Distinct age-associated molecular profiles in acute myeloid leukemia defined by comprehensive clinical genomic profiling

Abstract

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.

BCOR Involvement in Cancer

“…The involvement of BCOR alterations in clonal disorders of myeloid lineage (Table 2) has been assessed primarily for myelodysplasias [83,87,91–93] and acute myeloid leukemia (AML) [94,102–104], with cases ranging from less than 1–10% in unselected cohorts. By analyzing these and other cohort studies, it was possible to identify clinical contexts where the presence of BCOR alterations is most frequent.…”

“…By analyzing these and other cohort studies, it was possible to identify clinical contexts where the presence of BCOR alterations is most frequent. Particularly in AML, it is clear that the frequency of BCOR mutations is significantly higher in older patients than in pediatric ones [90,94,96,101], with pediatric AMLs with normal karyotype as the exception [88] and higher in secondary AML with respect to primary AML [102]. NGS techniques allow for the identification of new molecular subgroups potentially related to specific clinical characteristics, in addition to those already identifiable by cytogenetic studies.…”

Measurable residual disease in pediatric acute myeloid leukemia: a systematic review

“…A second way to improve the assessment of MRD in pediatric AML is to include RT-PCR in more patients, by the identification of more targets for RT-PCR. Large-scale genomic profiling showed that certain structural variants are highly present in pediatric AML cohorts [31]. Quantitative RT-PCR will enable a higher sensitivity of MRD assessment than flowcytometry (up to 10 −6 and 10 −4 , respectively).…”

Comprehensive genomic analysis identifying heterogeneity in peripheral T‐cell lymphoma

“…In other cancers, younger age is associated with particular genetic alterations, which are considered to be "driver" genes. [33][34][35][36][37][38] We speculated that ATLL in younger patients would exhibit distinct genetic alterations and, accordingly, performed genomic analysis. We identified eight patients with ATLL who were <50 years of age at the time of diagnosis and defined them as young ATLL.…”