The landscape of cancer genes and mutational processes in breast cancer

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.     

A single amino acid governs enhanced activity of DinB DNA polymerases on damaged templates

Translesion synthesis (TLS) by Y-family DNA polymerases is a chief mechanism of DNA damage tolerance. Such TLS can be accurate or error-prone, as it is for bypass of a cyclobutane pyrimidine dimer by DNA polymerase eta (XP-V or Rad30) or bypass of a (6-4) TT photoproduct by DNA polymerase V (UmuD'2C), respectively. Although DinB is the only Y-family DNA polymerase conserved among all domains of life, the biological rationale for this striking conservation has remained enigmatic. Here we report that the Escherichia coli dinB gene is required for resistance to some DNA-damaging agents that form adducts at the N2-position of deoxyguanosine (dG). We show that DinB (DNA polymerase IV) catalyses accurate TLS over one such N2-dG adduct (N2-furfuryl-dG), and that DinB and its mammalian orthologue, DNA polymerase kappa, insert deoxycytidine (dC) opposite N2-furfuryl-dG with 10-15-fold greater catalytic proficiency than opposite undamaged dG. We also show that mutating a single amino acid, the 'steric gate' residue of DinB (Phe13 --> Val) and that of its archaeal homologue Dbh (Phe12 --> Ala), separates the abilities of these enzymes to perform TLS over N2-dG adducts from their abilities to replicate an undamaged template. We propose that DinB and its orthologues are specialized to catalyse relatively accurate TLS over some N2-dG adducts that are ubiquitous in nature, that lesion bypass occurs more efficiently than synthesis on undamaged DNA, and that this specificity may be achieved at least in part through a lesion-induced conformational change.     

A photometric redshift of z = 6.39 +/- 0.12 for GRB 050904

Gamma-ray bursts (GRBs) and their afterglows are the most brilliant transient events in the Universe. Both the bursts themselves and their afterglows have been predicted to be visible out to redshifts of z approximately 20, and therefore to be powerful probes of the early Universe. The burst GRB 000131, at z = 4.50, was hitherto the most distant such event identified. Here we report the discovery of the bright near-infrared afterglow of GRB 050904 (ref. 4). From our measurements of the near-infrared afterglow, and our failure to detect the optical afterglow, we determine the photometric redshift of the burst to be z = 6.39 - 0.12 + 0.11 (refs 5-7). Subsequently, it was measured spectroscopically to be z = 6.29 +/- 0.01, in agreement with our photometric estimate. These results demonstrate that GRBs can be used to trace the star formation, metallicity, and reionization histories of the early Universe.     

A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome

Opitz-Kaveggia syndrome (also known as FG syndrome) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. We report here that the original family for whom the condition is named and five other families have a recurrent mutation (2881C>T, leading to R961W) in MED12 (also called TRAP230 or HOPA), a gene located at Xq13 that functions as a thyroid receptor-associated protein in the Mediator complex.     

Murine T lymphomas with retroviral inserts in the chromosomal 15 locus for plasmacytoma variant translocations

The frequent trisomy of murine chromosome 15 in T lymphomas suggests that it bears one or more genes conducive to T-cell neoplasia. One such gene seems to be c-myc, the oncogene frequently activated in B-lymphoid tumours either by retroviral insertion, as in the avian bursal lymphomas, or by a translocation to the immunoglobulin heavy-chain locus, as in the predominant t(12; 15) of murine plasmacytomas and the analogous t(14; 8) of human Burkitt lymphomas. The c-myc gene was strongly implicated in T-cell neoplasia when 15-25% of T lymphomas arising in AKR mice, a strain prone to leukaemia, were found to have retroviral inserts near c-myc. Proviruses near c-myc were also found in several T lymphomas induced by murine leukaemia viruses (MuLV) in both mice and rats, but many of the rat thymomas bear an insert instead at one of several other common sites, at least two of which have murine homologues on chromosome 15. We show here that some murine T lymphomas contain proviral inserts in the recently identified chromosome 15 locus for plasmacytoma variant (6; 15) translocations, which we have denoted pvt-1. Although 6; 15 breakpoints map cytogenetically to the same chromosome band as c-myc, the alterations of pvt-1 in tumours occur at least 72 kilobases (kb) from the c-myc promoters. The insertions in T lymphomas suggest that an altered pvt-1 locus is conducive to neoplasia in T cells as well as B cells, possibly via long-range effects on c-myc expression.     

Atomism and ‘subtlety’ in Francis Bacon's philosophy

Francis Bacon's reflections on atomism have generally been misunderstood because they have never been systematically studied in relation to the speculative chemical philosophy which he developed in the interval between about 1592 and his death in 1626. This philosophy, in many respects unknown to historians until quite recently, was the only body of positive science which Bacon ever accepted. The speculative philosophy was, on the whole, chemical and non-mechanical, and consequently not consistent with atomist doctrines. In fact, Bacon never at any time accepted the principal atomist tenets. It is therefore necessary to explain why he was interested in atomism at all. Of the several reasons for his interest one (hitherto unrecognised) is especially important—namely, his belief that the speculative and atomic philosophies had affinities. In particular, he believed that of all the ancient philosophies atomism alone approached the ideals associated with the key notion of ‘subtlety’—ideals represented in their highest form (as he imagined) in the speculative philosophy.     

A non representationalist view of model explanation

In this paper, I examine two idealized models in astrophysics, with the aim of showing that the idealizations in these models play an important explanatory role. I argue, against many representationalists, that it is because of the idealizations in these models, rather than in spite of them, that the models turn out to have explanatory power. In many cases, this claim can be extended to the use of idealized models in the sciences more generally, and thus it gives important insight into the nature of model explanation.