Association of promoter polymorphisms of Fas -FasL genes with development of Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is a monoclonal myeloproliferative disorder of hematopoietic stem cells (HSCs), characterized by reciprocal translocation, leading to the formation of BCR-ABL oncogene with constitutive tyrosine kinase (TK) activity. This oncogene is known to deregulate different downstream pathways which ultimately lead to cell proliferation, defective DNA repair, and inhibition of apoptosis. Fas (Fas cell surface death receptor) is a member of tumor necrosis factor (TNF) superfamily which interacts with its ligand, FasL, to initiate apoptosis. Promoter polymorphisms in Fas-FasL genes are known to influence the apoptotic signaling. Hence, the present study has been aimed to find out the association of the promoter polymorphisms in Fas and FasL genes with the development and progression of CML. Blood samples from 772 subjects (386 controls and 386 cases) were collected and genotyped for Fas-FasL gene polymorphisms through PCR-RFLP method. The association between SNPs and clinical outcome was analyzed using statistical softwares like SPSS version 20, SNPSTATs, and Haploview 2.1. The study revealed a significant association of Fas -670 G>A and FasL -844 T>C polymorphisms with the development of CML while Fas -670 AG was associated with accelerated phase. Combined risk analysis by taking the risk genotypes in cases and controls revealed a significant increase in CML risk with increase in number of risk genotypes (one risk genotype-OR 1.99 (1.44-2.76), p < 0.0001; two risk genotypes-OR 3.33 (1.91-5.81), p < 0.0001). Kaplan-Meier survival analysis of Fas -670 A>G and FasL -844 T>C showed reduced event-free survival in patients carrying the variant genotypes, Fas -670 GG, 32.363 ± 6.33, and FasL -844 CC, 33.489 ± 5.83, respectively. Our findings revealed a significant association of Fas -670 GG, FasL -844 TC, and CC genotypes with increased risk of CML.

Rrp1B gene polymorphism (1307T>C) in metastatic progression of breast cancer.

Rrp1B (ribosomal RNA processing1 homolog B) is a novel candidate metastasis modifier gene in breast cancer. Functional gene assays demonstrated that a physical and functional interaction existing between Rrp1b and metastasis modifier gene SIPA1 causes reduction in the tumor growth and metastatic potential. Ectopic expression of Rrp1B modulates various metastasis predictive extra cellular matrix (ECM) genes associated with tumor suppression. The aim of this study is to determine the functional significance of single nucleotide polymorphism (SNP) in human Rrp1B gene (1307 T>C; rs9306160) with breast cancer development and progression. The study consists of 493 breast cancer cases recruited from Nizam's Institute of Medical Sciences, Hyderabad, and 558 age-matched healthy female controls from rural and urban areas. Genomic DNA was isolated by non-enzymatic method. Genotyping was done by amplification refractory mutation system (ARMS-PCR) method. Genotypes were reconfirmed by sequencing and results were analyzed statistically. We have performed Insilco analysis to know the RNA secondary structure by using online tool m fold. The TT genotype and T allele frequencies of Rrp1B1307 T>C polymorphism were significantly elevated in breast cancer (χ (2); p = <0.008) cases compared to controls under different genetic models. The presence of T allele had conferred 1.75-fold risk for breast cancer development (OR = 1.75; 95% CI = 1.15-2.67). The frequency of TT genotype of Rrp1b 1307T>C polymorphism was significantly elevated in obese patients (χ (2); p = 0.008) and patients with advanced disease (χ (2); p = 0.01) and with increased tumor size (χ (2); p = 0.01). Moreover, elevated frequency of T allele was also associated with positive lymph node status (χ (2); p = 0.04) and Her2 negative receptor status (χ (2); p = 0.006). Presence of Rrp1b1307TT genotype and T allele confer strong risk for breast cancer development and progression.

Association of caspase9 promoter polymorphisms with the susceptibility of AML in south Indian subjects.

Abnormal apoptosis is one of the hallmarks of cancers including acute myeloid leukemia (AML), as it plays a pivotal role in precisely maintaining self-renewal, proliferation, and differentiation properties of hematopoietic stem cells (HSCs). Caspase9 (CASP9), an initiator caspase activated by mitochondrial-mediated apoptotic pathway (intrinsic pathway), triggers cascade of effector caspases and executes apoptosis. Functional SNPs in CASP9 might influence the gene expression leading to altered apoptosis which confer the risk to AML. To test this hypothesis, we have analyzed four CASP9 gene polymorphisms [CASP9 - 1263A > G (rs4645978), CASP9 - 712C > T (rs4645981), CASP9 - 293_275del CGTGAGGTC AGTGCGGGGA (-293del) (rs4645982), and CASP9 Ex5 + 32G > A (rs1052576)] in 180 AML cases and 304 age- and sex-matched healthy controls. We performed various statistical analyses to determine the potential interactions between these SNPs and AML. The study revealed that presence of G allele at CASP9 - 1263 position elevates the risk of AML 1.53-fold and CT/TT genotype at CASP9 - 712 position by 2.60-fold under dominant model of inheritance. Two CASP9 haplotypes, G-del(+)-C-A and G-del(+)-T-A, were found to be significantly associated with increased AML risk by 2.19- (95 % confidence interval (CI), 1.09-4.39; p = 0.028) and 11.75-fold (95 % CI, 1.01-136.57; p = 0.05), respectively. Further, multidimensionality reduction (MDR) analysis had revealed single locus CASP9 - 712C > T SNP and four loci CASP9 - 1263A > G, CASP9 - 293del, CASP9 - 712C > T, and CASP9 Ex5 + 32G > A SNPs as highest predicting models for AML development. Our results revealed a significant association of two SNPs in CASP9 (-1263A > G and -712C > T) and two haplotypes of the four SNP combinations with AML susceptibility.