Morsifications and mutations

We describe and investigate a connection between the topology of isolated singularities of plane curves and the mutation equivalence, in the sense of cluster algebra theory, of the quivers associated with their morsifications.Comment: Major revision and expansion. Several new results. 80 pages, 66 figure

NF2/merlin in hereditary neurofibromatosis 2 versus cancer: biologic mechanisms and clinical associations.

Inactivating germline mutations in the tumor suppressor gene NF2 cause the hereditary syndrome neurofibromatosis 2, which is characterized by the development of neoplasms of the nervous system, most notably bilateral vestibular schwannoma. Somatic NF2 mutations have also been reported in a variety of cancers, but interestingly these mutations do not cause the same tumors that are common in hereditary neurofibromatosis 2, even though the same gene is involved and there is overlap in the site of mutations. This review highlights cancers in which somatic NF2 mutations have been found, the cell signaling pathways involving NF2/merlin, current clinical trials treating neurofibromatosis 2 patients, and preclinical findings that promise to lead to new targeted therapies for both cancers harboring NF2 mutations and neurofibromatosis 2 patients

Stability-mediated epistasis constrains the evolution of an influenza protein.

John Maynard Smith compared protein evolution to the game where one word is converted into another a single letter at a time, with the constraint that all intermediates are words: WORD→WORE→GORE→GONE→GENE. In this analogy, epistasis constrains evolution, with some mutations tolerated only after the occurrence of others. To test whether epistasis similarly constrains actual protein evolution, we created all intermediates along a 39-mutation evolutionary trajectory of influenza nucleoprotein, and also introduced each mutation individually into the parent. Several mutations were deleterious to the parent despite becoming fixed during evolution without negative impact. These mutations were destabilizing, and were preceded or accompanied by stabilizing mutations that alleviated their adverse effects. The constrained mutations occurred at sites enriched in T-cell epitopes, suggesting they promote viral immune escape. Our results paint a coherent portrait of epistasis during nucleoprotein evolution, with stabilizing mutations permitting otherwise inaccessible destabilizing mutations which are sometimes of adaptive value. DOI:http://dx.doi.org/10.7554/eLife.00631.001

Evolutionary dynamics of tumor progression with random fitness values

Most human tumors result from the accumulation of multiple genetic and epigenetic alterations in a single cell. Mutations that confer a fitness advantage to the cell are known as driver mutations and are causally related to tumorigenesis. Other mutations, however, do not change the phenotype of the cell or even decrease cellular fitness. While much experimental effort is being devoted to the identification of the different functional effects of individual mutations, mathematical modeling of tumor progression generally considers constant fitness increments as mutations are accumulated. In this paper we study a mathematical model of tumor progression with random fitness increments. We analyze a multi-type branching process in which cells accumulate mutations whose fitness effects are chosen from a distribution. We determine the effect of the fitness distribution on the growth kinetics of the tumor. This work contributes to a quantitative understanding of the accumulation of mutations leading to cancer phenotypes.Comment: 33 pages, 2 Figure

Analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types

AbstractIn this study we use somatic cancer mutations to identify important functional residues within sets of related genes. We focus on protein kinases, a superfamily of phosphotransferases that share homologous sequences and structural motifs and have many connections to cancer. We develop several statistical tests for identifying Significantly Mutated Positions (SMPs), which are positions in an alignment with mutations that show signs of selection. We apply our methods to 21,917 mutations that map to the alignment of human kinases and identify 23 SMPs. SMPs occur throughout the alignment, with many in the important A-loop region, and others spread between the N and C lobes of the kinase domain. Since mutations are pooled across the superfamily, these positions may be important to many protein kinases. We select eleven mutations from these positions for functional validation. All eleven mutations cause a reduction or loss of function in the affected kinase. The tested mutations are from four genes, including two tumor suppressors (TGFBR1 and CHEK2) and two oncogenes (KDR and ERBB2). They also represent multiple cancer types, and include both recurrent and non-recurrent events. Many of these mutations warrant further investigation as potential cancer drivers.</jats:p

Afatinib use in recurrent epithelial ovarian carcinoma.

•Genomic tumor testing is an important tool in guiding treatment for gynecologic malignancies.•Targetable mutations may lead to new therapies in gynecologic cancer treatment.•Her2/neu mutations in serous ovarian carcinomas can be targeted with ERBB2 inhibitors.•Afatinib shows promising response rates in lung cancers carrying Her2/neu mutations.•Afatinib may be effective in serous ovarian tumors exhibiting Her2/neu or ERBB2 mutations

Impact of PNKP mutations associated with microcephaly, seizures and developmental delay on enzyme activity and DNA strand break repair

Microcephaly with early-onset, intractable seizures and developmental delay (MCSZ) is a hereditary disease caused by mutations in polynucleotide kinase/phosphatase (PNKP), a DNA strand break repair protein with DNA 5'-kinase and DNA 3'-phosphatase activity. To investigate the molecular basis of this disease, we examined the impact of MCSZ mutations on PNKP activity in vitro and in cells. Three of the four mutations currently associated with MCSZ greatly reduce or ablate DNA kinase activity of recombinant PNKP at 30°C (L176F, T424Gfs48X and exon15Δfs4X), but only one of these mutations reduces DNA phosphatase activity under the same conditions (L176F). The fourth mutation (E326K) has little impact on either DNA kinase or DNA phosphatase activity at 30°C, but is less stable than the wild-type enzyme at physiological temperature. Critically, all of the MCSZ mutations identified to date result in ∼10-fold reduced cellular levels of PNKP protein, and reduced rates of chromosomal DNA strand break repair. Together, these data suggest that all four known MCSZ mutations reduce the cellular stability and level of PNKP protein, with three mutations likely ablating cellular DNA 5'-kinase activity and all of the mutations greatly reducing cellular DNA 3'-phosphatase activity

The mutational meltdown in asexual populations

Loss of fitness due to the accumulation of deleterious mutations appears to be inevitable in small, obligately asexual populations, as these are incapable of reconstituting highly fit genotypes by recombination or back mutation. The cumulative buildup of such mutations is expected to lead to an eventual reduction in population size, and this facilitates the chance accumulation of future mutations. This synergistic interaction between population size reduction and mutation accumulation leads to an extinction process known as the mutational meltdown, and provides a powerful explanation for the rarity of obligate asexuality. We give an overview of the theory of the mutational meltdown, showing how the process depends on the demographic properties of a population, the properties of mutations, and the relationship between fitness and number of mutations incurred