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ASCO Talk Touches on Clinical Implications of AML Clonal Heterogeity, Evolution

CHICAGO (GenomeWeb News) – As researchers carve out a clearer view of clonal evolution in acute myeloid leukemia, new challenges are arising in trying to understand which sets of genes may be appropriate for testing and targeting in the context of personalized patient care, attendees heard at the American Society of Clinical Oncology annual meeting here this weekend.

Presenting at an educational session on Saturday morning, Massachusetts General Hospital Cancer Center's Timothy Graubert discussed key genetic and genomic features characterizing AML — from recurrent reciprocal translocations being detected by RNA sequencing to pathways that are prone to genetic glitches in AML tumors. He also highlighted findings from studies delineating the clonal heterogeneity present in AML as the disease develops and progresses.

This clonal evolution is not only scientifically interesting, but may also have clinical implications, Graubert explained. For the most part, he noted that studies done so far described AML evolution that follows a largely linear hierarchy of mutations, with mutations accumulating gradually in blood stem cells prior to the advent of mutations that drive cancer.

In a 2012 study published in Cell, for example, a Washington University-led team presented evidence for a slew of passenger mutations aggregating in hematopoietic stem/progenitor cells as individuals age. Sub-clones containing these background mutations continue to circulate and compete with one another after AML develops, according to that study and related research.

Graubert, formerly based at Washington University, led a team of researchers who profiled mutation patterns in seven patients who progressed from a cancer predisposition condition called myelodysplastic syndrome to AML. As members of that group reported in the New England Journal of Medicine in 2012, the analysis uncovered sub-clones within tumors that were present in myelodysplastic syndrome samples collected prior to AML onset.

Along with sub-clones stemming from the founding AML clone, additional sub-clones may emerge as well, Graubert said, making it tricky to narrow in on the "best" driver mutation to target. Consequently, he argued that additional research may be needed to figure out the most effective ways of dealing with clonal heterogeneity in AML, since some patients may carry sub-clones with driver mutations that are eligible for multiple types of targeted therapy.

Recurrent mutations identified in AML tumors through DNA and RNA sequencing studies — including a 2013 study in NEJM by members of the Cancer Genome Atlas — have defined frequently mutated AML genes that may serve as treatment targets, including the IDH1 and IDH2 genes and members of cohesion and spliceosome pathways, he said.

Such studies also defined multiple genetic features and epigenetic patterns that appear to be prognostically important. The disease tends involve recurrent reciprocal translocations, though internal tandem duplications of the FLT3 gene are a recurrent feature as well and have been linked to poor outcomes in several AML studies.

Although it now seems unlikely that many new, highly recurrent fusions will be detected, Graubert noted that there remains a "long tail" of rare or private reciprocal translocations that may be biologically important for individual cases, again highlighting the enormous heterogeneity of the disease.

Finally, he explained that while some recurrently altered genes are being tested in the clinic, others are not routinely tested — something that may change as the field moves to gene panel sequencing approaches for testing multiple genes simultaneously.

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