Summary
The first comprehensive analysis combining full genomic sequencing and gene expression profiles of more than 1,300 patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) has identified prognostic constellations of driver mutations in these myeloid neoplasms.
AML and MDS are a heterogeneous group of diseases characterized by clonal expansion of undifferentiated myeloid precursors, impaired hematopoiesis and bone marrow failure, said lead author Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital, at a press briefing at the 2019 ASH Annual Meeting. Recent genomic sequencing studies have advanced the understanding of the pathogenesis of myeloid malignancies, including AML and MDS, and improved classification of specific subgroups. Unfortunately, these studies have mostly analyzed specific subtypes and/or used targeted DNA-sequencing, thus limiting discovery of novel mutational patterns and gene expression clusters, said Iacobucci.
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Original Article
Driver Mutations Identified for AML & Myelodysplastic Syndrome
Oncology Times
By Mark L. Fuerst
The first comprehensive analysis combining full genomic sequencing and gene expression profiles of more than 1,300 patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) has identified prognostic constellations of driver mutations in these myeloid neoplasms.
AML and MDS are a heterogeneous group of diseases characterized by clonal expansion of undifferentiated myeloid precursors, impaired hematopoiesis and bone marrow failure, said lead author Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital, at a press briefing at the 2019 ASH Annual Meeting. Recent genomic sequencing studies have advanced the understanding of the pathogenesis of myeloid malignancies, including AML and MDS, and improved classification of specific subgroups. Unfortunately, these studies have mostly analyzed specific subtypes and/or used targeted DNA-sequencing, thus limiting discovery of novel mutational patterns and gene expression clusters, said Iacobucci.
She and her colleagues performed an integrated genome-wide mutational/transcriptomic analysis of a large cohort of adult AML and MDS samples to accurately define subtypes of diagnostic, prognostic, and therapeutic relevance. While previous research has identified the roles of various individual genes in these diseases and their subtypes, the new study is the first to take an unbiased, genome-wide approach to illuminate the links between genes, gene expression, the physical form of cancer cells, and patient outcomes.
“Treating these diseases is a challenge because subtypes present different features,” said Iacobucci. “Our study provides a much richer understanding of these subtypes, akin to a dictionary of all the genomic alterations. It also underscores the value of having comprehensive genomic information at the start of treatment to remove uncertainty and help clinicians better understand a patient’s outlook.”
In the study (Abstract LBA-4), the researchers analyzed blood and bone marrow samples from 598 adults with AML and 706 adults with MDS. In addition to sequencing all DNA, they also sequenced RNA, an indicator of which genes are being actively expressed and which are altered by chromosomal rearrangements, a common feature in AML. They combined these data with information on health outcomes and the physical features of each patient’s cancer.
Genomic/transcriptome sequencing confirmed diagnosis with recurrent genetic abnormalities in 10.9 percent of cases, according to WHO 2016 criteria of AML. These cases had a distinct gene expression profile, good prognosis, and a combination of mutations in the following genes: KIT, ZBTB7A, ASXL2, RAD21, CSF3R, and DNM2 in RUNX1-RUNXT1 leukemia; FLT3, DDX54, WT1 and CALR in PML-RARA promyelocytic leukemia; KIT and BCORL1 in CBFB-rearranged leukemia.
In addition, 9 percent of cases showed rearrangements of KMT2A, with known and non-canonical partners and poor outcome. Although common targets of mutations have been previously described for myeloid malignancies, the heterogeneity and complexity of mutational patterns, the expression signature and outcome described are novel, she said.
Gene expression analysis identified groups of AML and/or MDS lacking recurrent cytogenetic abnormalities (87%).
In addition to confirming known genetic subtypes driven by chromosomal lesions or mutations, the results shed light on previously unknown associations. For example, the researchers found pairs of genetic alterations that seem to change a patient’s prognosis when they occur together, such as combinatorial mutations in NPM1 and cohesin genes that confer good prognosis. Conversely, mutations and structural variants of RUNX1 in association to overexpression of MN1 have a very poor outcome. They also discovered unexpected genetic similarities among cancers that are morphologically different from each other, underscoring how genetic analysis combined with standard approaches provides a more complete picture than analysis of morphology alone.
These insights may have important implications for both cancer research and clinical decision-making. At a basic level, having a dictionary-like genetic reference for AML and MDS subtypes will be useful for future research into how these diseases develop and how they might be targeted with new drugs. From a clinical perspective, the study suggests full-genome sequencing is not only feasible but useful for identifying disease subtypes and prognosis in order to tailor the course of treatment to each patient’s disease in a precision medicine approach.
“This is the sort of dataset that is going to prove invaluable to precision medicine efforts,” said Iacobucci. “As we have seen in lymphoid malignancies, the study shows the power of integrated genome and transcriptome sequencing to identify new disease subgroups of clinical significance not evident on conventional pathologic and molecular analysis.”
Researchers from the Munich Leukemia Laboratory have recently sequenced DNA and RNA from more than 4,500 patients as part of a broader effort to move whole genome and transcriptome sequencing from the laboratory into the clinic for diagnosis and targeted treatment.
In conclusion, Iacobucci said: “The integration of mutational and expression data from a large cohort of adult pan-myeloid leukemia cases enabled the definition of subtypes and constellations of mutations and have prognostic significance that transcends prior gene panel-based classification schema.”
Mark L. Fuerst is a contributing writer.