AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

基礎講座 電気泳動(Electrophoresis)

Context: The interpretation of novel missense variants is a challenge with increasing numbers of such variants being identified and a responsibility to report the findings in the context of all available scientific evidence. Various in silico bioinformatic tools have been developed that predict the likely pathogenicity of missense variants; however, their utility within the diagnostic setting requires further investigation. Aim: The aim of our study was to test the predictive value of two of these tools, sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), in a set of 141 missense variants (131 pathogenic, 8 benign) identified in the ABCC8, GCK, and KCNJ11 genes. Methods: Sixty-six of the mutations caused a gain of protein function, while 67 were loss-of-function mutations. The evolutionary conservation at each residue was also investigated using multiple sequence alignments from the UCSC genome browser. Results: The sensitivity of SIFT and PolyPhen was reasonably high (69% and...

Using SIFT and PolyPhen to Predict Loss-of-Function and Gain-of-Function Mutations

Lamin A/C proteins are the major components of a thin proteinaceous filamentous meshwork, the lamina, that underlies the inner nuclear membrane. A few specific mutations in the lamin A/C gene cause a disease with remarkably different clinical features: FPLD, or familial partial lipodystrophy (Dunnigan-type), which mainly affects adipose tissue. Lamin A/C mutant R482W is the key variant that causes FPLD. Biomolecular interaction and molecular dynamics (MD) simulation analysis were performed to understand dynamic behavior of native and mutant structures at atomic level. Mutant lamin A/C (R482W) showed more interaction with its biological partners due to its expansion of interaction surface and flexible nature of binding residues than native lamin A/C. MD simulation clearly indicates that the flexibility of interacting residues of mutant are mainly due to less involvement in formation of inter and intramolecular hydrogen bonds. Our analysis of native and Mutant lamin A/C clearly shows that the structural and functional consequences of the mutation R482W causes FPLD. Because of the pivotal role of lamin A/C in maintaining dynamics of nuclear function, these differences likely contribute to or represent novel mechanisms in laminopathy development.

https://link.springer.com/content/pdf/10.1007%2Fs00726-011-1108-7.pdf

In silico investigation of molecular mechanism of laminopathy caused by a point mutation (R482W) in lamin A/C protein

Tuberculosis continues to be a global health threat. Pyrazinamide (PZA) is an important first-line drug in multidrug-resistant tuberculosis treatment. The emergence of strains resistant to PZA represents an important public health problem, as both first- and second-line treatment regimens include PZA. It becomes toxic to Mycobacterium tuberculosis when converted to pyrazinoic acid by the bacterial pyrazinamidase (PncA) enzyme. Resistance to PZA is caused mainly by the loss of enzyme activity by mutation, the mechanism of resistance is not completely understood. In our studies, we analysed three mutations (D8G, S104R and C138Y) of PncA which are involved in resistance towards PZA. Binding pocket analysis solvent accessibility analysis, molecular docking and interaction analysis were performed to understand the interaction behaviour of mutant enzymes with PZA. Molecular dynamics simulations were conducted to understand the three-dimensional (3D) conformational behaviour of native and mutants PncA. Our analy...

Drug resistance mechanism of PncA in Mycobacterium tuberculosis

Studies on flexibility and binding affinity of Asp25 of HIV-1 protease mutants.

Effect of deleterious nsSNP on the HER2 receptor based on stability and binding affinity with herceptin: a computational approach.

Titanium dioxide has been proven for toxicity by in vitro and in vivo approaches, however, further studies are needed in nano-toxicological research using in silico analysis. In this study, Autodock 4.0.5 was used in an attempt to evaluate the interaction of titanium dioxide with proteins. Different cellular proteins were sorted to study the interaction, binding sites, and active sites as a pocket. These pockets have been determined using CastP - an online server. The analysis for the docked structures was performed with regard to the most efficient binding with amino acids. This study is the first of its kind to report on the in silico docking interaction of titanium dioxide nanoparticles without any surface modification. The higher negative binding energy shows strong binding of titanium dioxide with proteins. A strong interaction with different cellular proteins was observed, and more specifically, titanium dioxide nanoparticles showed frequent interaction with proline, lysine, as well as leusine.

/pdf/titanium-dioxide-nanoparticle-protein-interaction-explained-28y1idqbyn.pdf

Titanium dioxide nanoparticle-protein interaction explained by docking approach.

Cadmium toxicity has been reported to have major health effects including carcinogenicity, respiratory disorders, kidney failure, neurotoxicity and liver dysfunction. Understanding the nature of the association of cadmium with biomolecules has thus become imperative and a key factor in predicting the phenomena behind predisposition to disease. Accordingly, a computational investigation of cadmium-binding characteristics was performed using about 140 cadmium-bound structures and 34 cadmium-binding sequences. The metal-coordinating architecture defining the chelate loops, residue arrangement, secondary-structural characteristics, distances and angles were analyzed. Binding patterns were predicted based on the probability of occurrence of residues within the coordination distance and were further corroborated with sequence patterns obtained from cadmium-binding proteins. About 56 different chelate loops were identified. Based on these chelate loops, putative cadmium-binding patterns were derived that resembled short-length motifs, namely Y-X-G-X-­G, Q-X9-E, E-X2-E-X2-E and T-X5-E-X2-E, which were observed within the conserved regions of the cadmium-binding proteins. The poorer conservation of residues around these motifs resulted in a deviating pattern against the coordination loops. These structure-based motifs are proposed to be an efficient tool in building chelators for the effective removal of cadmium.

C. Sudandiradoss

Papers

Studies on flexibility and binding affinity of Asp25 of HIV-1 protease mutants.

Effect of deleterious nsSNP on the HER2 receptor based on stability and binding affinity with herceptin: a computational approach.

Titanium dioxide nanoparticle-protein interaction explained by docking approach.

Pattern prediction and coordination geometry analysis from cadmium-binding proteins: a computational approach.

Insight into pattern of codon biasness and nucleotide base usage in serotonin receptor gene family from different mammalian species.