Abstract 23: Somatic mutation of cancer susceptibility genes in acute myeloid leukemia
Authors: Brown Anna L. , Gray James X. , Leo Paul , Zeya Maung Kway , Bassal Mahmoud , Engler Grant , Bray Sarah , Gardiner Brooke , Marshall Mhairi , Tiong Ing Soo , Cummings Nik , Wei Andrew , To Bik , Lewis Ian , D'Andrea Alan , Gonda Thomas , D'Andrea Richard 
Published: May 2015

Abstract
Acute myeloid leukemia (AML), which is the most common acute leukemia in adults, is a particularly devastating disease that is universally fatal without therapy and has the longest hospital length of stay of any cancer. In addition there are a number of familial diseases described that have as a feature an increased susceptibility to AML. Examples of this are MDS/AML associated with germline mutations in the gene encoding the transcription factor GATA2, the ribosomopathies such as Diamond Blackfan Anemia, and Fanconi Anemia (FA) which is caused by bi-allelic mutations in any of the genes in FA complementation groups. Interestingly genes associated with predisposition to hematological malignancy, such as CEBPA, RUNX1 and GATA2 have also been described as targets of somatic mutation in AML.
The application of next-generation whole-genome and whole-exome sequencing is greatly facilitating the dissection of the pathways altered during AML development. The discovery of new classes of mutations is increasing knowledge of the leukemogenesis process, improving disease classification and providing potential therapeutic targets. We have performed whole exome capture and next generation sequencing (NGS) of a series of 96 diagnostic AML samples. Analysis of the NGS data and comparison with genotyping performed using traditional methods, and a custom-designed Sequenom mutation panel, has confirmed the sensitivity and specificity of the NGS approach. Novel variants have been grouped into gene networks using a number of approaches, including pathway analysis, protein interaction databases, and known functional relationships. We have identified novel variants in a number of cancer susceptibility genes, and in particular we are characterising potential pathogenic mutations in a network of genes involved in the pathogenesis of Fanconi Anemia. Given that FA patients have a greatly increased predisposition to AML (at least 600-fold), we are performing functional assays to determine the significance for AML of somatic and germline variants in this network. Data will also be presented describing the clinical characteristics, mutation profile, gene expression signatures, and treatment outcomes for patients with mutations in this network.
Citation Format: Anna L. Brown, James X. Gray, Paul Leo, Maung Kway Zeya, Mahmoud Bassal, Grant Engler, Sarah Bray, Brooke Gardiner, Mhairi Marshall, Ing Soo Tiong, Nik Cummings, Andrew Wei, Bik To, Ian Lewis, Alan D'Andrea, Thomas Gonda, Richard D'Andrea. Somatic mutation of cancer susceptibility genes in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 23. doi:10.1158/1538-7445.CANSUSC14-23