DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome

Abstract

Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient’s skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies. The technologies that made it possible to characterize individual African and Chinese genomes have broad application in the biomedical field. A demonstration of what can be achieved in a medical context is the first comprehensive sequence of an individual cancer genome, for a patient with acute myeloid leukaemia. By comparing DNA from cancer and normal tissue from the same individual, ten mutations of possible relevance for pathogenesis were identified. As well as pointing to genes that may respond to targeted therapy, this work is a step towards the long-term goal of establishing the contextual relevance of such mutants, a process that will involve the analysis of many more personal genomes.