Whole genome sequencing in acute myeloid leukemia

Whole genome sequencing in acute myeloid leukemiaWhen this study by The Cancer Genome Atlas (TCGA) Research Network on adult de novo acute myeloid leukemia (AML) appeared in 2013, it rewrote the model of the disease. 1 It showed that AML is not a genetic jungle, but a relatively "low-mutation" cancer whose complexity lies in which lesions co-occur, in which clones, and with which epigenetic consequences.The authors sequenced 200 adults with de novo AML using whole-genome sequencing or whole-exome sequencing, combined with RNA and microRNA analyses, single nucleotide polymorphism arrays, and DNA methylation profiling.On average, each leukemia carried 13 coding mutations, of which five affected recurrently mutated genes, far fewer than in many solid tumors.Yet they identified 23 significantly mutated genes and another 237 genes mutated in at least two samples, revealing AML as combinatorially complex despite its modest mutation number.Almost every case harbored at least one non-synonymous mutation in one of nine functional categories -transcription-factor fusions, NPM1, tumor suppressors, DNA-methylation genes, activated signaling, chromatin modifiers, myeloid transcription factors, cohesin, or spliceosome components -turning a list of "interesting genes" into an organized map of leukemogenic pathways.A particularly elegant element of the paper was the move from single mutations to rules of cooperation and mutual exclusivity.Transcription-factor fusions such as PML::RARA, RUNX1::RUNX1T1, or CBFB::MYH11 were largely mutually exclusive with NPM1 and DNMT3A, implying that these lesions can substitute as founding events.