CLINICAL AND MOLECULAR IMPACT OF RS3824662 POLYMORPHISM IN GATA3 IN THE DEVELOPMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA IN ADOLESCENTS AND YOUNG ADULTS

Abstract

Introduction and objectives: The rs3824662 polymorphism in GATA3 is a risk variant for the development of B-cell precursor acute lymphoblastic leukemia (B-ALL), particularly BCR::ABL1-like ALL, a subtype of B-ALL defined by a gene expression profile similar to the observed in BCR::ABL1 positive patients. The predominance of high-risk alterations jointly with the absence of specific treatment protocols for adolescents and young adults (AYA) has negatively impacted the prognosis of this age subgroup. Besides that, studies evaluating the GATA3 SNP in AYA are rarely observed. Given this scenario, this study aims to evaluate the clinical and molecular impact of the SNP rs3824662 on the development of B-ALL in AYA. Material and methods: 76 samples from AYA patients (15 to 39 years old) diagnosed with B-ALL according to the World Health Organization criteria were included between 2018 and 2023. This project was approved by the INCA Research Ethics Committee (#87793418.0.0000.5274). The samples were obtained from different cancer treatment centers in Brazil. DNA was extracted using the DNA MiniBlood kit (Qiagen) following the standard protocol. The rs3824662 polymorphism was identified using the TaqMan allelic discrimination assay (C_27522049_10, Life Technologies). The observed genotypes were validated by direct sequencing using the ABI 3500 Genetic Analyzer (Life Technologies). The BCR::ABL1-like subtype was characterized by the presence of rearrangements in PDGFRB, CRLF2, JAK2, ABL1, ABL2, IGH, and/or CSF1R evaluated by FISH. GATA3 SNP was correlated with previously characterized clinical and molecular variables, including primary alterations detected by qPCR and additional alterations identified by the SALSA MLPA P335-C1 kit (MRC Holland). Results: We successfully analyzed 76 patients, displaying a median age of 19.5 years-old and the majority had a low white blood cell (WBC) count (77.0%). Regarding molecular subgroups, most of the patients did not present recurrent alterations and were characterized as B-other (35.9%). Heterozygote and mutant genotypes of rs3824662 SNP were observed in 39.7% and 8.2% of patients, respectively. The mutant allele A rarely occurred in concomitance with BCR::ABL1 or TCF3::PBX1, and was particularly overrepresented in B-other patients and BCR::ABL1-like subtypes (P < 0.05). Additionally, it was more common in patients with low WBC count (86.1%). Curiously, patients with the mutant genotype had a very low frequency of deletions in IKZF1, EBF1, JAK2, CDKN2A/B, PAX5, ETV6, BTG1, RB1, and deletions in the PAR1 region were not observed (P < 0.05). Discussion and conclusion: Our findings are consistent with previous studies in AYA B-ALL, corroborating that rs3824662 SNP is a significant factor for the development of BCR::ABL1-like B-ALL. Furthermore, there is an underrepresentation of this SNP in concomitance with deletions in genes involved in differentiation, proliferation, and cell cycle that are frequently affected in B-ALL. These findings suggest that this SNP can directly impact the development and progression of leukemogenesis, and could be incorporated in the diagnostic routine of B-ALL patients. Support: FAPERJ, CNPq, Ministério da Saúde, Swiss Bridge Foundation.