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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

Extended family pedigree showing sampled individuals and their relations. Four sampled individuals (colored arrowhead) are shown – patients P17 and P61, and controls P39 and P26. P84 is distantly related and not shown. Shaded individuals are diagnosed with colorectal cancer. Decease status is not shown. Double-lines indicate second degree consanguinous marriage. Multiple healthy siblings and/or branches with no affected offspring are depicted as diamonds for simplification.
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Figure 1: Extended family pedigree showing sampled individuals and their relations. Four sampled individuals (colored arrowhead) are shown – patients P17 and P61, and controls P39 and P26. P84 is distantly related and not shown. Shaded individuals are diagnosed with colorectal cancer. Decease status is not shown. Double-lines indicate second degree consanguinous marriage. Multiple healthy siblings and/or branches with no affected offspring are depicted as diamonds for simplification.

Mentions: The study examined whole exome sequences of samples from five subjects chosen from a Sudanese family with a strong family history of hereditary colorectal cancer (as well as other tumors and diseases) by convenience non-probability sample selection. Two patients (male/female) were selected from two different branches of the extended family. Cancer patients had a histopathological diagnosis of Microsatellite Instability-High moderately differentiated colorectal adenocarcinoma. A diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) was made based on Bethesda Criteria. Three controls were selected to comprise a sibling to one patient, a second closely related individual, and a third distantly related control. The family pedigree is shown in Figure 1. Tumor tissue samples are labeled P17 and P61, and controls are labeled P39, P26, and P84. The relations between individuals are shown in the pedigree (Figure 1). The family of individuals P39, P26, P61, and P17 is related to a common grandparent. Individual P84 is a distant relative of the family and hence not shown in the pedigree.


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)

Extended family pedigree showing sampled individuals and their relations. Four sampled individuals (colored arrowhead) are shown – patients P17 and P61, and controls P39 and P26. P84 is distantly related and not shown. Shaded individuals are diagnosed with colorectal cancer. Decease status is not shown. Double-lines indicate second degree consanguinous marriage. Multiple healthy siblings and/or branches with no affected offspring are depicted as diamonds for simplification.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Extended family pedigree showing sampled individuals and their relations. Four sampled individuals (colored arrowhead) are shown – patients P17 and P61, and controls P39 and P26. P84 is distantly related and not shown. Shaded individuals are diagnosed with colorectal cancer. Decease status is not shown. Double-lines indicate second degree consanguinous marriage. Multiple healthy siblings and/or branches with no affected offspring are depicted as diamonds for simplification.
Mentions: The study examined whole exome sequences of samples from five subjects chosen from a Sudanese family with a strong family history of hereditary colorectal cancer (as well as other tumors and diseases) by convenience non-probability sample selection. Two patients (male/female) were selected from two different branches of the extended family. Cancer patients had a histopathological diagnosis of Microsatellite Instability-High moderately differentiated colorectal adenocarcinoma. A diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) was made based on Bethesda Criteria. Three controls were selected to comprise a sibling to one patient, a second closely related individual, and a third distantly related control. The family pedigree is shown in Figure 1. Tumor tissue samples are labeled P17 and P61, and controls are labeled P39, P26, and P84. The relations between individuals are shown in the pedigree (Figure 1). The family of individuals P39, P26, P61, and P17 is related to a common grandparent. Individual P84 is a distant relative of the family and hence not shown in the pedigree.

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