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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 226

[127]
The Ph chromosome translocation [t(9;22), i.e., Ph+], which results in the BCR-ABL1 fusion gene , is
infrequent among childhood B-ALL patients (< 5%) but presents in up to half of adult B-ALL cases and
becomes more prevalent with increased age (22% in patients < 40 years of age, 41% in patients ≥ 40 years
and nearly 50% in patients aged 60 years or older) [97,112,113] . A higher percent of Ph+ B-ALL has been reported
in Black AYA/adult patients compared with in NHW and Hispanic/Latino patients [99,128] . A similar pattern
has been identified in children - compared with Ph-negative ALL patients, Ph+ ALL patients were more
likely to be Black . Although Ph chromosome has been historically recognized as an adverse prognostic
[129]
factor for ALL, Ph+ ALL now has noninferior or even superior outcomes compared to Ph-negative ALL in
older adult ALL patients [113,130,131] , due to recent advances in novel therapies such as CAR-T cell therapy and
[117]
tyrosine kinase inhibitor therapy .

The WHO 2017 revision introduced Ph-like ALL as an additional subgroup for B-ALL . Ph-like B-ALL
[118]
shares a similar gene-expression profile with Ph+ B-ALL, but does not harbor the BCR-ABL1 fusion protein
[118]
expressed from the t(9;22) . Unlike Ph+ ALL that occurs more frequently with increased age, Ph-like ALL
has the highest incidence in AYAs (19%-28%), a lower frequency in childhood (10%), and is relatively
common among adults aged 40 or above (20%) [96-99] . Ph-like ALL partly contributes to the AYA “survival
cliff” , and the continuing poor outcomes in older age groups [77-82] . Patients with Ph-like ALL had a
[110]
significantly inferior event-free and disease-free survival, a lower complete remission rate, and an elevated
level of minimal residual disease at the end of the induction therapy compared to non-Ph-like patients .
[95]
Furthermore, Ph-like ALL likely plays a role in both the high incidence and the inferior survival of ALL in
[99]
Hispanics/Latinos. Ph-like ALL occurs more frequently in Hispanics/Latinos in particular in AYA/adults .
Indeed, Hispanics/Latinos have been shown to account for up to two-thirds of Ph-like ALL in AYA/adult
patients . Notably, nearly half of the patients with Ph-like ALL had CRLF2 rearrangements . Both Ph-like
[99]
[96]
ALL and its subtype with CRLF2 rearrangements have significantly worse outcomes compared to other
subtypes [96,98,99,132-134] , and are more prevalent among Hispanics/Latinos compared to other racial/ethnic
groups . In sum, the Ph-like subtype contributes significantly to the poor survival of Hispanic/Latino
[132]
AYA ALL patients.

Genetic variation
Genetic variants contribute to racial/ethnic disparities in ALL incidence
Several ALL risk loci identified by GWAS have been associated with genetic ancestry, and have
demonstrated differences in risk allele frequency and/or differences in effect size across population
groups [15-32,135,136] [Figure 2]. For example, an increased number of risk alleles at 5 ALL risk single nucleotide
polymorphisms (SNPs) rs3731217 (CDKN2A), rs7088318 (PIP4K2A), rs2239633 (CEBPE), rs7089424
(ARID5B), and rs3824662 (GATA3) was correlated with increased genome-wide Indigenous American
ancestry in Hispanic/Latino children [137,138] . ARID5B SNP risk allele frequency has also been associated with
increased local Indigenous American ancestry in Hispanics/Latinos . At the GATA3 risk locus, SNP
[139]
rs3824662 has a markedly higher risk allele frequency in Hispanic/Latino than in European ancestry
populations, with 39% compared with only 17% frequency in the Genome Aggregation Database (gnomAD)
[57]
v2.1.1. [Table 1 and Figure 3] . Further, the GATA3 SNP rs3824662 risk allele has been shown to confer a
remarkably high risk for Ph-like ALL in both children and AYAs, with an almost 4-fold risk of this
subtype [21,135] , supporting that this risk locus likely contributes significantly to the increased prevalence of
Ph-like ALL in Hispanic/Latino ALL patients.

In two recent GWAS of ALL conducted in Hispanic/Latino-only discovery studies, a novel ALL risk locus
was identified at the chromosome 21 gene ERG [29,31] . The effect of this locus on ALL risk was larger in
Hispanics/Latinos than in NHWs and, in addition, this locus was associated with an increased risk of ALL
in Hispanic/Latino individuals both with higher genome-wide and higher local Indigenous American