Bioinformatics Institute, 30 Biopolis Str, Singapore.
BMC Genomics. 2010 Feb 10;11 Suppl 1(Suppl 1):S9. doi: 10.1186/1471-2164-11-S1-S9.
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.
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 co-regulatory 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.
We have identified a novel TNFAIP1/POLDIP2 CSAGA and characterized its co-regulatory transcription profile in cancerous breast tissues. We suggest that the TNFAIP1/POLDIP2 CSAGA represents a clinically significant transcriptional structural-functional gene module 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.
反义基因对（SAGP）是指两个转录方向相反的基因共享一个共同的核苷酸序列区域的基因对。在真核基因组中，SAGP 可以组织在复杂的反义基因结构（CSAGAs）中，其中至少一个有意义的基因与两个或更多的反义伙伴共享基因座。正如在几个案例研究中所示，SAGP 可能与癌症、神经疾病和复杂综合征有关。然而，CSAGAs 在人类疾病或癌症的背景下尚未得到描述。
我们描述了在 17q11.2 上组织成 CSAGA 的五个基因（TMEM97、IFT20、TNFAIP1、POLDIP2 和 TMEM199）（我们将其命名为 TNFAIP1/POLDIP2 CSAGA），并证明了它们在乳腺癌肿瘤中强烈且可重复的共调控转录模式。TNFAIP1/POLDIP2 CSAGA 的基因位于 17q11.2 上反复扩增的最小区域内，其表达谱与该区域的 DNA 拷贝数相关。对 410 名乳腺癌患者的生存分析显示，TNFAIP1/POLDIP2 CSAGA 中存在与生存相关的个体基因和基因对。此外，与生存相关的几个基因对表现出协同作用。TNFAIP1/POLDIP2 CSAGA 基因的表达也与反复扩增的 ERBB2 核心区域的基因表达强烈相关。我们清楚地表明，TNFAIP1/POLDIP2 CSAGA 的观察到的共调控转录模式不仅由 DNA 扩增机制维持，还由染色质重塑和局部转录激活维持。
我们鉴定了一个新的 TNFAIP1/POLDIP2 CSAGA，并在癌性乳腺组织中对其共调控转录模式进行了表征。我们认为，TNFAIP1/POLDIP2 CSAGA 代表了一个与 17q11.2 上基因组区域扩增相关的具有临床意义的转录结构功能基因模块，并与乳腺癌中 ERBB2 扩增核心基因的表达相关。该模块的共表达模式与乳腺癌的组织学分级和预后不良相关，当过度表达时。TNFAIP1/POLDIP2 CSAGA 将乳腺癌复发的风险映射到 17q11.2 上的复杂基因组位置。
