Systematic associations between germ-line mutations and human cancers

View/ Open
Tobin_et_al_Int_Jnl_Computational_Biology_and_Drug_Design.pdf (843.4Kb)
Download
Publication date
2016Rights
© 2016 Inderscience Enterprises Ltd. Reproduced in accordance with the publisher's self-archiving policy.Peer-Reviewed
Yes
Metadata
Show full item recordAbstract
The revolution in Big Data has opened the gate for new research challenges in biomedical science. The aim of this study was to investigate whether germ-line gene mutations are a significant factor in 29 major primary human cancers. Using data obtained from multiple biological databases, we identified 424 genes from 8879 cancer mutation records. By integrating these gene mutation records a human cancer map was constructed from which several key results were obtained. These include the observations that missense/nonsense and regulatory mutations might play central role in connecting cancers/genes, and tend to be distributed in all chromosomes. This suggests that, of all mutation classes missense/nonsense and regulatory mutation classes are over-expressed in human genome and so are likely to have a significant impact on human cancer aetiology and pathomechanism. This offers new insights into how the distribution and interconnections of gene mutations influence the development of cancers.Version
Accepted ManuscriptCitation
Al-Shammari M, Tobin DJ and Peng Y (2016) Systematic associations between germ-line mutations and human cancers. International Journal of Computational Biology and Drug Design. 9(1-2): 135-148.Link to publisher’s version
http://www.inderscienceonline.com/doi/abs/10.1504/IJCBDD.2016.074980Type
ArticleRelated items
Showing items related by title, author, creator and subject.
-
Biallelic Mutations in the Autophagy Regulator DRAM2 Cause Retinal Dystrophy with Early Macular InvolvementEl-Asrag, M.E.; Sergouniotis, P.I.; McKibbin, M.; Plagnol, V.; Sheridan, E.; Waseem, N.; Abdelhamed, Z.; McKeefry, Declan J.; Van Schil, K.; Poulter, J.A.; et al. (2015-06)Retinal dystrophies are an overlapping group of genetically heterogeneous conditions resulting from mutations in more than 250 genes. Here we describe five families affected by an adult-onset retinal dystrophy with early macular involvement and associated central visual loss in the third or fourth decade of life. Affected individuals were found to harbor disease-causing variants in DRAM2 (DNA-damage regulated autophagy modulator protein 2). Homozygosity mapping and exome sequencing in a large, consanguineous British family of Pakistani origin revealed a homozygous frameshift variant (c.140delG [p.Gly47Valfs∗3]) in nine affected family members. Sanger sequencing of DRAM2 in 322 unrelated probands with retinal dystrophy revealed one European subject with compound heterozygous DRAM2 changes (c.494G>A [p.Trp165∗] and c.131G>A [p.Ser44Asn]). Inspection of previously generated exome sequencing data in unsolved retinal dystrophy cases identified a homozygous variant in an individual of Indian origin (c.64_66del [p.Ala22del]). Independently, a gene-based case-control association study was conducted via an exome sequencing dataset of 18 phenotypically similar case subjects and 1,917 control subjects. Using a recessive model and a binomial test for rare, presumed biallelic, variants, we found DRAM2 to be the most statistically enriched gene; one subject was a homozygote (c.362A>T [p.His121Leu]) and another a compound heterozygote (c.79T>C [p.Tyr27His] and c.217_225del [p.Val73_Tyr75del]). DRAM2 encodes a transmembrane lysosomal protein thought to play a role in the initiation of autophagy. Immunohistochemical analysis showed DRAM2 localization to photoreceptor inner segments and to the apical surface of retinal pigment epithelial cells where it might be involved in the process of photoreceptor renewal and recycling to preserve visual function.
-
Genetic characterisation of Escherichia coli RecN protein as a member of SMC family of proteinsYoussef, M.M.; Al-Omair, M.A.; Picksley, Stephen M. (2014)The proteins of SMC family are characterised by having Walker A and B sites. The Escherichia coli RecN protein is a prokaryotic member of SMC family that involved in the induced excision of Tn10 and the repair of the DNA double strand breaks. In this work, the Walker A nucleotide binding site of the E. coli RecN protein was mutated by changing the highly conserved lysine residue 35 to the aspartic acid (D), designated as recN(K35D). Reverse genetics was utilized to delete the entire recN gene (Delta recN108) or introduce the recN(K35D) gene into the E. coli chromosomal DNA. The recN(K35D) cells showed decreasing in the frequency of excision of Tn10 from gal76
-
Agonist-induced PKC phosphorylation regulates GluK2 SUMOylation and kainate receptor endocytosisKonopacki, F.A.; Jaafari, N.; Rocca, D.L.; Wilkinson, K.A.; Chamberlain, S.E.; Rubin, P.; Kantamneni, Sriharsha; Mellor, J.R.; Henley, J.M. (2011)The surface expression and regulated endocytosis of kainate (KA) receptors (KARs) plays a critical role in neuronal function. PKC can modulate KAR trafficking, but the sites of action and molecular consequences have not been fully characterized. Small ubiquitin-like modifier (SUMO) modification of the KAR subunit GluK2 mediates agonist-evoked internalization, but how KAR activation leads to GluK2 SUMOylation is unclear. Here we show that KA stimulation causes rapid phosphorylation of GluK2 by PKC, and that PKC activation increases GluK2 SUMOylation both in vitro and in neurons. The intracellular C-terminal domain of GluK2 contains two predicted PKC phosphorylation sites, S846 and S868, both of which are phosphorylated in response to KA. Phosphomimetic mutagenesis of S868 increased GluK2 SUMOylation, and mutation of S868 to a nonphosphorylatable alanine prevented KA-induced SUMOylation and endocytosis in neurons. Infusion of SUMO-1 dramatically reduced KAR-mediated currents in HEK293 cells expressing WT GluK2 or nonphosphorylatable S846A mutant, but had no effect on currents mediated by the S868A mutant. These data demonstrate that agonist activation of GluK2 promotes PKC-dependent phosphorylation of S846 and S868, but that only S868 phosphorylation is required to enhance GluK2 SUMOylation and promote endocytosis. Thus, direct phosphorylation by PKC and GluK2 SUMOylation are intimately linked in regulating the surface expression and function of GluK2-containing KARs.