Dataset Information

Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.

ABSTRACT: Germline mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS) and the clinically related LEOPARD syndrome (LS), whereas somatic mutations in the same gene contribute to leukemogenesis. On the basis of our previously gathered genetic and biochemical data, we proposed a model that splits NS- and leukemia-associated PTPN11 mutations into two major classes of activating lesions with differential perturbing effects on development and hematopoiesis. To test this model, we investigated further the diversity of germline and somatic PTPN11 mutations, delineated the association of those mutations with disease, characterized biochemically a panel of mutant SHP-2 proteins recurring in NS, LS, and leukemia, and performed molecular dynamics simulations to determine the structural effects of selected mutations. Our results document a strict correlation between the identity of the lesion and disease and demonstrate that NS-causative mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated ones. Furthermore, we show that the recurrent LS-causing Y279C and T468M amino acid substitutions engender loss of SHP-2 catalytic activity, identifying a previously unrecognized behavior for this class of missense PTPN11 mutations.

SUBMITTER: Tartaglia M

PROVIDER: S-EPMC1380235 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature

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Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.

Tartaglia Marco M Martinelli Simone S Stella Lorenzo L Bocchinfuso Gianfranco G Flex Elisabetta E Cordeddu Viviana V Zampino Giuseppe G Burgt Ineke van der Iv Palleschi Antonio A Petrucci Tamara C TC Sorcini Mariella M Schoch Claudia C Foa Robin R Emanuel Peter D PD Gelb Bruce D BD

American journal of human genetics 20051207 2

Germline mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS) and the clinically related LEOPARD syndrome (LS), whereas somatic mutations in the same gene contribute to leukemogenesis. On the basis of our previously gathered genetic and biochemical data, we proposed a model that splits NS- and leukemia-associated PTPN11 mutations into two major classes of activating lesions with differential perturbing effects on development and hematopoiesis. ...[more]

PMID: 16358218

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Project description:BackgroundRecently, a number of large-scale cancer genome sequencing projects have generated a large volume of somatic mutations; however, identifying the functional consequences and roles of somatic mutations in tumorigenesis remains a major challenge. Researchers have identified that protein pocket regions play critical roles in the interaction of proteins with small molecules, enzymes, and nucleic acid. As such, investigating the features of somatic mutations in protein pocket regions provides a promising approach to identifying new genotype-phenotype relationships in cancer.MethodsIn this study, we developed a protein pocket-based computational approach to uncover the functional consequences of somatic mutations in cancer. We mapped 1.2 million somatic mutations across 36 cancer types from the COSMIC database and The Cancer Genome Atlas (TCGA) onto the protein pocket regions of over 5,000 protein three-dimensional structures. We further integrated cancer cell line mutation profiles and drug pharmacological data from the Cancer Cell Line Encyclopedia (CCLE) onto protein pocket regions in order to identify putative biomarkers for anticancer drug responses.ResultsWe found that genes harboring protein pocket somatic mutations were significantly enriched in cancer driver genes. Furthermore, genes harboring pocket somatic mutations tended to be highly co-expressed in a co-expressed protein interaction network. Using a statistical framework, we identified four putative cancer genes (RWDD1, NCF1, PLEK, and VAV3), whose expression profiles were associated with overall poor survival rates in melanoma, lung, or colorectal cancer patients. Finally, genes harboring protein pocket mutations were more likely to be drug-sensitive or drug-resistant. In a case study, we illustrated that the BAX gene was associated with the sensitivity of three anticancer drugs (midostaurin, vinorelbine, and tipifarnib).ConclusionsThis study provides novel insights into the functional consequences of somatic mutations during tumorigenesis and for anticancer drug responses. The computational approach used might be beneficial to the study of somatic mutations in the era of cancer precision medicine.

Project description:BACKGROUND:Mutations arise in the human genome in two major settings: the germline and the soma. These settings involve different inheritance patterns, time scales, chromatin structures, and environmental exposures, all of which impact the resulting distribution of substitutions. Nonetheless, many of the same single nucleotide variants (SNVs) are shared between germline and somatic mutation databases, such as between the gnomAD database of 120,000 germline exomes and the TCGA database of 10,000 somatic exomes. Here, we sought to explain this overlap. RESULTS:After strict filtering to exclude common germline polymorphisms and sites with poor coverage or mappability, we found 336,987 variants shared between the somatic and germline databases. A uniform statistical model explains 34% of these shared variants; a model that incorporates the varying mutation rates of the basic mutation types explains another 50% of shared variants; and a model that includes extended nucleotide contexts (e.g. surrounding 3 bases on either side) explains an additional 4% of shared variants. Analysis of read depth finds mixed evidence that up to 4% of the shared variants may represent germline variants leaked into somatic call sets. 9% of the shared variants are not explained by any model. Sequencing errors and convergent evolution did not account for these. We surveyed other factors as well: Cancers driven by endogenous mutational processes share a greater fraction of variants with the germline, and recently derived germline variants were more likely to be somatically shared than were ancient germline ones. CONCLUSIONS:Overall, we find that shared variants largely represent bona fide biological occurrences of the same variant in the germline and somatic setting and arise primarily because DNA has some of the same basic chemical vulnerabilities in either setting. Moreover, we find mixed evidence that somatic call-sets leak appreciable numbers of germline variants, which is relevant to genomic privacy regulations. In future studies, the similar chemical vulnerability of DNA between the somatic and germline settings might be used to help identify disease-related genes by guiding the development of background-mutation models that are informed by both somatic and germline patterns of variation.

Dataset Information

Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.

Publications

Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.

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