For unexplained reasons, the incidence of ALL is substantially higher in white children than in black children, with a nearly threefold higher incidence from age 2 to 3 years in white children compared with black children.[3,4] The incidence of ALL appears to be highest in Hispanic children (43 per million).[3,4]
Risk Factors for Developing ALL
Few factors associated with an increased risk of ALL have been identified. The primary accepted risk factors for ALL include the following:
- Prenatal exposure to x-rays.
- Postnatal exposure to high doses of radiation (e.g., therapeutic radiation as previously used for conditions such as tinea capitis and thymus enlargement).
- Down syndrome and other genetic conditions.
- Inherited genetic polymorphisms.
Children with Down syndrome have an increased risk of developing both ALL and acute myeloid leukemia (AML),[6,7] with a cumulative risk of developing leukemia of approximately 2.1% by age 5 years and 2.7% by age 30 years.[6,7] Approximately one-half to two-thirds of cases of acute leukemia in children with Down syndrome are ALL. Patients with ALL and Down syndrome have a lower incidence of both favorable (t[12;21] and hyperdiploidy) and unfavorable (t[9;22], t[4;11], and hypodiploidy) cytogenetic findings and a lower incidence of T-cell phenotype.[8,9,10,11] Approximately 50% of children with Down syndrome and ALL have a recurring interstitial deletion of the pseudoautosomal region (PAR) of chromosomes X and Y that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2. The resulting P2RY8-CRLF2 fusion gene is observed at a much lower frequency (<10%) in non-Down children with B-precursor ALL.[12,13] Approximately 20% of ALL cases arising in children with Down syndrome have somatically acquired JAK2 mutations,[14,15,16] a finding that is uncommon among younger children with ALL but that is observed in a subset of primarily older children and adolescents with high-risk B-precursor ALL. Almost all Down syndrome ALL cases with JAK2 mutations also have the PAR deletion and express the P2RY8-CRLF2 fusion gene. Preliminary evidence suggests no correlation between JAK2 mutation status and 5-year event-free survival in children with Down syndrome and ALL.
While the vast majority of cases of AML in children with Down syndrome occur before the age of 4 years (median age, 1 year), ALL in children with Down syndrome has an age distribution similar to that of ALL in non-Down syndrome children, with a median age of 3 to 4 years.[9,10] Increased occurrence of ALL is also associated with other genetic conditions, including neurofibromatosis, Shwachman syndrome,[19,20] Bloom syndrome, and ataxia telangiectasia.
Genome-wide association studies show that germline (inherited) genetic polymorphisms are associated with the development of childhood ALL. For example, the risk alleles of ARID5B, a gene that encodes a transcriptional factor important in embryonic development, cell type-specific gene expression, and cell growth regulation, are strongly associated with the development of hyperdiploid B-precursor ALL.[24,25]