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

Grinchuk OV, Motakis E, Kuznetsov VA - BMC Genomics (2010)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bioinformatics Institute, 30 Biopolis Str, Singapore. olegg@bii.a-star.edu.sg

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 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.

Conclusion: 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.

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Related in: MedlinePlus

Correlation matrix for ERBB2 amplicon (Uppsala cohort). A -- correlation matrix (Pearson, α = 1%); B - heat map analysis in different breast cancer grades.
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Figure 6: Correlation matrix for ERBB2 amplicon (Uppsala cohort). A -- correlation matrix (Pearson, α = 1%); B - heat map analysis in different breast cancer grades.

Mentions: We produced correlation matrices that included 6 validated genes of the ERBB2 CR (see above) and 12 neighboring genes based on data from the Uppsala and Stockholm cohorts. Genes in a matrix were placed one by one in the order of their chromosome localization (from RPL19 centromerically to ORMDL3 telomerically; Figures 6 and 7). Interestingly, we reproducibly (in both cohorts) observed a clear co-regulatory pattern (as we did for the TNFAIP1/POLDIP2 SFGM) of a transcriptional module that included not only the genes that were validated as members of the ERBB2 CR (see above and [33]), but also - the genes TCAP and PPP1R1B (Figures 6 and 7, Z-value correlation, α = 1%). The neighboring genes NEUROD2, IKZF3 (ZNFN1A3) and ZPBP2 were 'dropped' from the module due to a lack of significant correlations with any member of the module and matrix.


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

Grinchuk OV, Motakis E, Kuznetsov VA - BMC Genomics (2010)

Correlation matrix for ERBB2 amplicon (Uppsala cohort). A -- correlation matrix (Pearson, α = 1%); B - heat map analysis in different breast cancer grades.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2822537&req=5

Figure 6: Correlation matrix for ERBB2 amplicon (Uppsala cohort). A -- correlation matrix (Pearson, α = 1%); B - heat map analysis in different breast cancer grades.
Mentions: We produced correlation matrices that included 6 validated genes of the ERBB2 CR (see above) and 12 neighboring genes based on data from the Uppsala and Stockholm cohorts. Genes in a matrix were placed one by one in the order of their chromosome localization (from RPL19 centromerically to ORMDL3 telomerically; Figures 6 and 7). Interestingly, we reproducibly (in both cohorts) observed a clear co-regulatory pattern (as we did for the TNFAIP1/POLDIP2 SFGM) of a transcriptional module that included not only the genes that were validated as members of the ERBB2 CR (see above and [33]), but also - the genes TCAP and PPP1R1B (Figures 6 and 7, Z-value correlation, α = 1%). The neighboring genes NEUROD2, IKZF3 (ZNFN1A3) and ZPBP2 were 'dropped' from the module due to a lack of significant correlations with any member of the module and matrix.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bioinformatics Institute, 30 Biopolis Str, Singapore. olegg@bii.a-star.edu.sg

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 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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus