Understanding the impacts of missense mutations on structures and functions of human cancer-related genes: A preliminary computational analysis of the COSMIC Cancer Gene Census

Hereditary spastic paraplegias (HSPs) are a genetically heterogeneous collection of neurodegenerative disorders categorized by progressive lower-limb spasticity and frailty. The complex HSP forms are characterized by various neurological features including progressive spastic weakness, urinary sphincter dysfunction, extra pyramidal signs and intellectual disability (ID). The kinesin superfamily proteins (KIFs) are microtubule-dependent molecular motors involved in intracellular transport. Kinesins directionally transport membrane vesicles, protein complexes, and mRNAs along neurites, thus playing important roles in neuronal development and function. Recent genetic studies have identified kinesin mutations in patients with HSPs. In this study, we used the computational approaches to investigate the 40 missense mutations associated with HSP and ID in KIF1A and KIF5A. We performed homology modeling to construct the structures of kinesin–microtubule binding domain and kinesin–tubulin complex. We applied structure-based energy calculation methods to determine the effects of missense mutations on protein stability and protein–protein interaction. The results revealed that the most of disease-causing mutations could change the folding free energy of kinesin motor domain and the binding free energy of kinesin–tubulin complex. We found that E253K associated with ID in KIF1A decrease the protein stability of kinesin motor domains. We showed that the HSP mutations located in kinesin–tubulin complex interface, such as K253N and R280C in KIF5A, can destabilize the kinesin–tubulin complex. The computational analysis provides useful information for understanding the roles of kinesin mutations in the development of ID and HSPs.

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STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation

Communications Biology ◽

10.1038/s42003-020-1092-0 ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 2

Author(s):

Paula Granado-Martínez ◽

Sara Garcia-Ortega ◽

Elena González-Sánchez ◽

Kimberley McGrail ◽

Rafael Selgas ◽

...

Keyword(s):

Tumor Growth ◽

Somatic Mutations ◽

Human Cancer ◽

Tumor Biology ◽

Missense Mutations ◽

Expression Of Genes ◽

Promote Tumor Growth ◽

Genes Encoding ◽

Differential Gene ◽

Somatic Mutant

AbstractElucidating the contribution of somatic mutations to cancer is essential for personalized medicine. STK11 (LKB1) appears to be inactivated in human cancer. However, somatic missense mutations also occur, and the role/s of these alterations to this disease remain unknown. Here, we investigated the contribution of four missense LKB1 somatic mutations in tumor biology. Three out of the four mutants lost their tumor suppressor capabilities and showed deficient kinase activity. The remaining mutant retained the enzymatic activity of wild type LKB1, but induced increased cell motility. Mechanistically, LKB1 mutants resulted in differential gene expression of genes encoding vesicle trafficking regulating molecules, adhesion molecules and cytokines. The differentially regulated genes correlated with protein networks identified through comparative secretome analysis. Notably, three mutant isoforms promoted tumor growth, and one induced inflammation-like features together with dysregulated levels of cytokines. These findings uncover oncogenic roles of LKB1 somatic mutations, and will aid in further understanding their contributions to cancer development and progression.

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Abstract 2599: COSMIC Cancer Gene Census: expert descriptions across genes in oncogenesis

10.1158/1538-7445.am2017-2599 ◽

2017 ◽

Author(s):

Zbyslaw Sondka ◽

Sally Bamford ◽

Charlotte G. Cole ◽

Elisabeth Dawson ◽

Laura Ponting ◽

...

Keyword(s):

Cancer Gene ◽

Cancer Gene Census

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BRB-ArrayTools Data Archive for Human Cancer Gene Expression: A Unique and Efficient Data Sharing Resource

Cancer Informatics ◽

10.4137/cin.s448 ◽

2008 ◽

Vol 6 ◽

pp. CIN.S448 ◽

Cited By ~ 53

Author(s):

Yingdong Zhao ◽

Richard Simon

Keyword(s):

Gene Expression ◽

Microarray Data ◽

Human Cancer ◽

Data Archive ◽

Cancer Gene ◽

Expression Array ◽

Smooth Interface ◽

Efficient Data ◽

Potential Benefits ◽

Cancer Types

The explosion of available microarray data on human cancer increases the urgency for developing methods for effectively sharing this data among clinical cancer investigators. Lack of a smooth interface between the databases and statistical analysis tools limits the potential benefits of sharing the publicly available microarray data. To facilitate the efficient sharing and use of publicly available microarray data among cancer investigators, we have built a BRB-ArrayTools Data Archive including over one hundred human cancer microarray projects for 28 cancer types. Expression array data and clinical descriptors have been imported into BRB-ArrayTools and are stored as BRB-ArrayTools project folders on the archive. The data archive can be accessed from: http://www.linus.nci.nih.gov/~brb/DataArchive.html Our BRB-ArrayTools data archive and GEO importer represent ongoing efforts to provide effective tools for efficiently sharing and utilizing human cancer microarray data.

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Human cancer gene sequenced

Science ◽

10.1126/science.3823884 ◽

1987 ◽

Vol 235 (4794) ◽

pp. 1323-1323

Author(s):

G. Kolata

Keyword(s):

Human Cancer ◽

Cancer Gene

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Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer

eLife ◽

10.7554/elife.02935 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 153

Author(s):

Young Seok Ju ◽

Ludmil B Alexandrov ◽

Moritz Gerstung ◽

Inigo Martincorena ◽

Serena Nik-Zainal ◽

...

Keyword(s):

Human Cancer ◽

Missense Mutations ◽

Mtdna Mutations ◽

Dna Mutations ◽

Mtdna Sequence ◽

Sequencing Studies ◽

Functional Consequences ◽

Somatic Alterations ◽

Mtdna Replication ◽

Tumor Types

Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.

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Comprehensive characterization of protein-protein interaction network perturbations by human disease mutations

10.1101/2020.09.18.302588 ◽

2020 ◽

Author(s):

Feixiong Cheng ◽

Junfei Zhao ◽

Yang Wang ◽

Weiqiang Lu ◽

Zehui Liu ◽

...

Keyword(s):

Protein Interaction ◽

Large Scale ◽

Human Cancer ◽

The Cancer Genome Atlas ◽

Binary Interaction ◽

Missense Mutations ◽

Cancer Subtypes ◽

Protein Protein Interaction ◽

Protein Interfaces ◽

Disease Mutations

AbstractTechnological and computational advances in genomics and interactomics have made it possible to identify rapidly how disease mutations perturb interaction networks within human cells. In this study, we investigate at large-scale the effects of network perturbations caused by disease mutations within the human three-dimensional (3D), structurally-resolved macromolecular interactome. We show that disease-associated germline mutations are significantly enriched in sequences encoding protein-protein interfaces compared to mutations identified in healthy subjects from the 1000 Genomes and ExAC projects; these interface mutations correspond to protein-protein interaction (PPI)-perturbing alleles including p.Ser127Arg in PCSK9 at the PCSK9-LDLR interface. In addition, somatic missense mutations are significantly enriched in PPI interfaces compared to non-interfaces in 10,861 human exomes across 33 cancer subtypes/types from The Cancer Genome Atlas. Using a binomial statistical model, we computationally identified 470 PPIs harboring a statistically significant excess number of missense mutations at protein-protein interfaces (termed putative oncoPPIs) in pan-cancer analysis. We demonstrate that the oncoPPIs, including histone H4 complex in individual cancer types, are highly correlated with patient survival and drug resistance/sensitivity in human cancer cell lines and patient-derived xenografts. We experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay. We further showed that ALOX5 p.Met146Lys at the ALOX5-MAD1L1 interface and RXRA p.Ser427Phe at the RXRA-PPARG interface promote significant tumor cell growth using cell line-based functional assays, providing a functional proof-of-concept. In summary, if broadly applied, this human 3D interactome network analysis offers a powerful tool for prioritizing alleles with mutations altering PPIs that may contribute to the pathobiology of human diseases, and may offer disease-specific targets for genotype-informed therapeutic discovery.

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