OVARIAN CANCER POSSIBLE TUMOR-SUPPRESSIVE ROLE OF BATF2 IN OVARIAN CANCER

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1 POSSIBLE TUMOR-SUPPRESSIVE ROLE OF BATF2 IN OVARIAN CANCER Rissa Fedora, OMS-III OVARIAN CANCER 5 th leading cause of death among American women Risk factors: Age Gender female Greater lifetime ovulations Smoking Obesity IUD Inherited gene mutation BRCA1 (5% in < age 70); BRCA1/2 arising from fallopian tubes Currently no genetic screening Staging: I IV Stage I 90% five-year survival rate Stage IV 25% five-year survival rate 75% diagnoses made after Stage I Overall five-year survival rate < 45% 1

2 OBJECTIVES 1. Identify genes highly associated with ovarian cancer 2. Identify genes highly associated with survival OBJECTIVES 1. Identify genes highly associated with ovarian cancer 2. Identify genes highly associated with survival 2

3 THE CANCER GENOME ATLAS (TCGA) 291 stage 3 serous ovarian tumor patients DNA microarray Gene expression level Quantile normalization JAMMIT singular value algorithm Cluster analysis 16,020 ~ OSM 21 Pearson correlation analysis Bonferroni adjustment withstands extreme space / 3

4 RESULTS 23,325 out of 23,436 significant relations (p 0.05) 21,436 out of 23,436 significant relations (p 1.06 x 10 6 ) OBJECTIVES 1. Identify genes highly associated with ovarian cancer 2. Identify genes highly associated with survival Cox proportional-hazards model Bonferroni adjustment Benjamini-Hochberg adjustment (more lenient) 4

5 RESULTS Table 1. List of the 28 survival genes with their Hazard Ratio (HR) and p-values Rank Gene HR p-value Potential Biological Role 1 BATF tumor suppressor gene 2 MMD maturation of macrophages 3 EDG6 (now S1PR4) endothelial differentiation G-protein-coupled receptor in lymphoid tissue 4 VDR regulation of mineral metabolism, immune response and cancer 5 TNFRSF regulation of T cells and downstream activation of NFkB 6 TXNDC3 (now NME8) ciliary function 7 CD lymphocyte proliferation and apoptosis suppression 8 RCAN inhibition of calcineurin-dependent signaling pathways 9 PAPSS modification of endogenous and exogenous compounds 10 CCR lymphocyte regulation 11 Rgr retinal G-protein coupled receptor 12 ICOS regulation of cell-cell signaling, immune responses and cell proliferation 13 FMO N-oxidation of some primary alkylamines 14 IL21R proliferation and differentiation of T cells, B cells and NK cells, and activation of multiple JAK-STAT signaling pathways 15 ITGB adhesion receptor signaling from extracellular matrix into cell 16 SUCNR G-protein-coupled receptor for succinate in citric acid cycle and development of hematopoietic progenitor cell 17 MAF oncogene 18 GBP hyrolyzation of GTP to GDP 19 DHRS oxidoreductase activity of hydroxysteroids and transcriptional repression in nucleus 20 FLJ21438 (or RASAL3) negative regulation of Ras signaling pathway 21 SMPDL3A hydrolase activity and sphingomyelin phosphodiesterase activity 22 AMICA1 (now JAML) leukocyte transmembrane migration 23 ARHGAP GTPase activator activity 24 SLAMF regulation of immune response 25 CD optimization of immune recognition of antigen presenting cells 26 KLHL B-cell maturation and antigen receptor signaling 27 CXCR leukocyte traffic 28 TRAF3IP transcription factor activity and regulation of cell growth RESULTS Table 1. List of the 28 survival genes with their Hazard Ratio (HR) and p-values Rank Gene HR p-value Potential Biological Role 1 BATF tumor suppressor gene 2 MMD maturation of macrophages 3 EDG6 (now S1PR4) endothelial differentiation G-protein-coupled receptor in lymphoid tissue 4 VDR regulation of mineral metabolism, immune response and cancer 5 TNFRSF regulation of T cells and downstream activation of NFkB 6 TXNDC3 (now NME8) ciliary function 7 CD lymphocyte proliferation and apoptosis suppression 8 RCAN inhibition of calcineurin-dependent signaling pathways 9 PAPSS modification of endogenous and exogenous compounds 10 CCR lymphocyte regulation 11 Rgr retinal G-protein coupled receptor 12 ICOS regulation of cell-cell signaling, immune responses and cell proliferation 13 FMO N-oxidation of some primary alkylamines 14 IL21R proliferation and differentiation of T cells, B cells and NK cells, and activation of multiple JAK-STAT signaling pathways 15 ITGB adhesion receptor signaling from extracellular matrix into cell 16 SUCNR G-protein-coupled receptor for succinate in citric acid cycle and development of hematopoietic progenitor cell 17 MAF oncogene 18 GBP hyrolyzation of GTP to GDP 19 DHRS oxidoreductase activity of hydroxysteroids and transcriptional repression in nucleus 20 FLJ21438 (or RASAL3) negative regulation of Ras signaling pathway 21 SMPDL3A hydrolase activity and sphingomyelin phosphodiesterase activity 22 AMICA1 (now JAML) leukocyte transmembrane migration 23 ARHGAP GTPase activator activity 24 SLAMF regulation of immune response 25 CD optimization of immune recognition of antigen presenting cells 26 KLHL B-cell maturation and antigen receptor signaling 27 CXCR leukocyte traffic 28 TRAF3IP transcription factor activity and regulation of cell growth 5

6 CONCLUSIONS The chosen 217 genes act in collaboration to affect the progress of ovarian cancer BATF2 is highly associated with better survival in ovarian cancer Further studies Plot survival curves Possible indication of treatment options LIMITATIONS Chosen cluster of genes Strictness of linearity of Pearson correlation analysis Possible skewing of data to indicate linearity through quantile normalization Lack of validation on independent test set Requires additional independently collected samples 6

7 ACKNOWLEDGMENT University of Hawaii at Manoa Department of Mathematics Office of Biostatistics & Quantitative Health Sciences at John A. Burns School of Medicine 7