Complex sense-antisense architecture of TNFAIP1/POLDIP2 on 17q11.2 represents a novel transcriptional structural-functional gene module involved in breast cancer progression

BMC Genomics BioMed Central Research Open Access Complex sense-antisense architecture of TNFAIP1/POLDIP2 on 17q11.2 represents a novel transcriptional structural-functional gene module involved in breast cancer progression Oleg V Grinchuk, Efthimios Motakis and Vladimir A Kuznetsov* Address: Bioinformatics Institute, 30 Biopolis Str. #07-01, 138672, Singapore E-mail: Oleg V Grinchuk - ; Efthimios Motakis - ; Vladimir A Kuznetsov* - *Corresponding author from International Workshop on Computational Systems Biology Approaches to Analysis of Genome Complexity and Regulatory Gene Networks Singapore 20-25 November 2008 Published: 10 February 2010 BMC Genomics 2010, 11(Suppl 1):S9 doi: 10.1186/1471-2164-11-S1-S9 This article is available from: http://www.biomedcentral.com/1471-2164/11/S1/S9 Publication of this supplement was made possible with help from the Bioinformatics Agency for Science, Technology and Research of Singapore and the Institute for Mathematical Sciences at the National University of Singapore. © 2010 Grinchuk et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: A sense-antisense gene pair (SAGP) is a gene pair where two oppositely transcribed genes share a common nucleotide sequence region. In eukaryotic genomes, SAGPs can be organized in complex sense-antisense architectures (CSAGAs) in which at least one sense gene shares loci with two or more antisense partners. As shown in several case studies, SAGPs may be involved in cancers, neurological diseases and complex syndromes. However, CSAGAs have not yet been characterized in the context of human disease or cancer. Results: We characterize five genes (TMEM97, IFT20, TNFAIP1, POLDIP2 and TMEM199) organized in a CSAGA on 17q11.2 (we term this the TNFAIP1/POLDIP2 CSAGA) and demonstrate their strong and reproducible co-regulatory transcription pattern in breast cancer tumours. Genes of the TNFAIP1/POLDIP2 CSAGA are located inside the smallest region of recurrent amplification on 17q11.2 and their expression profile correlates with the DNA copy number of the region. Survival analysis of a group of 410 breast cancer patients revealed significant survival-associated individual genes and gene pairs in the TNFAIP1/POLDIP2 CSAGA. Moreover, several of the gene pairs associated with survival, demonstrated synergistic effects. Expression of genes-members of the TNFAIP1/POLDIP2 CSAGA also strongly correlated with expression of genes of ERBB2 core region of recurrent amplification on 17q12. We clearly demonstrate that the observed coregulatory transcription profile of the TNFAIP1/POLDIP2 CSAGA is maintained not only by a DNA amplification mechanism, but also by chromatin remodelling and local transcription activation. Conclusion: We have identified a novel TNFAIP1/POLDIP2 CSAGA and characterized its coregulatory transcription profile in cancerous breast tissues. We suggest that the TNFAIP1/POLDIP2 CSAGA represents a clinically significant transcriptional structural-functional gene module Page 1 of 21 (page number not for citation purposes) BMC Genomics 2010, 11(Suppl 1):S9 http://www.biomedcentral.com/1471-2164/11/S1/S9 associated with amplification of the genomic region on 17q11.2 and correlated with expression ERBB2 amplicon core genes in breast cancer. Co-expression pattern of this module correlates with histological grades and a poor prognosis in breast cancer when over-expressed. TNFAIP1/POLDIP2 CSAGA maps the risks of breast cancer relapse onto the complex genomic locus on 17q11.2. Background A cis-sense antisense gene pair (SAGP) comprises a gene pair in which the individual genes map to opposite strands on the same DNA locus and are, therefore, transcribed in opposite directions. The corresponding pairs of cis-antisense transcripts are mRNAs that are at least partially complementary to each other. Cis-antisense mRNAs that are naturally transcribed from a SAGP are known as naturally occurring sense-antisense (SA) RNAs. Studies have shown that changes in the transcription of SAGPs could be implicated in pathological processes such as some cancers and neurological diseases [1-3]. For example, it was shown experimentally in leukemia cells that genes BAL1 and BBA, which form a SAGP, are bidirectionally transcribed and concordantly expressed due to INF-gamma induction and that their products can directly interact at the protein level [4]. Previously we reported that 12 high-confidence SAGPs pairs are concordantly regulated in human breast cancer tissues [5]. Among these, two pairs (RAF1/MKRN2 and CKAP1/ POLR2I) are constitutively co-regulated in breast tumors of different genetic grades (G1, G1-like, G3-like, and G3), while the co-expression of the CR590216/EAP30 SAGP is observed specifically in G3 genetic grade. In mammalian genomes, SAGPs can be organized in more complex sense-antisense gene architectures (CSAGAs) in which at least one gene shares loci with two or more antisense partners [6-8]. Many dozens of CSAGAs can be found in the human genome - [8-10]; therefore, it is an intriguing speculation that not only SAGPs, but also CSAGAs, as integrated modules, may play important roles in human diseases, including cancer. In this regard, the study of the co-regulatory profiles of genes in the same CSAGA and, possibly, between different CSAGAs or other transcriptional modules would shed new light on the complex nature of the entire transcriptome. There are many oncogenes on chromosome 17, although the localization of these genes is not uniform. For example, according to Cancer Genetics Web http://www. cancer-genetics.org, the oncogenes TAF2N, NF1 and THRA are located on 17q11.1-q12. ERBB2 (Her-2/neu), a well-known oncogene, is located on 17q12. The gene BIRC5 on 17q25.3, which encodes the apoptosis inhibitor survivin, co-amplifies with ERBB2 and correlates with high histological grade and a poor prognosis in breast cancer when overexpressed [11]. Many other genes located close to ERBB2 on 17q12 could be over-expressed or/and amplified and are known or suspected to play a role in carcinogenesis, specifically, breast carcinogenesis. Previous studies have demonstrated that the negative effect on the prognosis of breast cancer attributed to ERBB2 amplification could, in fact, be due to co-amplification of the region adjacent to ERBB2 [12]. The ERBB2 gene and its neighbour genes could be amplified and over-expressed in 25% of invasive breast carcinomas [13,14]. In general, ERBB2 amplification and over-expression confers an unfavourable prognosis, although its significance is less than that of the traditional prognostic factors of stage and grade. It also seems that the prognosis and response to therapy varies considerably within the spe (...truncated)