The Genetic Signatures of AML Vary Between Younger and Older Patients

Acute myeloid leukemia (AML) is a collection of molecularly diverse diseases with similar phenotypes, and the distribution of these diseases differs between children and adults, according to an analysis of the TARGET (Therapeutically Applicable Research to Generate Effective Treatments) AML Initiative published in Nature Medicine. These findings provide a rationale for revisiting the “trickle-down” approach of treating children and adolescents with regimens studied in adults.

“No single treatment strategy is likely to be effective for all pediatric AML subtypes, which may explain the repeated failures of randomized clinical trials to improve outcomes in recent years,” Hamid Bolouri, PhD, of the Human Biology Division at the Fred Hutchinson Cancer Research Center in Seattle, and co-authors wrote. “In keeping with the shift toward comprehensive, molecularly based classification schemas in AML, the time has come to develop targeted therapies that address specific vulnerabilities of pediatric subtypes.”

Using data from the TARGET AML Initiative, a collaboration between the Children’s Oncology Group (COG) and the National Cancer Institute, the researchers assessed cases of pediatric and adult AML to describe the mutational, transcriptional, and epigenetic landscape of the disease.

The TARGET AML dataset included 1,023 children enrolled in COG studies, with comprehensive clinical data – including clinical outcomes and test results for common sequence aberrations – available for 993 participants. Of these patients, 815 were profiled for somatic mutations at presentation: 197 by whole-genome sequencing and 800 by targeted capture sequencing.

The median age of TARGET AML participants was 10 years (range = 3-14 years). The authors found that infants (<3 years), children (3-14 years), and adolescents and young adults (15-39 years) differed broadly by cytogenetic and clinical risk group classifications.

Approximately one-quarter of patients had a normal karyotype, yet nearly all had at least one recurrent verified somatic DNA alteration.

Of the clinically detected abnormalities, only five mutations and five structural aberrations occurred in more than 5 percent of patients: FLT3, NPM1, WT1, CEBPA, and KIT mutations; RUNX1, CBFB, and KMT2A  (formerly known as MLL) fusions; and trisomy 8 and loss of the Y chromosome.

The researchers then compared the genetic makeup of AML in younger patients with findings from 177 adults (≥40 years) enrolled in The Cancer Genome Atlas (TCGA) project.

“Like adult AML, pediatric AML has one of the lowest rates of mutation among cancers that are molecularly well characterized, with less than one somatic change in a protein-coding region … in most cases,” the authors reported. “However, the landscape of somatic variants in pediatric AML was markedly different from that reported in adults.”

Alterations in RAS genes, KIT and FLT3 – including new, pediatric-specific FLT3 mutations – were more common in children than adults. Mutational burden increased with age, but older individuals had relatively fewer recurrent cytogenetic alterations, the researchers noted.

Among younger patients, recurrent structural alterations, fusions, and focal copy number aberrations were more common.

NRAS and WT1 were mutated significantly more often in younger patients. “Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases,” the investigators noted.

KRAS, CBL, GATA2, SETD2, and PTPN11 mutations also were more common in younger patients.

“Our data also demonstrate that DNA methylation and microRNA expression profiles both accompany and complement DNA alterations and can stratify pediatric subjects with AML in terms of both overall and progression-free survival,” the authors concluded. “These findings suggest a need to update pediatric AML clinical risk categories beyond current classifications, with important implications for clinical practice.”

The study is limited by the small sample sizes of certain subgroup analyses.

The authors report no financial conflicts.                                              


Reference

Bolouri H, Farrar JE, Triche Jr. T, et al. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nat Med. 2018;24:103-12.

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