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Xu et al. J Transl Genet Genom 2021;5:218-39 https://dx.doi.org/10.20517/jtgg.2021.20 Page 230

Environmental exposures and ALL risk
Genetic variation undoubtedly contributes to the racial/ethnic disparities in ALL risk and outcomes, but
non-genetic factors also play an important role. In terms of the natural history of the disease, it has been
proposed that childhood ALL, in particular B-ALL, follows a “two-hit” model of leukemogenesis [45,157] , with
in utero development of a pre-leukemic clone [158,159] that progresses to overt leukemia following postnatal
[160]
acquisition of secondary genetic changes . A lack of microbial infectious exposure perinatally or in
infancy impacts immune function [161-163] , and this in combination with delayed exposure to infections may
[45]
lead to abnormal immune responses that result in secondary somatic events that drive leukemogenesis .
This is supported by epidemiological evidence, including from studies that have assessed the impact of
early-life infectious exposure on ALL risk, using proxies such as day-care attendance [164-166] , birth
order [166-168] , and timing of birth . Intriguingly, day-care attendance and higher birth order have been
[168]
found to have a protective effect on ALL risk among NHWs supporting the “delayed infection”
[45]
hypothesis , but not in Hispanic/Latino children [164-166,168] . On the other hand, Caesarean section and in
utero CMV infection, found to be risk factors for childhood ALL, conferred a more prominent effect in
Hispanics/Latinos compared to NHWs [169-171] . As described above, several genetic variants and high-risk
cytogenetic features are more prevalent in Hispanics/Latinos and are correlated with Indigenous American
ancestry. More studies are needed to investigate the joint effects of both genetic and environmental risk
factors and their potential interactions, particularly in Hispanics/Latinos.

Socioeconomic status and ALL risk and survival
Socioeconomic status (SES) also correlates with the racial/ethnic disparities in ALL risk. For example, in a
recent study, when adjusting for percent foreign-born in areas, neighborhood SES was inversely associated
with the AAIR of ALL among NHWs and Blacks, but was positively associated with ALL AAIR in
Hispanics/Latinos across all age groups . This observed racial/ethnic difference in the relationship between
[66]
[66]
SES and the risk of ALL was reported to be largely driven by data from California , where there was an
excessive ALL risk in Los Angeles County and a highly diverse population in which Hispanics/Latinos are of
an elevated Indigenous American ancestry. This contrasts with another study conducted in children without
adjusting for percent foreign-born, in which they found a higher incidence of ALL among lower SES
[172]
populations for Hispanics/Latinos, but among higher SES populations for other races/ethnicities . One
potential reason that leads to this difference is that the former study additionally controlled for percent
foreign-born, which is a crucial indicator of the “Hispanic paradox” [100,101] , and represents a variety of
potential underlying risk factors that may differ by individual and racial/ethnic group.

On the other hand, low SES is consistently associated with poor outcomes in ALL patients. Living in high
poverty areas has been associated with high rates of relapse in childhood ALL patients . Children with
[173]
ALL in the United States residing in neighborhoods with the highest poverty rate have been found to have
an almost 2-fold increase in mortality compared with those in neighborhoods with the lowest poverty rate
[HR = 1.8 (95%CI: 1.41-2.30)], when adjusting for sex, age at diagnosis, race/ethnicity, and treatment era .
[174]
Moreover, the difference in 5-year overall survival comparing NHW children with ALL residing in the
lowest poverty neighborhoods vs. Black patients residing in the highest poverty neighborhoods can be as
high as 22% . Furthermore, in SEER data, SES as measured at the neighborhood level significantly
[174]
mediated the association between race/ethnicity and childhood ALL survival, leading to a 44% reduction
from the total to the direct effect of the Black-NHW survival disparity and 31% reduction of the
Hispanic/Latino-NHW disparity in survival . The inferior outcomes in high poverty neighborhoods
[175]
might be attributable to multiple elements, including a poor adherence to therapy (e.g., long-term oral
administration of antimetabolites) [176,177] , lack of insurance, and the discontinuous coverage of
insurance [178-180] .