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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

Position of NFkB1 mutations found in tumor samples P17 and P61 compared to TCGA database, and its relation to protein domains. (A)NFkB1 mutations in this study. (B)NFkB1 mutations in TCGA queried using cbioportal.org. RHD, Rel homology DNA binding domain; ANK, ankyrin repeat domain; Death, death domain.
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Figure 5: Position of NFkB1 mutations found in tumor samples P17 and P61 compared to TCGA database, and its relation to protein domains. (A)NFkB1 mutations in this study. (B)NFkB1 mutations in TCGA queried using cbioportal.org. RHD, Rel homology DNA binding domain; ANK, ankyrin repeat domain; Death, death domain.

Mentions: We utilized a different approach to draw only direct PPI networks for genes affected by all (not only damaging) exonic/splice site variants, for each sample, based on Reactome database. Network centrality was investigated using three different methods of un-weighted centrality (degree, betweenness, and closeness centrality). In tumor samples, we found that NFKB1, HDAC2, PIK3R1, TCF7L2, ITGAV, TRAF2, and CDC27 were top central nodes in sample P17, while in sample P61, NFKB1, ACTN2, PPP2R1B, RELA, PIK3CB, SIRT1, and CAMK2B were central nodes. Overlap of interaction networks of tumor samples showed an interesting feature of increased sharing around central nodes (Supplementary Data: Image 8). As well, clusters of related genes (e.g., receptor variants) were also prominent. NFKB1, TCF7L2, TGFBR2, NCOR2, CDC27, ACTN2, PIK3R1/2, PPP2R1B/2A, PABPC1, TBP along with different MAPK and STAT proteins were centrally shared. NFkB1 was the most central protein in direct PPI network, and both cases in our study had NFkB1 mutations (Figure 5). Bearing in mind the intricacies of NFkB interactions, it is almost impossible to predict the change in the signaling pathways based on mutational testing alone. However, the centrality of NFkB1 in the interaction networks of mutated genes is not something to overlook.


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)

Position of NFkB1 mutations found in tumor samples P17 and P61 compared to TCGA database, and its relation to protein domains. (A)NFkB1 mutations in this study. (B)NFkB1 mutations in TCGA queried using cbioportal.org. RHD, Rel homology DNA binding domain; ANK, ankyrin repeat domain; Death, death domain.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4584935&req=5

Figure 5: Position of NFkB1 mutations found in tumor samples P17 and P61 compared to TCGA database, and its relation to protein domains. (A)NFkB1 mutations in this study. (B)NFkB1 mutations in TCGA queried using cbioportal.org. RHD, Rel homology DNA binding domain; ANK, ankyrin repeat domain; Death, death domain.
Mentions: We utilized a different approach to draw only direct PPI networks for genes affected by all (not only damaging) exonic/splice site variants, for each sample, based on Reactome database. Network centrality was investigated using three different methods of un-weighted centrality (degree, betweenness, and closeness centrality). In tumor samples, we found that NFKB1, HDAC2, PIK3R1, TCF7L2, ITGAV, TRAF2, and CDC27 were top central nodes in sample P17, while in sample P61, NFKB1, ACTN2, PPP2R1B, RELA, PIK3CB, SIRT1, and CAMK2B were central nodes. Overlap of interaction networks of tumor samples showed an interesting feature of increased sharing around central nodes (Supplementary Data: Image 8). As well, clusters of related genes (e.g., receptor variants) were also prominent. NFKB1, TCF7L2, TGFBR2, NCOR2, CDC27, ACTN2, PIK3R1/2, PPP2R1B/2A, PABPC1, TBP along with different MAPK and STAT proteins were centrally shared. NFkB1 was the most central protein in direct PPI network, and both cases in our study had NFkB1 mutations (Figure 5). Bearing in mind the intricacies of NFkB interactions, it is almost impossible to predict the change in the signaling pathways based on mutational testing alone. However, the centrality of NFkB1 in the interaction networks of mutated genes is not something to overlook.

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