Childhood and Adult Acute Myeloid Leukemia: Genetically Distinct Diseases
Childhood cancers constitute a diverse group of malignancies that are diagnosed in patients ranging in age from newborns to young adults. Although they are quite rare compared to adult malignancies, pediatric cancers, as a whole, are the leading cause of death from disease in children. Coordinated efforts from large cooperative groups, such as the Children’s Oncology Group (COG), have helped reduce mortality more than 50% between 1975 and 20021. Despite this considerable improvement in overall outcome, mortality rates have plateaued in recent years. Furthermore, conventional treatment regimens are particularly harsh on developing children, because the protocols are largely modified adult protocols. In children, they often lead to devastating effects, such as developmental delays and infertility. Therefore, a novel approach to treatment is needed. Because targeted therapies can be less toxic and more effective than current cancer treatments, agents directed at underlying genomic abnormalities have the potential to improve both survival and quality of life of pediatric patients.
Many childhood cancers appear as genetically distinct diseases from their adult counterparts and will benefit from independent genomic studies and novel therapeutic strategies. Acute myeloid leukemia (AML), a heterogeneous group of myeloid cancers, is a prime example of a cancer type that demonstrates different genomic signatures between pediatric and adult patients despite phenotypic similarities (Figure 1). For instance, most AML patients less than 2 years of age have MLL translocations (11q23) (~60% of all AML < 1 year) and it declines with increasing age (<5% in adults). MLL is a methyltransferase gene involved in the regulation of hematopoietic differentiation and proliferation. Conversely, the normal karyotype (NL) AML is much less common in young children, but increases in prevalence with age (<10% in children under 2 years; 40% in adults). Patients with NL lack identifiable cytogenetic alterations, and are enriched in FLT3 and NPM somatic mutations. FLT3 regulates stem cell differentiation and proliferation, and NPM participates in many basic cellular processes, including biosynthesis of ribosomes and regulation of centrosome duplication. Similar differences in age-related prevalence of Core Binding Factor (CBF) alterations (inv(16) or t(8;21) translocations) have also been observed. Finally, recent studies identified novel clinically relevant genomic alterations (IDH1, DNMT3A) in adult AML that were absent in childhood AML (data not shown in the figure), providing more support that these cancers are distinct diseases with distinct underlying etiologies.
Age-associated variations in AML incidence are also detected (Figure 2). A decline in AML incidence is observed over the first decade of life from its highest rate (infant) to its lowest rate (9 years of age). This trend starts to reverse by age 10, where there is a slow increase in incidence up to age 40. This is followed by two successive bursts in AML incidences in older populations up to the highest recorded levels at age 84.
The differences in both the genomic makeup and frequency of AML between children and adults suggest that different molecular mechanisms contribute to AML tumorigenesis through various stages of life. This age-associated molecular variation underscores a need to develop therapies that target the underlying molecular aberrations identified in both children and adult AML patients.
In the last decade, there have been a number of large-scale genomic studies interrogating cancer genomes for clinically actionable genomic alterations. Some of them exclusively study childhood cancers (e.g. Therapeutically Applicable Research to Generate Effective Treatments; TARGET) or adult cancers (e.g. The Cancer Genome Atlas; TCGA), while others study both (e.g. Cancer Genome Characterization Initiative; CGCI). Through extensive sequencing and genome-wide analysis, the pediatric initiative TARGET will help identify novel molecules for clinical intervention in five pediatric cancer types, including AML, neuroblastoma, kidney tumors, osteosarcoma, and acute lymphoblastic leukemia. TARGET will soon provide comprehensive data and analyses on the whole genomes, transcriptomes (RNA-seq, miRNA-seq) and epigenomes of these diseases. This multi –omic information will be integrated to determine potential therapeutic targets as well as biomarkers for risk identification in pediatric patients to improve outcomes.
As more genomic data on various malignancies are being generated, it is important for investigators to consider the age of patients in their interpretation of the data. As we are learning with AML, the stage of development can be a factor in the underlying disease processes of tumorigenesis. Moreover, frequency of mutation varies between age groups, highlighting the need for targeted therapies based on these differences. Molecular differences identified between certain age cohorts should be accounted for in future clinical studies to ensure that appropriate treatment is available for all patients.
- Horan JT, Hasle H, Meshinchi S. Acute Myeloid Leukemia. In: Smith FO, GH R, JM aR, editors. Hematopoietic Cell Transplantation in Children with Cancer: Springer; 2013.
- Altekruse S, Kosary C, Krapcho M, Neyman N, Aminou R, Waldron W, et al. SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD.
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