Distinct age-associated molecular profiles in acute myeloid leukemia defined by comprehensive clinical genomic profiling
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Katherine Tarlock1,2,*, Shan Zhong3,*, Yuting He3,*, Rhonda Ries2, Eric Severson3, Mark Bailey3, Samantha Morley3, Sohail Balasubramanian3, Rachel Erlich3, Doron Lipson3, Geoff A. Otto3, Jo-Anne Vergillo3, E. Anders Kolb4, Jeffrey S. Ross3, Tariq Mughal3,5, Philip J. Stephens3, Vincent Miller3, Soheil Meshinchi2 and Jie He3
1Department of Hematology/Oncology, Seattle Children’s Hospital, Seattle WA, USA
2Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle WA, USA
3Foundation Medicine, Cambridge MA, USA
4Nemours Center for Cancer and Blood Disorders, Nemours-Alfred I. DuPont Hospital for Children, Wilmington DE, USA
5Tufts University Medical Center, Boston MA, USA
*These authors contributed equally to this work
Katherine Tarlock, email: firstname.lastname@example.org
Keywords: acute myeloid leuekmia; sequencing; pediatric; adult; genomic profiling
Received: February 28, 2018 Accepted: April 27, 2018 Published: May 29, 2018
Large scale comprehensive genomic profiling (CGP) has led to an improved understanding of oncogenic mutations in acute myeloid leukemia (AML), as well as identification of alterations that can serve as targets for potential therapeutic intervention. We sought to gain insight into age-associated variants in AML through comparison of extensive DNA and RNA-based GP results from pediatric and adult AML. Sequencing of 932 AML specimens (179 pediatric (age 0–18), 753 adult (age ≥ 19)) from diagnostic, relapsed, and refractory times points was performed. Comprehensive DNA (405 genes) and RNA (265) sequencing to identify a variety of structural and short variants was performed. We found that structural variants were highly prevalent in the pediatric cohort compared to the adult cohort (57% vs. 30%; p < 0.001), with certain structural variants detected only in the pediatric cohort. Fusions were the most common structural variant and were highly prevalent in AML in very young children occurring in 68% of children < 2 years of age. We observed an inverse trend in the prevalence of fusions compared to the average number of mutations per patient. In contrast to pediatric AML, adult AML was marked by short variants and multiple mutations per patient. Mutations that were common in adult AML were much less common in the adolescent and young adult cohort and were rare or absent in the pediatric cohort. Clinical CGP demonstrates the biologic differences in pediatric vs. adult AML that have significant therapeutic impacts on prognosis, therapeutic allocation, disease monitoring, and the use of more targeted therapies.
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