title: Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways.
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.
authors.affiliation: Faculty of Medicine, University of Khartoum Khartoum, Sudan.
authors.forename: Suleiman H
authors.initials: SH
authors.lastname: Suleiman
authors.affiliation: Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum Khartoum, Sudan.
authors.forename: Mahmoud E
authors.initials: ME
authors.lastname: Koko
authors.affiliation: Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum Khartoum, Sudan.
authors.forename: Wafaa H
authors.initials: WH
authors.lastname: Nasir
authors.affiliation: Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum Khartoum, Sudan.
authors.forename: Ommnyiah
authors.initials: O
authors.lastname: Elfateh
authors.affiliation: Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum Khartoum, Sudan.
authors.forename: Ubai K
authors.initials: UK
authors.lastname: Elgizouli
authors.affiliation: Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum Khartoum, Sudan.
authors.forename: Mohammed O E
authors.initials: MO
authors.lastname: Abdallah
authors.affiliation: Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum Khartoum, Sudan.
authors.forename: Khalid O
authors.initials: KO
authors.lastname: Alfarouk
authors.affiliation: Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum Khartoum, Sudan.
authors.forename: Ayman
authors.initials: A
authors.lastname: Hussain
authors.affiliation: Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum Khartoum, Sudan.
authors.forename: Shima
authors.initials: S
authors.lastname: Faisal
authors.affiliation: Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum Khartoum, Sudan.
authors.forename: Fathelrahamn M A
authors.initials: FM
authors.lastname: Ibrahim
authors.affiliation: International Centre for Genetic Engineering and Biotechnology Trieste, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Romano
authors.affiliation: Weill Cornell Medical College Doha, Qatar.
authors.forename: Ali
authors.initials: A
authors.lastname: Sultan
authors.affiliation: International Centre for Genetic Engineering and Biotechnology Trieste, Italy.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Banks
authors.affiliation: University of Sussex Brighton, UK.
authors.forename: Melanie
authors.initials: M
authors.lastname: Newport
authors.affiliation: International Centre for Genetic Engineering and Biotechnology Trieste, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Baralle
authors.affiliation: Faculty of Medicine, University of Khartoum Khartoum, Sudan.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Elhassan
authors.affiliation: Faculty of Medicine, University of Khartoum Khartoum, Sudan.
authors.forename: Hiba S
authors.initials: HS
authors.lastname: Mohamed
authors.affiliation: Faculty of Medicine, University of Khartoum Khartoum, Sudan.
authors.forename: Muntaser E
authors.initials: ME
authors.lastname: Ibrahim
keywords: ELAVL1/HuR; NFkB; colorectal cancer; exome sequencing; network analysis; pathway analysis