Identification of Complex Sense-antisense Gene's Module on 17q11.2 Associated with Breast Cancer Aggressiveness and Patient's Survival
Sense-antisense gene pair (SAGP) is a pair of two oppositely transcribed genes sharing a common region on a chromosome. In the mammalian genomes, SAGPs can be organized in more complex sense-antisense gene architectures (CSAGA) in which at least one gene could share loci with two or more antisense partners. Many dozens of CSAGAs can be found in the human genome. However, CSAGAs have not been systematically identified and characterized in context of their role in human diseases including cancers. In this work we characterize the structural-functional properties of a cluster of 5 genes –TMEM97, IFT20, TNFAIP1, POLDIP2 and TMEM199, termed TNFAIP1 / POLDIP2 module. This cluster is organized as CSAGA in cytoband 17q11.2. Affymetrix U133A&B expression data of two large cohorts (410 atients, in total) of breast cancer patients and patient survival data were used. For the both studied cohorts, we demonstrate (i) strong and reproducible transcriptional co-regulatory patterns of genes of TNFAIP1/POLDIP2 module in breast cancer cell subtypes and (ii) significant associations of TNFAIP1/POLDIP2 CSAGA with amplification of the CSAGA region in breast cancer, (ii) cancer aggressiveness (e.g. genetic grades) and (iv) disease free patient-s survival. Moreover, gene pairs of this module demonstrate strong synergetic effect in the prognosis of time of breast cancer relapse. We suggest that TNFAIP1/ POLDIP2 cluster can be considered as a novel type of structural-functional gene modules in the human genome.
Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1058661Procedia APA BibTeX Chicago EndNote Harvard JSON MLA RIS XML ISO 690 PDF Downloads 1335
 V.A. Kuznetsov, G.D. Knott, R.F. Bonner, "General statistics of stochastic process of gene expression in eukaryotic cells," Genetics, vol.161(3), pp.1321-32, 2002.
 Y. Zhang, X.S. Liu, Q.R. Liu and L .Wei, "Genome-wide in silico identification and analysis of cis natural antisense transcripts (cis-NATs) in ten species," Nucleic Acids Res, vol. 34, pp. 3465-75, 2006.
 P.G. Engström, H. Suzuki, N. Ninomiya, A. Akalin, L. Sessa et al., "Complex loci in human and mouse genomes,". PLoS Genet., vol.2(4), pp.e47, 2006.
 P. Kapranov, A.T. Willigham, T.R. Gingeras, "Genome-wide transcription and the implications for genomic organization," Nat Rev Genet, vol.8(6), pp.413-423, 2007.
 I.B. Rogozin, A.N. Spiridonov, A.V. Sorokin, Y.I. Wolf, I.K. Jordan et al., "Purifying and directional selection in overlapping prokaryotic genes," Trends Genet, vol.18(5), pp. 228-322002.
 Z.I. Johnson and S.W. Chisholm, "Properties of overlapping genes are conserved across microbial genomes," Genome Res., vol.14(11), pp. 2268-72, 2004.
 E. Enerly, Z. Sheng and K.B. Li, "Natural antisense as potential regulator of alternative initiation, splicing and termination," In Silico Biol, vol.5(4), pp. 367-77, 2005.
 C.M. Henderson, C.B. Anderson, M.T. Howard, "Antisense-induced ribosomal frameshifting," Nucleic Acids Res, vol.34(15), pp. 4302-10, 2006.
 U. Orfanelli, A.K. Wenke, C. Doglioni, V. Russo, A.K. Bosserhoff, G. Lavorgna, "Identification of novel sense and antisense transcription at the TRPM2 locus in cancer," Cell Res, vol.18, pp. 1128-1140, 2008.
 E. Gallagher, A. Mc Goldrick, W.Y. Chung, O. Mc Cormack, M. Harrison et al., "Gain of imprinting of SLC22A18 sense and antisense transcripts in human breast cancer," Genomics, vol. 88(1), pp.12-7, 2006.
 W. Yu, D. Gius, P. Onyango, K. Muldoon-Jacobs, J. Karp et al., "Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA, " Nature, , vol.451 (7175), pp. 202-6, 2008.
 Y. Ogawa and J.T. Lee, "Antisense regulation in X inactivation and autosomal imprinting," Cytogenet. Genome Res., vol.99(1-4), pp.59-65, 2002.
 G. Alfano, C. Vitiello, C. Caccioppoli, T. Caramico, A. Carola et al., "Natural antisense transcripts associated with genes involved in eye development, " Hum Mol Genet, vol.14(7), pp. 913-23, 2005.
 J.H. Guo, H.P. Cheng, L. Yu and S. Zhao, "Natural antisense transcripts of Alzheimer's disease associated genes, " DNA Seq, vol.17(2), pp.170- 3, 2006.
 P.Juszczynski, J.L. Kutok, C. Li, J. Mitra, R.C. Aguiar, M.A. Shipp,"BAL1 and BBAP are regulated by a gamma interferonresponsive bidirectional promoter and are overexpressed in diffuse large B-cell lymphomas with a prominent inflammatory infiltrate," Mol Cell Biol., vol.26(14), pp.5348-59, 2006.
 Kuznetsov V.A. et al. (2006) Genome-wide co-expression patterns of human cis-antisense gene pairs," Proc. of the 5-th Intern Conf on Bioinformatics of Genome Regulation and Structures. Novosibirsk, Inst. of Cytology&Genetics, 1, 90-93.
 Y. Ohinata, S. Sutou, M. Kondo, T. Takahashi, Y. Mitsui, " Maleenhanced antigen-1 gene flanked by two overlapping genes is expressed in late spermatogenesis," Biol Reprod. Vol.67(6), pp.1824-31, 2002.
 V. Veeramachaneni, W. Makalowski, M. Galdzicki, R. Sood and I. Makalowska, "Mammalian overlapping genes: the comparative perspective," Genome Res, vol.14(2), pp.280-6, 2004.
 I. Makalowska, C.F. Lin and W. Makalowski, "Overlapping genes in vertebrate genomes," Comput Biol Chem, vol.29(1), pp. 1-12. 2005.
 Hu, H.M. Stern, L. Ge, C. O'Brien, L. Haydu, " Genetic alterations and oncogenic pathways associated with breast cancer subtypes," Mol Cancer Res., vol.7(4), pp.511-22, 2009.
 P.M. Haverty, J. Fridlyand, L. Li, G. Getz, R. Beroukhim et al., "Highresolution genomic and expression analyses of copy number alterations in breast tumors," Genes Chromosomes Cancer., vol.47(6), pp.530-42, 2008.
 I .Vanden Bempt, M. Drijkoningen, C. De Wolf-Peeters, " The complexity of genotypic alterations underlying HER2-positive breast cancer: an explanation for its clinical heterogeneity," Curr Opin Oncol. vol.19(6), pp. 552-7, 2007.
 Rody A, Kam T, Ruckhaberle E, Muller V, Gehrmann M, Solbach C, Ahr A, Gatje R, Holtrich U, Kaufmann M. Gene expression of topoisomerase II alpha (TOP2A) by microarray analysis is highly prognostic in estrogen receptor (ER) positive breast cancer. Breast Cancer Res Treat. 2009 Feb;113(3):457-66
 A.V. Ivshina, J. George, 0. Senko, B. Mow, T.C. Putti et al., "Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer," Cancer Res., vol.66(21), pp. 10292-301, 2006.
 M.S. Bartlett, "Test of significance in factor analysis," Br. J. Psycho)., vol.3, pp.77 — 85, 1950.
 B. Efron, and R.J. Tibshirani, An Introduction to the Bootstrap. New York: Chapman and Hall, 1994.
 G. E. P. Box," A general distribution theory for a class of likelihood criteria", Biometrika, vol.36, pp. 317-346, 1949.
 E. Motakis, A.V. Ivshina, V.A. Kuznetsov, "Identification of essential genes and gene pairs associated with survival time of cancer patients". In Proceedings of the 2007 international conference on bioinformatics& computational biology (BIOCOMP 2007): 25-28 June 2007; Las Vegas Nevada USA. Edited by Hamid R. Arabnia, Mary Qu Yang and Jack Y. Yang: CSREA Press; vol.II: pp.753-'759, 2007.
 R.D. Cox and D. Oakes, Analysis of Survival Data. London: Chapman and Hall, 1984.
 Y.L. Orlov, J. Zhou, L. Lipovich, A. Shahab, V.A. Kuznetsov, "Quality assessment of the Affymetrix U133A&B probesets by target sequence mapping and expression data analysis," In Silico Biol., vol.7(3), pp.241- 60, 2007.
 E. Arriola, C. Marchio, D.S. Tan, S.C. Drury, M.B. Lambros, R. Natrajan, S.M. Rodriguez-Pinilla, A. Mackay, N. Tamber, K. Fenwick et al., "Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines", Lab Invest, vol.88(5), pp.491-503, 2008.
 P. Deloukas, G.D. Schuler, G. Gyapay, E.M. Beasley, C. Soderlund et al. "A Physical Map of 30,000 Human Genes", Science, vol.282(5389), p.744 — 746, 1998.
 V.A. Kuznetsov, J.T. Zhou, J. George and Yu.L. Orlov, "Genome-wide co-expression patterns of human cis-antisense gene pairs". In Proc of the 5-th Intern Conf on Bioinformatics of Genome Regulation and Structures: Novosibirsk, Inst. of Cytology&Genetics, vol.1, pp. 90-93, 2006.
 Y. Benjamini and Y.Hochberg, "Controlling the false discovery rate: a practical and powerful approach to multiple testing", Journal of the Royal Statistical Society. Series B (Methodological), vol.57, pp.289— 300, 1995.
 Y. Benjamini and Yekutieli D., "The control of the false discovery rate in multiple testing under dependency", Annals of Statistics, vol.29, pp. 1165-1188, 2001.
 S.B. Moparthi, G. Arbman, A. Wallin, H. Kayed, J. Kleeff et al., "Expression of MAC30 protein is related to survival and biological variables in primary and metastatic colorectal cancers," Int J Oncol., vol.30(1), pp.91-5, 2007.
 A. Barski, S. Cuddapah, K. Cui, T.Y. Roh, D.E. Schones et al. "High-resolution profiling of histone methylations in the human genome" Cell, vol.129(4), pp. 823-37, 2007.
 X.D. Zhao, X. Han, J.L. Chew, J. Liu, K.P. Chiu et al., "Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells". Cell Stem Cell, vol.1(3), pp.286-98,2007.
 R. Yelin, D. Dahary, R. Sorek, E.Y. Levanon, 0. Goldstein et al. "A Widespread occurrence of antisense transcription in the human genome", Nat Biotechnol, vol.21, pp. 379-86, 2003.
 S. Katayama, Y. Tomaru, T. Kasukawa, K. Wald, M. Nakanishi et al. "Antisense transcription in the mammalian transcriptome," Science, vol.309(5740), pp.1564-6, 2005.
 M. Baguma-Nibasheka, A.W. Li, M.S. Osman, L. Geldenhuys, A.G. Casson et al., "Coexpression and regulation of the FGF-2 and FGF antisense genes in leukemic cells", Leuk Res., vol.29(4), pp.423-33.
 L. Liu, E.M. Rodriguez-Belmonte, N. Mazloum, B. Xie and M.Y. Lee, "Identification of a novel protein, PD1P38, that interacts with the p50 subunit of DNA polymerase delta and proliferating cell nuclear antigen," J.Biol Chem., vol. 278(12), pp.10041-'7, 2003.
 T. Paunesku, S. Mittal, M. Protie, J. Oryhon, S.V. Korolev, A. et al., "Proliferating cell nuclear antigen (PCNA): ringmaster of the genome", Int. J. Radiat. Biol., vol.77 (10), pp.1007-21, 2001.
 S. Aaltomaa, P. Lipponen, K. Syrjanen, "Proliferating cell nuclear antigen (PCNA) immunolabeling as a prognostic factor in axillary lymph node negative breast cancer,"Anticancer Res., vol. 13(2), pp.533- 8, 1993.
 G.W. Jr. Sledge, K.D. Miller, " Exploiting the hallmarks of cancer: the future conquest of breast cancer," Eur. J. Cancer., vol. 39(12), pp.1668- 75, 2003.
 L.H. Malkas, B.S. Herbert, W. Abdel-Aziz, L.E. Dobrolecki, Y. Liu, et al., "A cancer-associated PCNA expressed in breast cancer has implications as a potential biomarker," Proc Natl Acad Sci U S A, vol.103(51), pp.19472-'7, 2006.
 J. Zhou, X. Hu, X. Xiong, X. Liu, Y. Liu et al., "Cloning of two rat PD1P1 related genes and their interactions with proliferating cell nuclear antigen," J Exp Zoolog A Comp Exp Biol, vol.303(3), pp.227-40, 2005.
 E. Klaile, A. Kukalev, B. Obrink, M.M. Muller, "PD1P38 is a novel mitotic spindle-associated protein that affects spindle organization and chromosome segregation", Cell cycle, vol. 7(20), pp. 3180-3186, 2008.
 J.A. Jonassen, J. San Agustin, J.A. Follit, G.J. Pazour, "Deletion of IFT20 in the mouse kidney causes misorientation of the mitotic spindle and cystic kidney disease," J. Cell Biol., vol. 183(3), pp.377-84, 2008.
 E. Klaile, M.M. Muller, C. Kannicht, W. Otto, B.B. Singer et al., "The cell adhesion receptor carcinoembryonic antigen-related cell adhesion molecule 1 regulates nucleocytoplasmic trafficking of DNA polymerase delta-interacting protein 38," J. Biol. Chem., vol. 282(36), pp.26629-40, 2007.
 X. Cheng, T. Kanki, A. Fukuoh, K. Ohgaki, R. Takeya et al., "PD1P38 associates with proteins constituting the mitochondria) DNA nucleoid," J. Biochem., vol.138(6), pp.673-8, 2005.
 F.W. Wolf, R.M. Marks, V. Sarma, M.G. Byers, R.W. Katz et al., "Characterization of a novel tumor necrosis factor-alpha-induced endothelial primary response gene," J. Biol. Chem., vol.267(2), pp. 1317-26, 1992.