title: Influence of BCL2-938C>A and BAX-248G>A promoter polymorphisms in the development of AML: case-control study from South India.
abstract: B-cell lymphoma 2 (BCL2) and BCL2-associated X protein (BAX) proteins are anti-apoptotic and pro-apoptotic determinants of mitochondrial-mediated apoptosis, and their relative expression determines the cell fate. The promoter polymorphisms in these genes were shown to alter the protein function or expression and exert an impact on apoptosis regulation. Deregulation in the expression of any of these genes leads to disruption of cellular homeostasis and malignant transformation. The present study was aimed to determine the association of BCL2-938C>A and BAX-248G>A promoter polymorphisms with origin and progression of acute myeloid leukemia (AML). We also have performed combined genotype analysis to evaluate the cumulative effect of risk genotypes in the AML development. These polymorphisms were genotyped by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) in 221 AML patients and 305 age- and sex-matched healthy controls. Our study revealed that BCL2-938CA (p = 0.018) and BAX-248GG (0.043) genotypes were significantly associated with increased risk for AML occurrence. BAX-248A allele had shown decreased risk for AML. The combined analysis had shown that BCL2-938CA+AA-BAX-248GG group had a 1.63-fold (95 % CI: 1.08-2.45, p = 0.02) increased risk for AML. None of the clinical variables had shown any significant association with both polymorphisms. With respect to complete remission (CR) rate, BAX-248GG genotype (p = 0.002) and G allele (p = 0.009) had conferred significant risk for complete remission failure. Although the log rank test was not significant, survival analysis had shown a trend where BCL2-938CA genotype, and BAX-248GG had reduced median disease-free survival (DFS) of 9 and 10 months, respectively. In conclusion, BCL2-938C>A and BAX-248G>A gene polymorphisms might contribute to the origin of AML. Moreover, influence of BAX-248GG genotype on CR and DFS rate suggests that the BAX-248G>A polymorphism can serve as marker for poor prognosis in AML.
authors.affiliation: Department of Genetics, Osmania University, Hyderabad, 500007, India.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Cingeetham
authors.affiliation: Department of Genetics, Osmania University, Hyderabad, 500007, India.
authors.forename: Sugunakar
authors.initials: S
authors.lastname: Vuree
authors.affiliation: School of Chemical and Biotechnology, SASTRA University, Thanjuvur, India.
authors.forename: Nageswara Rao
authors.initials: NR
authors.lastname: Dunna
authors.affiliation: Department of Genetics, Osmania University, Hyderabad, 500007, India.
authors.forename: Manjula
authors.initials: M
authors.lastname: Gorre
authors.affiliation: Department of Genetics, Osmania University, Hyderabad, 500007, India.
authors.forename: Santhoshi Rani
authors.initials: SR
authors.lastname: Nanchari
authors.affiliation: Department of Genetics, Osmania University, Hyderabad, 500007, India.
authors.forename: Prajitha Mohandas
authors.initials: PM
authors.lastname: Edathara
authors.affiliation: Department of Genetics, Osmania University, Hyderabad, 500007, India.
authors.forename: Phannibhushann
authors.initials: P
authors.lastname: Meka
authors.affiliation: Department of Genetics, Osmania University, Hyderabad, 500007, India.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Annamaneni
authors.affiliation: Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam, 530053, India.
authors.forename: Raghunadharao
authors.initials: R
authors.lastname: Digumarthi
authors.affiliation: MNJ Institute of Oncology Regional Cancer Center, Hyderabad, India.
authors.forename: Sudha
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Department of Genetics, Osmania University, Hyderabad, 500007, India. sattivishnupriya@gmail.com.
authors.forename: Vishnupriya
authors.initials: V
authors.lastname: Satti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000032:analysis / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007194:India; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D015996:Survival Rate; D055815:Young Adult; D051028:bcl-2-Associated X Protein / Q000235:genetics*
chemical_list: C494826:BAX protein, human; C000595707:BCL2 protein, human; D014408:Biomarkers, Tumor; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D004247:DNA
keywords: AML; BAX; BCL2; Complete remission; Disease-free survival; PCR-RFLP