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Page 229 Xu et al. J Transl Genet Genom 2021;5:218-39 https://dx.doi.org/10.20517/jtgg.2021.20

Apart from the risk loci described above that are associated with Indigenous American ancestry, a novel risk
locus for T-ALL was recently identified at the USP7 gene and was found to be overrepresented in children
of African ancestry. This locus may, therefore, contribute to the higher incidence of T-ALL in Black
[30]
children compared to their counterparts of other races/ethnicities .

Finally, we summarized established GWAS-identified SNPs for ALL [15-32] in Table 1, and we observed
[57]
disparities in risk allele frequency and in effect size of these SNPs. In gnomAD (v2.1.1.) , the risk allele
frequency of the Ph-like ALL-related SNP rs3824662 (GATA3) is 130% higher in Latinos/Admixed
Americans compared to in Europeans; further, SNPs in ARID5B have a 20%-50% higher risk allele
frequency in Latinos/Admixed Americans compared to Europeans [Figure 3A]. Many of the established
ALL GWAS SNPs have a higher absolute risk allele frequency in Latinos/Admixed Americans than in
Europeans [Figure 3B]. In Blacks, risk allele frequency of the T-ALL-related SNP at rs74010351 (USP7) is
strikingly high, nearly 200% higher than in Europeans, but the absolute difference is only ~10% because of
the low frequency of this risk allele across all populations [Table 1]; other GWAS SNPs did not show
consistent differences in risk allele frequency between African and European populations [Figure 3]. The
strongest risk effect is seen for the GATA3 SNP rs3824662 association with Ph-like ALL, with an effect size
of nearly 4.0 [Figure 3C].

Genetic variants are associated with racial/ethnic disparities in ALL outcomes
Genetic variation contributes to racial/ethnic disparities not only in ALL susceptibility but also in treatment
outcomes [139,152] [Figure 2]. Indigenous American ancestry has been associated with an increased risk of
relapse in Hispanic/Latino ALL patients, which may result from the effects of ancestry-related genetic
variants on therapy response . For example, in a study conducted in children treated on Children's
[153]
Oncology Group (COG) clinical trials, ARID5B genetic risk alleles that have a higher frequency in
Hispanic/Latino populations and are associated with increased Indigenous American ancestry were
[139]
associated with both ALL susceptibility and relapse risk . In another example, the GATA3 risk SNP
rs3824662, associated with Indigenous American ancestry and Ph-like ALL, has been found additionally
[138]
[155]
to contribute to the increased risk of relapse in both childhood [21,154] and adult ALL patients .
Two variants in TPMT (rs1142345) and NUDT15 (rs116855232) have been discovered by GWAS to be
strongly associated with thiopurine intolerance during therapy resulting in excessive toxicity in children
[142]
[142]
with ALL . The TPMT variant is most prevalent in Blacks and least common in East Asians . The
NUDT15 variant is most prevalent in East Asians, followed by Hispanics/Latinos, and extremely rare in
[142]
NHWs and Blacks . In a recent sequencing study, 4 additional germline loss-of-function variants were
identified in NUDT15 that confer a major risk for thiopurine intolerance, and appear to be highly prevalent
in East Asians, South Asians and Indigenous American populations .
[156]
Moreover, a study of children with high-risk B-ALL enrolled in COG clinical trials revealed 19 genetic loci
associated with increased relapse risk, of which 12 were specific to an ancestry group, including 7 SNPs
specific to Hispanics/Latinos and 3 SNPs specific to Black patients . These loci are associated with
[152]
pharmacokinetic and pharmacodynamic phenotypes (e.g., resistance or rapid clearance of
[152]
chemotherapy) . Further, including ancestry-specific SNPs in multivariate models of relapse risk
significantly attenuated the increased risk of relapse in Hispanic/Latino and Black patients compared to
white patients .
[152]