DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome

TLDR

Acute myeloid leukaemia is a highly malignant haematopoietic tumour affecting ~13,000 adults annually in the U.S., yet treatment has changed little because most initiating genetic events remain undiscovered, and whole‑genome sequencing is now affordable for unbiased discovery of tumour‑specific somatic mutations. The study aims to present the sequencing results of a typical AML genome and its matched normal skin sample. Whole‑genome sequencing of the tumour and matched normal was performed to identify somatic mutations across the genome. Ten genes with acquired mutations were identified, including two previously described drivers and eight novel mutations present in virtually all tumour cells at presentation and relapse, demonstrating that whole‑genome sequencing is an unbiased method for discovering cancer‑initiating mutations that may be targetable.

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.