapse, suggesting the strategies to assess clonal heterogeneity are needed to optimize therapy. As sequencing technologies improve and costs decrease, it is likely that whole-genome sequencing of cancer cells will become commonplace in the diagnostic work-up of patients with AML and other cancers.