Is There Etiologic Heterogeneity between Subtypes of Childhood Acute Lymphoblastic Leukemia? A Review of Variation in Risk by Subtype

Abstract

Although substantial advances in the identification of cytogenomic subtypes of childhood acute lymphoblastic leukemia (ALL) have been made in recent decades, epidemiologic research characterizing the etiologic heterogeneity of ALL by subtype has not kept pace. The purpose of this review is to summarize the current literature concerning subtype-specific epidemiologic risk factor associations with ALL subtype defined by immunophenotype (e.g., B-cell vs. T-cell) and cytogenomics (including gross chromosomal events characterized by recurring numerical and structural abnormalities, along with cryptic balanced rearrangements, and focal gene deletions). In case-control analyses investigating nongenetic risk factors, home paint exposure is associated with hyperdi-ploid, MLL-rearranged, and ETV6-RUNX1 subtypes, yet there are few differences in risk factor associations between T-and B-ALL. Although the association between maternal smoking and ALL overall has been null, maternal smoking is associated with an increasing number of gene deletions among cases. GWAS-identified variants in ARID5B have been the most extensively studied and are strongly associated with hyperdiploid B-ALL. GATA3 single nucleotide variant rs3824662 shows a strong association with Ph-like ALL (OR ¼ 3.14). However, there have been relatively few population-based studies of adequate sample size to uncover risk factors that may define etiologic heterogeneity between and within the currently defined cytogenomic ALL subtypes.

Survival Differences Between Males and Females Diagnosed With Childhood Cancer

“…Sex differences in tumor biology may be an important factor in the observed sex differences in survival after a childhood cancer diagnosis. Concerning ALL, where we observed the strongest increased risk of death among males for children aged 5–9 years at diagnosis, there are known differences the distribution of cytogenomic subtypes by age at diagnosis (29), which also have differing prognoses (30,31). However, there is little information available on sex differences in ALL subtypes, particularly the cytogenomic subtypes.…”

Male Sex and the Risk of Childhood Cancer: The Mediating Effect of Birth Defects

“…Analyses of the birth defect and cancer associations have also seen age-dependent results, with stronger effect estimates for younger age at cancer onset ( 3 , 7 ). Finally, evidence suggests that there are age-dependent biologically distinct subtypes of a single cancer (ie, acute lymphoblastic leukemia) based on the differing etiology and molecular subtypes that vary by age at diagnosis ( 29 , 30 ). We believe that these factors are driving the differences that we observed by age at diagnosis.…”

Association of genes ARID5B, CEBPE and folate pathway with acute lymphoblastic leukemia in a population from the Brazilian Amazon region

“…And the rs2239633 variant of the CEBPE gene is largely null in children with and without MLL rearrangements. Most of these association studies were performed in poorly mixed populations [36]. Furthermore, the association between ALL cytogenetic subtypes and ethnic variation is poorly verified in the literature.…”