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Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways.

Suleiman SH, Koko ME, Nasir WH, Elfateh O, Elgizouli UK, Abdallah MO, Alfarouk KO, Hussain A, Faisal S, Ibrahim FM, Romano M, Sultan A, Banks L, Newport M, Baralle F, Elhassan AM, Mohamed HS, Ibrahim ME - Front Genet (2015)

Bottom Line: Network analysis identified multiple hub genes of centrality.A likely explanation to such mutation pattern is DNA/RNA editing, suggested here by nucleotide transition-to-transversion ratio that significantly departed from expected values (p-value 5e-6).NFKB1 also showed significant centrality along with ELAVL1, raising the suspicion of viral etiology given the known interaction between oncogenic viruses and these proteins.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, University of Khartoum Khartoum, Sudan.

ABSTRACT
The molecular basis of cancer and cancer multiple phenotypes are not yet fully understood. Next Generation Sequencing promises new insight into the role of genetic interactions in shaping the complexity of cancer. Aiming to outline the differences in mutation patterns between familial colorectal cancer cases and controls we analyzed whole exomes of cancer tissues and control samples from an extended colorectal cancer pedigree, providing one of the first data sets of exome sequencing of cancer in an African population against a background of large effective size typically with excess of variants. Tumors showed hMSH2 loss of function SNV consistent with Lynch syndrome. Sets of genes harboring insertions-deletions in tumor tissues revealed, however, significant GO enrichment, a feature that was not seen in control samples, suggesting that ordered insertions-deletions are central to tumorigenesis in this type of cancer. Network analysis identified multiple hub genes of centrality. ELAVL1/HuR showed remarkable centrality, interacting specially with genes harboring non-synonymous SNVs thus reinforcing the proposition of targeted mutagenesis in cancer pathways. A likely explanation to such mutation pattern is DNA/RNA editing, suggested here by nucleotide transition-to-transversion ratio that significantly departed from expected values (p-value 5e-6). NFKB1 also showed significant centrality along with ELAVL1, raising the suspicion of viral etiology given the known interaction between oncogenic viruses and these proteins.

No MeSH data available.


Related in: MedlinePlus

Centrality of ELAVL1/HuR. This figure shows ELAVL1/HuR direct interaction network with genes harboring high impact genetic alterations in both tumor samples in this study. Input included perturbed genes harboring damaging genetic changes (both SNVs and INDELs). Only genes shared by both tumor samples were included. This interaction network was constructed using GeneMania cytoscape app. ELAVL1 is highlighted in yellow. The complete set of ELAVL1 interactions is also available as supplementary Image 2.
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Figure 4: Centrality of ELAVL1/HuR. This figure shows ELAVL1/HuR direct interaction network with genes harboring high impact genetic alterations in both tumor samples in this study. Input included perturbed genes harboring damaging genetic changes (both SNVs and INDELs). Only genes shared by both tumor samples were included. This interaction network was constructed using GeneMania cytoscape app. ELAVL1 is highlighted in yellow. The complete set of ELAVL1 interactions is also available as supplementary Image 2.

Mentions: We used two different interaction databases to study our gene sets (Reactome and VanBuren Lab Cognoscente). To study the genetic and protein interactions of mutated genes (genes harboring high impact or damaging mutations) with other molecules (including Protein–Protein, Protein–RNA, and Protein–DNA interactions), we used VanBuren Lab online tool Cognoscente that draws genetic interaction networks between input genes and also highlights potential genetic interactions with other intermediates. The advantage of such network approach is the insights it gives into the potential biological mechanisms involved that are not based directly on mutations within the gene sets. We used all genes affected by exonic or splice site variants (INDELs and damaging SNPs defined by ConDel scores) in both tumor samples as input. The most spectacular feature was the interaction of SNVs and INDELs with the RNA-binding protein ELAVL1/HuR, a hub protein of remarkable centrality interacting with over 2000 proteins in the human proteome, together with another central hubs: UBC, TP73, and NFKB1 (Supplementary Data: Image 2). The direct interactions between ELAVL1 and mutated genes in tumor samples are shown in (Figure 4). Although ELAVL1/HuR and UBC are not mutated in our samples, they were extensively interacting with a large number of input genes. To address whether such interaction particularly the centrality of the ELAVL1/HuR is an artifact of the large interacting partners or true interactions we compared the percentage of interactions in genes having non-synonymous SNVs and genes with synonymous SNVs to test the randomness of interactions. The synonymous set had no significant interactions and ELAVL1/HuR was interacting with only less than five nodes (Supplementary Data: Image 3). We queried The Cancer Genome Atlas database for case records with comparable clinical and pathological phenotypes to our studied samples (family history of colorectal cancer and loss of hMSH2 expression). We looked at exonic somatic mutation data for four patients we could identify (TCGA IDs: TCGA-CM-5864, TCGA-CM-6674, TCGA-CM-6164, and TCGA-AY-6196). In two cases, ELAVL1/HuR had relatively few interactions. Instead, another hub protein, TP53, showed marked centrality (Supplementary Data: Images 4–7).


Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways.

Suleiman SH, Koko ME, Nasir WH, Elfateh O, Elgizouli UK, Abdallah MO, Alfarouk KO, Hussain A, Faisal S, Ibrahim FM, Romano M, Sultan A, Banks L, Newport M, Baralle F, Elhassan AM, Mohamed HS, Ibrahim ME - Front Genet (2015)

Centrality of ELAVL1/HuR. This figure shows ELAVL1/HuR direct interaction network with genes harboring high impact genetic alterations in both tumor samples in this study. Input included perturbed genes harboring damaging genetic changes (both SNVs and INDELs). Only genes shared by both tumor samples were included. This interaction network was constructed using GeneMania cytoscape app. ELAVL1 is highlighted in yellow. The complete set of ELAVL1 interactions is also available as supplementary Image 2.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4584935&req=5

Figure 4: Centrality of ELAVL1/HuR. This figure shows ELAVL1/HuR direct interaction network with genes harboring high impact genetic alterations in both tumor samples in this study. Input included perturbed genes harboring damaging genetic changes (both SNVs and INDELs). Only genes shared by both tumor samples were included. This interaction network was constructed using GeneMania cytoscape app. ELAVL1 is highlighted in yellow. The complete set of ELAVL1 interactions is also available as supplementary Image 2.
Mentions: We used two different interaction databases to study our gene sets (Reactome and VanBuren Lab Cognoscente). To study the genetic and protein interactions of mutated genes (genes harboring high impact or damaging mutations) with other molecules (including Protein–Protein, Protein–RNA, and Protein–DNA interactions), we used VanBuren Lab online tool Cognoscente that draws genetic interaction networks between input genes and also highlights potential genetic interactions with other intermediates. The advantage of such network approach is the insights it gives into the potential biological mechanisms involved that are not based directly on mutations within the gene sets. We used all genes affected by exonic or splice site variants (INDELs and damaging SNPs defined by ConDel scores) in both tumor samples as input. The most spectacular feature was the interaction of SNVs and INDELs with the RNA-binding protein ELAVL1/HuR, a hub protein of remarkable centrality interacting with over 2000 proteins in the human proteome, together with another central hubs: UBC, TP73, and NFKB1 (Supplementary Data: Image 2). The direct interactions between ELAVL1 and mutated genes in tumor samples are shown in (Figure 4). Although ELAVL1/HuR and UBC are not mutated in our samples, they were extensively interacting with a large number of input genes. To address whether such interaction particularly the centrality of the ELAVL1/HuR is an artifact of the large interacting partners or true interactions we compared the percentage of interactions in genes having non-synonymous SNVs and genes with synonymous SNVs to test the randomness of interactions. The synonymous set had no significant interactions and ELAVL1/HuR was interacting with only less than five nodes (Supplementary Data: Image 3). We queried The Cancer Genome Atlas database for case records with comparable clinical and pathological phenotypes to our studied samples (family history of colorectal cancer and loss of hMSH2 expression). We looked at exonic somatic mutation data for four patients we could identify (TCGA IDs: TCGA-CM-5864, TCGA-CM-6674, TCGA-CM-6164, and TCGA-AY-6196). In two cases, ELAVL1/HuR had relatively few interactions. Instead, another hub protein, TP53, showed marked centrality (Supplementary Data: Images 4–7).

Bottom Line: Network analysis identified multiple hub genes of centrality.A likely explanation to such mutation pattern is DNA/RNA editing, suggested here by nucleotide transition-to-transversion ratio that significantly departed from expected values (p-value 5e-6).NFKB1 also showed significant centrality along with ELAVL1, raising the suspicion of viral etiology given the known interaction between oncogenic viruses and these proteins.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, University of Khartoum Khartoum, Sudan.

ABSTRACT
The molecular basis of cancer and cancer multiple phenotypes are not yet fully understood. Next Generation Sequencing promises new insight into the role of genetic interactions in shaping the complexity of cancer. Aiming to outline the differences in mutation patterns between familial colorectal cancer cases and controls we analyzed whole exomes of cancer tissues and control samples from an extended colorectal cancer pedigree, providing one of the first data sets of exome sequencing of cancer in an African population against a background of large effective size typically with excess of variants. Tumors showed hMSH2 loss of function SNV consistent with Lynch syndrome. Sets of genes harboring insertions-deletions in tumor tissues revealed, however, significant GO enrichment, a feature that was not seen in control samples, suggesting that ordered insertions-deletions are central to tumorigenesis in this type of cancer. Network analysis identified multiple hub genes of centrality. ELAVL1/HuR showed remarkable centrality, interacting specially with genes harboring non-synonymous SNVs thus reinforcing the proposition of targeted mutagenesis in cancer pathways. A likely explanation to such mutation pattern is DNA/RNA editing, suggested here by nucleotide transition-to-transversion ratio that significantly departed from expected values (p-value 5e-6). NFKB1 also showed significant centrality along with ELAVL1, raising the suspicion of viral etiology given the known interaction between oncogenic viruses and these proteins.

No MeSH data available.


Related in: MedlinePlus