A clinical transcriptome approach to patient stratification and therapy selection in acute myeloid leukemia

T. Roderick Docking, Jeremy D. K. Parker, Martin Jädersten, Gerben Duns, Linda Chang, Jihong Jiang, Jessica A. Pilsworth, Lucas A. Swanson, Simon K. Chan, Readman Chiu, Ka Ming Nip, Samantha Mar, Angela Mo, Xuan Wang, Sergio Martinez-Høyer, Ryan J. Stubbins, Karen L. Mungall, Andrew J. Mungall, Richard A. Moore, Steven J. M. Jones, İnanç Birol, Marco A. Marra, Donna Hogge and Aly Karsan ()
Additional contact information
T. Roderick Docking: University of British Columbia
Jeremy D. K. Parker: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Martin Jädersten: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Gerben Duns: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Linda Chang: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Jihong Jiang: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Jessica A. Pilsworth: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Lucas A. Swanson: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Simon K. Chan: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Readman Chiu: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Ka Ming Nip: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Samantha Mar: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Angela Mo: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Xuan Wang: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Sergio Martinez-Høyer: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Ryan J. Stubbins: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Karen L. Mungall: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Andrew J. Mungall: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Richard A. Moore: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Steven J. M. Jones: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
İnanç Birol: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Marco A. Marra: Canada’s Michael Smith Genome Sciences Centre, BC Cancer
Donna Hogge: Vancouver General Hospital
Aly Karsan: University of British Columbia

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract As more clinically-relevant genomic features of myeloid malignancies are revealed, it has become clear that targeted clinical genetic testing is inadequate for risk stratification. Here, we develop and validate a clinical transcriptome-based assay for stratification of acute myeloid leukemia (AML). Comparison of ribonucleic acid sequencing (RNA-Seq) to whole genome and exome sequencing reveals that a standalone RNA-Seq assay offers the greatest diagnostic return, enabling identification of expressed gene fusions, single nucleotide and short insertion/deletion variants, and whole-transcriptome expression information. Expression data from 154 AML patients are used to develop a novel AML prognostic score, which is strongly associated with patient outcomes across 620 patients from three independent cohorts, and 42 patients from a prospective cohort. When combined with molecular risk guidelines, the risk score allows for the re-stratification of 22.1 to 25.3% of AML patients from three independent cohorts into correct risk groups. Within the adverse-risk subgroup, we identify a subset of patients characterized by dysregulated integrin signaling and RUNX1 or TP53 mutation. We show that these patients may benefit from therapy with inhibitors of focal adhesion kinase, encoded by PTK2, demonstrating additional utility of transcriptome-based testing for therapy selection in myeloid malignancy.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22625-y

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DOI: 10.1038/s41467-021-22625-y

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