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Risk assessment of FLT3 and PAX5 variants in B-acute lymphoblastic leukemia: a case-control study in a Pakistani
Ammara Khalid1, Sara Aslam1, Mehboob Ahmed1
1Department of Microbiology & Molecular Genetics, Quaid-e-Azam Campus, University of the Punjab, Lahore, Pakistan.
Insights
Genetic variations in FLT3 and PAX5 are linked to childhood B-cell acute lymphoblastic leukemia (B-ALL) in Pakistan. Specific FLT3 polymorphisms increase risk, while a PAX5 polymorphism offers protection, aiding future therapeutic strategies.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- B-cell acute lymphoblastic leukemia (B-ALL) is a common childhood cancer in Pakistan.
- Genetic variations in FLT3 and PAX5 are implicated in B-ALL development and progression.
- FLT3 auto-phosphorylation and PAX5's role in B-cell differentiation are key mechanisms.
Purpose of the Study:
- To investigate the association between FLT3 and PAX5 gene polymorphisms and B-ALL risk in a Pakistani cohort.
- To analyze the impact of specific single nucleotide polymorphisms (SNPs) on B-ALL susceptibility.
- To explore potential genetic markers for B-ALL risk assessment.
Main Methods:
- Genotyping of 155 B-ALL patients and 155 controls using tetra ARMS-PCR.
- Statistical analysis of demographic factors and SNP associations with B-ALL using SPSS.
- Evaluation of allele and genotype frequencies for specific FLT3 and PAX5 loci.
Main Results:
- The FLT3 polymorphism rs35958982 (13q12.2) showed a significant positive association with B-ALL risk (OR=2.30, P=0.005).
- The PAX5 polymorphism rs3780135 (9p13.2) demonstrated a protective effect (OR=0.55, P=0.029) with higher risk allele frequency in B-ALL subjects.
- Another FLT3 polymorphism, rs12430881 (13q12.2), was also significantly associated with B-ALL risk (minor allele freq. OR=1.15, P=0.043; genotype freq. OR=2.52, P=0.006).
Conclusions:
- Specific FLT3 polymorphisms (rs35958982, rs12430881) are strongly associated with an increased risk of B-ALL.
- The PAX5 polymorphism rs3780135 exhibits a protective effect against B-ALL.
- Demographic factors including family history, smoking, and consanguinity also play a role in B-ALL risk assessment, informing future therapeutic approaches.
Aims:
B-cell acute lymphoblastic leukemia (B-ALL) is amongst the most prevalent cancers of children in Pakistan. Genetic variations in FLT3 are associated with auto-phosphorylation of kinase domain that leads to increased proliferation of blast cells. Paired box family of transcription factor (PAX5) plays a critical role in commitment and differentiation of B-cells. Variations in PAX5 are associated with the risk of B-ALL. We aimed to analyze the association of FLT3 and PAX5 polymorphisms with B cell leukemia in Pakistani cohort.
Methods:
We collected 155 B-ALL subject and 155 control blood samples. For analysis, genotyping was done by tetra ARMS-PCR. SPSS was used to check the association of demographic factors of SNPs present in the population with the risk of B-ALL.
Results:
Risk allele frequency A at locus 13q12.2 (rs35958982, FLT3) was conspicuous and showed positive association (OR = 2.30, CI [1.20-4.50], P = 0.005) but genotype frequency (OR = 3.67, CI [0.75-18.10], P = 0.088) failed to show any association with the disease. At locus 9p13.2 (rs3780135, PAX5), the risk allele frequency was significantly higher in B-ALL subjects than ancestral allele frequency (OR = 2.17, CI [1.37-3.43], P = 0.000). Genotype frequency analysis of rs3780135 polymorphism exhibited the protective effect (OR = 0.55, CI [0.72-1.83], P = 0.029). At locus 13q12.2 (rs12430881, FLT3), the minor allele frequency G (OR = 1.15, CI [1.37-3.43], P = 0.043) and genotype frequency (OR = 2.52, P = 0.006) reached significance as showed p < 0.05.
Conclusion:
In the present study, a strong risk of B-cell acute lymphoblastic leukemia was associated with rs35958982 and rs12430881 polymorphisms. However, rs3780135 polymorphism showed the protective effect. Additionally, other demographic factors like family history, smoking and consanguinity were also found to be important in risk assessment. We anticipate that the information from genetic variations in this study can aid in therapeutic approach in the future.
