| Abstract |
Background: Acute lymphoblastic leukemia (ALL) is the most prevalent neoplasia of
childhood. During the last decades, event-free and overall survival have exceeded
85% and 90%, respectively. Nevertheless, relapsed ALL remains a major issue and
has been linked with high mortality rates. MicroRNAs have been recently utilized as
biomarkers of relapsed/refractory disease and adverse outcomes. MicroRNAs are
regulatory small non-coding RNAs with distinct gene targets and biological features
(exhibiting oncogenic or tumor-suppressor functions). MicroRNAs were recently
identified as key regulators of lymphoid differentiation, playing a significant role in
leukemia biology, whereas miRNA signatures can be used to recognize ALL patients,
discriminate high-risk subtypes, and define prognosis, thus enhancing our ability to
predict and improve outcomes and survival. Maturation of miRNAs involves the
processing of pri-miRNAs to pre-miRNAs by the Microprocessor complex, their
export to the cytoplasm, and their subsequent processing by Dicer within the RNA-
induced silencing complex (RISC), which initiates the RNA interference process
mediated by Argonaute (AGO) proteins. The systematic review of the literature
revealed that specific genotypes of SNPs rs3742330 in DICER1 and rs636832 in
AGO1 have been associated significantly with the occurrence of several cancers.
Aims: The present case-control study investigated the frequencies of genotypes in
rs3742330 DICER1 and rs636832 AGO1 and their association with relapsed ALL and
mortality. This is the first study of both SNPs in the Greek population, while it is the
first study in the literature to investigate the role of DICER1 rs3742330 in ALL.
Methods: 216 individuals participated in the study. The control group consisted of 99
healthy children, adolescents, and young adults, while 117 children and adolescents
with ALL were included in the ALL group. Genotyping was performed using RT-qPCR
and TaqMan® SNP Genotyping Assay in CFX96.
Results: Minor G allele of rs3742330 in DICER1 has been associated with ALL
occurrence, described best by the recessive genetic model (GG vs. AA+AG) OR 9.2
(95% CI: 1.1–75.2; p=0.019). Minor allele A homozygotes of rs636832 in AGO1 have
been only identified among ALL patients, and OR under the recessive model (AA vs.
GG+AG) was 26.5 (95% CI: 1.5–457.3; p=0.024). Moreover, the AG genotype of
rs636832 seems protective against ALL (heterozygote model AG vs. GG) with OR 0.3
(95% CI: 0,1–0.8; p=0.006). The combination of genotypes AA/AA in rs3742330 and
rs636832, respectively, was associated with ALL diagnosis: OR 31.1 (95% CI: 1.8– - 8 -
544.9; p=0.0187), while the AG/GG combination was associated with ALL onset at
higher age (10.6 ±2,6 years old; p=0.042). Both relapsed and deceased cases failed
to correlate significantly with a specific genotype.
Conclusion: Minor allele G carriers in rs3742330 (AG+GG) are expected to have lower
Dicer mRNA levels and have been associated with ALL. AA genotype carriers of
rs636832, who were significantly correlated with the disease, are not expected to
have lower levels of AGO1, but lower RISC functionality and high Th17 populations
are anticipated. More studies in the field are needed to confirm the observed
associations and investigate the role of these SNPs in relapse and survival rates.
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