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Page 219 Xu et al. J Transl Genet Genom 2021;5:218-39 https://dx.doi.org/10.20517/jtgg.2021.20

to care, and inclusion of more diverse populations in future clinical trials.

Keywords: Acute lymphoblastic leukemia, disparities, race/ethnicity, genetic variation, socioeconomic status,
access to care, recruitment to clinical trials, children, adolescents and young adults

INTRODUCTION
Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by impaired differentiation,
proliferation, and accumulation of B- and T-lineage lymphoid precursor cells in the bone marrow,
peripheral blood, and other organs . In the United States, the age-adjusted incidence rate (AAIR) for ALL
[1,2]
[3]
was estimated to be 1.64 per 100,000 people , with approximately 5700 new cases and 1600 deaths projected
to occur in 2021 . The incidence rate (IR) of ALL demonstrates a bimodal age pattern, in which the initial
[4]
peak occurs at age 1-4 years, followed by a decline at age 20-59 years and a modest rise at ages above 60
[5]
years . Indeed, ALL is the most common childhood malignancy, with approximately 2700 incident ALL
[6]
cases diagnosed under age 15 each year in the United States .
The causes of ALL are multifactorial, and likely vary based on the molecular subtype and patient age of
diagnosis . Only a small proportion (< 10%) of ALL cases are attributable to known risk factors with large
[7]
effects , namely ionizing radiation and congenital syndromes [9-13] , although both common and rare genetic
[8]
variants are now known to contribute to childhood ALL risk . Genome-wide association studies (GWAS)
[14]
of childhood ALL have identified multiple genomic regions harboring common risk alleles for ALL,
including at: 7p12.2 (IKZF1), 8q24.21, 9p21.3 (CDKN2A/B), 10p12.2 (PIP4K2A), 10p12.31 (BMI1), 10p14
(GATA3), 10q21.2 (ARID5B), 10q26.13 (LHPP), 12q23.1 (ELK3), 14q11.2 (CEBPE), 16p13.3 (USP7), 17q12,
and 21q22.2 (ERG) [15-32] [Table 1]. In addition, sequencing studies of familial and sporadic ALL have
discovered rare germline variants in PAX5 [33,34] , ETV6 [35-39] , IKZF1 [40-42] , and TP53 [43,44] that are associated with
disease risk. Non-genetic factors also contribute to ALL risk; for example, there is strong epidemiological
evidence supporting a role for early life infections and modulation of the developing immune system in
[45]
childhood ALL etiology, which has been reviewed in detail elsewhere . Studies have also reported modest
associations for childhood ALL risk with several environmental exposures , including tobacco smoke [47-49] ,
[46]
pesticides [50,51] , paint [52,53] , and air pollution [54-56] . The vast majority of epidemiologic studies for ALL have
been conducted in children, and very little is known regarding potential differences in ALL etiology across
age groups.

One factor that consistently shows association with ALL incidence is race/ethnicity. We acknowledge that
race and ethnicity are dynamic and multifactorial concepts , and in this review we use the term
[60]
race/ethnicity to refer to heterogeneous groups of people defined by the USA Office of Management and
Budget as African Americans/Blacks (hereafter, Blacks); Hispanics/Latinos; American Indians and Alaska
Natives (AI/ANs); and Asians and Native Hawaiians/other Pacific Islanders (APIs) . Race/ethnicity
[61]
reflects genetic ancestry, and additionally conveys important epidemiologic information as to how social
determinants such as racism and discrimination, socioeconomic position, and environmental exposures can
[60]
influence disease incidence and mortality . In the United States, the incidence of ALL is highest in
Hispanics/Latinos and lowest in Blacks, and this is consistent across age groups [5,62-66] .

Race/ethnicity is also associated with ALL patient outcomes. Overall, survival of ALL patients has improved
dramatically in recent decades , primarily in children [2,67] , which can largely be attributed to improvements
[3]
[2]
in combination chemotherapy protocols , as well as advances in the understanding of cytogenetics and
genetics of the disease and, more recently, the development of immunotherapy and targeted therapies [68-70] .