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Ulcerative colitis (UC) is a persistent inflammatory illness, which is clinically categorised as Inflammatory bowel disease (IBD), affecting millions of people worldwide. The precise cause behind the pathology of the disease remains unknown. However, the involvement of multiple factors including genetic predisposition, immunological deregulations, microbiota imbalance, and environmental triggers has been suggested. Amongst all these factors, the over-active immunological response reported in UC patients seems to be a promising target for therapy. Moreover, identification of gene signatures associated with disease onset and progression would help in better understanding of the molecular mechanisms involved in the disease pathogenesis. Here, we have conducted meta-analysis of gene expression profiles of UC patient microarray datasets accessible in public databases and further validated the in-silico findings in UC patients' blood samples. Our study reveals that UC pathogenesis perturbs expression of several inflammatory genes. In addition, we report a novel gene signature comprising of TIA1 (T cell restricted intracellular antigen) and TIAR (TIA1 related protein; also known as TIAL1), which were found to be significantly downregulated in UC patients. TIA1 and TIAR are RNA-binding proteins (RBPs), which function as a translational represser by binding to ARE sequences in the 3' UTR of mRNAs encoding inflammatory mediators including cytokines. Our findings demonstrate that deletion of TIAR using gene specific siRNAs in-vitro results in enhanced production of inflammatory cytokine IL-1β. In conclusion, the findings of this study reveal that down regulation of TIA1/TIAR genes could be responsible for UC associated inflammation. This study highlights the usefulness of the meta-analysis approach in the identification of unique gene signatures that might deliver mechanistic insights into UC pathogenesis and possibly assist in discovery of prognostic markers and therapeutic interventions.

Background Development of chronic myeloid leukemia (CML) involves formation of double strand breaks (DSBs) which are initially sensed by the ataxia telangiectasia mutated (ATM) signal kinase to induce a DNA damage response (DDR). Mutations or single nucleotide polymorphisms in ATM gene are known to influence the signaling capacity resulting in susceptibility to certain genetic diseases such as cancers. Materials and methods In the present study, we have analyzed -5144A>T (rs228589) and C4138T (rs3092856) polymorphisms of theATM gene through polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) in 925 subjects (476 CML cases and 449 controls). Results The A allele of -5144A>T polymorphism and T allele of C4138T polymorphism which were known to be influencing ATM signaling capacity are significantly associated with enhanced risk for CML independently and also in combination (evident from the haplotype and diplotype analyses). Significant elevation in the frequencies of both the risk alleles among high risk groups under European Treatment and Outcome Study (EUTOS) score suggests the possible role of these polymorphisms in predicting the prognosis of CML patients. Conclusions This study provides the first evidence of association of functional ATM gene polymorphisms with the increased risk of CML development as well as progression.

LCN2 (Lipocalin 2) is a 25 KD secreted acute phase protein, reported to be a novel regulator of angiogenesis in breast cancer. Up regulation of LCN2 had been observed in multiple cancers including breast cancer, pancreatic cancer and ovarian cancer. However, the role of LCN2 promoter methylation in the formation of microvessels is poorly understood. The aim of this study was to analyze the association of LCN 2 promoter methylation with microvessel formation and tumor cell proliferation in breast cancer patients. The LCN2 promoter methylation status was studied in 64 breast cancer tumors by methylation specific PCR (MSP). Evaluation of microvessel density (MVD) and Ki67 cell proliferation index was achieved by immunohistochemical staining using CD34 and MIB-1 antibodies, respectively. LCN2 promoter unmethylation status was observed in 43 (67.2%) of breast cancer patients whereas LCN2 methylation status was seen in 21 (32.8%). Further, LCN2 promoter unmethylation status was associated with aggressive tumor phenotype and elevated mean MVD in breast cancer patients.

Hypoxia-inducible factor 1α (HIF-1α) is an important transcription factor that regulates different cellular responses to hypoxia. HIF-1α is rapidly degraded by von Hippel-Lindau (VHL) protein under normoxic conditions and stabilized under hypoxia. A common variant of HIF-1α (1772CT) (rs 11549465) polymorphism, corresponding to an amino acid change from proline to serine at 582 position within the oxygen-dependent degradation domain, results in increased stability of the protein and altered transactivation of its target genes. The present study was aimed to find the association between HIF-1α (1772CT) (rs 11549465) polymorphism and breast cancer development. For this purpose, 348 primary breast cancer patients and 320 healthy and age-matched controls were genotyped through PCR-RFLP method. The genotype frequencies were compared between patients and controls, and their influence on clinical characteristics of breast cancer patients was analyzed. Our study revealed a significant increase of TT genotype in breast cancer patients compared to controls (p = 0.038). Further, TT genotype and T allele were found to be associated with progesterone receptor (PR)-negative status (p0.09). None of the clinical variables revealed significant association with HIF-1α (1772CT) (rs 11549465) polymorphism.

Aim: The Androgen Receptor (AR) is a ligand-dependent transcriptional activator and the AR gene contains a highly polymorphic trinucleotide repeat CAG and GGN in the first exon. Given the lack of information AR-CAG and GGN repeat polymorphism and its potential correlation with breast cancer in South Indian women, we conducted a case-control study to observe the effects of CAG & GGN repeat length polymorphism and risk of breast cancer. Methods: Polymorphisms for AR-CAG and GGN repeat length was detected by Gene Scan analysis in the genomic DNA from cases with breast cancer and controls. Results: Association between AR genotype was calculated by categorising alleles as short (S) and long (L) and taking median value as the cut-off. LL genotype of CAG repeat was found to be associated with breast cancer (OR, 4.58; 95% CI, 10.61-1.98; p—0.0004). GGN repeat having ≥21 was found in most of the cases and none of the cases showed 20 repeats thus indicate that alleles having homozygous repeat 20 may be protective towards breast cancer. Also, SS genotype was observed in 56.84% of cases and in 73.03% of controls (OR, 0.48; 95% CI, 0.26-0.89; p value, 0.02). Conclusion: Our results indicate that longer CAG and GGN repeat may be associated with breast cancer whereas, the shorter GGN repeat length genotype of AR are protective.

Ulcerative colitis is considered frequent in majority of European and North American population and exceptional in most of the developing Asian countries. There is a dearth of reported data from South India on the incidence of the disease and its prevalence. Hence the present study was designed to estimate the prevalence of ulcerative colitis in a tertiary care hospital of Hyderabad, South India. The study population consisted of 157 Ulcerative colitis and 204 healthy subjects. All subjects were interviewed by means of a questionnaire for general demographical details and socioeconomic conditions, health related quality of life and history of UC. Patients were categorized based on disease severity; moderate: 95, and severe: 62 and disease manifestation: 73 (46.5%) pancolitis, 60 (38.2%) left-sided colitis and 24 (15.3%) had proctosigmoiditits. Disease prevalence was high in patients of

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 TC; 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 TC 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 1307TC 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.

Background Mitochondrial displacement loop (D-loop) is the hot spot for mitochondrial DNA (mtDNA) alterations which influence the generation of cellular reactive oxygen species (ROS). Association of D-loop alterations with breast cancer has been reported in few ethnic groups; however none of the reports were documented from Indian subcontinent. Methodology We screened the entire mitochondrial D-loop region (1124 bp) of breast cancer patients (n = 213) and controls (n = 207) of south Indian origin by PCR-sequencing analysis. Haplotype frequencies for significant loci, the standardized disequilibrium coefficient (D') for pair-wise linkage disequilibrium (LD) were assessed by Haploview Software. Principal findings We identified 7 novel mutations and 170 reported polymorphisms in the D-loop region of patients and/or controls. Polymorphisms were predominantly located in hypervariable region I (60%) than in II (30%) of D-loop region. The frequencies of 310'C' insertion (P = 0.018), T16189C (P = 0.0019) variants and 310'C'ins/16189C (P = 0.00019) haplotype were significantly higher in cases than in controls. Furthermore, strong LD was observed between nucleotide position 310 and 16189 in controls (D' = 0.49) as compared to patients (D' = 0.14). Conclusions Mitochondrial D-loop alterations may constitute inherent risk factors for breast cancer development. The analysis of genetic alterations in the D-loop region might help to identify patients at high risk for bad progression, thereby helping to refine therapeutic decisions in breast cancer.

CCAAT/enhancer binding protein alpha is one of the crucial transcription factors for myeloid cell development that has been found to be involved in hematopoietic differentiation and leukemiogenesis. Recently, epigenetic regulation of CEBPA expression through DNA methylation has been demonstrated in leukemia. The aim of this study was to investigate the methylation status of CEBPA gene in chronic myeloid leukemia (CML) patients. The methylation status of CEBPA promoter was studied in 100 patients with CML and 98 normal healthy individuals from Hyderabad, India, using methylation-specific polymerase chain reaction. The aberrant methylation of CEBPA gene promoter was found in 32 of the 100 CML cases. A highly significant association was found between the frequency of CEBPA gene promoter hypermethylation and the CML stages (P = 0.017), but association with respect to age and gender of the patient was not found. The results suggest that aberrant methylation in the CpG island of the promoter region of this gene might be a common event in CML, and systemic expression studies will be needed to unfold the role of CEBPA promoter methylation in the development, progression, and prognosis of CML.

Background: Apoptosis plays a pivotal role in maintaining cellular homeostasis mainly in rapidly proliferating tissue like hematopoietic tissue. Defective apoptosis is one of the hallmarks of cancer as it plays a crucial role in malignant transformation through disruption of homeostasis mechanism resulting in acquired chemo-resistance. Aim: The functional single nucleotide polymorphisms (SNPs) in apoptotic genes can influence the gene expression leading to altered apoptosis that may promote malignancy. Moreover, these SNPs might also influence the treatment outcome, since most of the chemotherapeutic drugs being used are aimed to induce apoptosis of malignant cells. The present study mainly aims to evaluate the role of SNPs in BCL2 (-938C>A (rs2279115); BAX (-248G>A (rs4645878), CASP9 [-1263A>G (rs4645978); -712C>T (rs4645981); -293del (rs4645982); Ex5+32G>A (rs1052576)] with development of acute myeloid leukemia (AML) and treatment outcome in terms of disease free survival (DFS) among patients who have achieved complete remission(CR) rates after first induction chemotherapy. Methods: The study includes 225 AML cases and 307 age-gender matched controls for case-control comparison. The study was approved by ethical committee of Osmania University. Before collecting 5ml of blood sample, each participant had provided written informed consent. Baseline line clinical characteristics and follow-up data were collected from the tumor registries with the help of oncologist. Genomic DNA was extracted and SNPs were genotyped using PCR, RFLP, Tetra primer techniques. The genotype data was subjected to various statistical analyses to correlate with disease occurrence and treatment outcome in terms of CR and DFS rates using SPSS Software. We have also performed non parametric analysis to know gene-gene interaction through Multi Dimensionality Reduction (MDR). Results: The single SNP analysis had revealed that BCL2 (rs2279115), BAX (rs4645878), CASP9 (rs4645978) and CASP9 (rs4645982) were significantly associated with the origin of AML. Survival analysis had shown that minor alleles of both CASP9 (rs4645978 and rs4645982) SNPs were associated with reduced DFS rates (log rank p = 0.02). Further, cox regression analysis had also confirmed these observations where CASP9 rs4645978 (HR = 1.91; 95%CI = 1.19-3.07; p = 0.008) and rs4645982 (HR = 1.88; 95%CI = 1.06-3.35; p = 0.03) had elevated risk for relapse and shorter DFS rates. The MDR analysis had revealed that CASP9 (rs4645981) is the highest predicting variable. The best interaction model was found to be CASP9 (-1263A>G (rs4645978); -712C>T (rs4645981); and BCL2 (rs2279115) with CVC = 8/10 and TAB = 0.604. Conclusion: Our results suggest that CASP9 (rs4645978 and rs4645982) SNPs might influence the AML development and DFS rates after first induction chemotherapy. Citation Format: Anuradha Cingeetham, Sugunakar Vuree, Nageswara Rao Dunna, Manjula Gorre, Raghunadharao Digumarti, Sudha Sinha, Vishnupriya Satti. Influence of intrinsic apoptotic pathway gene polymorphisms on the development and progression of acute myeloid leukemia: Case-control study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4625. doi:10.1158/1538-7445.AM2015-4625