Retrospective analysis of molecular scores for the prediction of distant recurrence according to baseline risk factors

This work was funded by grants from Cancer Research UK (programme Grant C569-A16891), the Royal Marsden NIHR Biomedical Research Centre, and AstraZenec

Prediction and Testing of Biological Networks Underlying Intestinal Cancer

Colorectal cancer progresses through an accumulation of somatic mutations, some of which reside in so-called “driver” genes that provide a growth advantage to the tumor. To identify points of intersection between driver gene pathways, we implemented a network analysis framework using protein interactions to predict likely connections – both precedented and novel – between key driver genes in cancer. We applied the framework to find significant connections between two genes, Apc and Cdkn1a (p21), known to be synergistic in tumorigenesis in mouse models. We then assessed the functional coherence of the resulting Apc-Cdkn1a network by engineering in vivo single node perturbations of the network: mouse models mutated individually at Apc (Apc1638N+/−) or Cdkn1a (Cdkn1a−/−), followed by measurements of protein and gene expression changes in intestinal epithelial tissue. We hypothesized that if the predicted network is biologically coherent (functional), then the predicted nodes should associate more specifically with dysregulated genes and proteins than stochastically selected genes and proteins. The predicted Apc-Cdkn1a network was significantly perturbed at the mRNA-level by both single gene knockouts, and the predictions were also strongly supported based on physical proximity and mRNA coexpression of proteomic targets. These results support the functional coherence of the proposed Apc-Cdkn1a network and also demonstrate how network-based predictions can be statistically tested using high-throughput biological data

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Fatherhood, religious belief and the protection of children in nineteenth-century English families

A core aspect of fatherhood in nineteenth-century England was providing protection for dependants, a complex role which shaped inequalities of power between genders and generations. The transmission of religious and moral orthodoxies between generations emerged as a key index of fatherly competence and a significant arena for the reshaping of familial relationships. In this chapter, three case studies are used to explore these processes: the poet Percy Bysshe Shelley; Annie Besant, the campaigner for secularism and worker’s rights; and Chester Armstrong, a mineworker and socialist. Each of these parents adopted a radical perspective towards religious belief which profoundly challenged norms of parenting, masculinity and fatherhood. Throughout this period, mothers were seen as playing an essential role in inculcating moral ideals, but protection was framed around the presence of a father who was both responsible and in control of the moral safety of his children. Most fathers struggled to do what they thought was right, even when this meant overriding social conventions, in order to pass on their values and ideas to their children. However, mothers claimed a stronger voice in bringing up children through linking their longstanding concern with child care with a desire to be effectively protective, while at the same time there was a growing view that fathers should offer a protectiveness which would allow their children to grow and develop as individuals, rather than imposing rigid conventions and discipline upon them. Through day to day conflicts and interactions relating to moral and religious belief, family life and the position of fathers within it were subject to constant examination and, over the course of the century, social transformation

Development of Oculimacula yallundae and O-acuformis (eyespot) on leaf sheaths of winter wheat in the UK in relation to thermal time

In a controlled environment (15/10 degrees C) (day/night) container experiment on winter wheat (cv. Avalon), eyespot incidence (percentage of plants affected) and number of leaf sheaths penetrated after 6 weeks increased with inoculum concentration (10(2)-10(6) conidia mL(-1)) of Oculimacula yallundae (OY) or Oculimacula acuformis (OA), but there was no difference between the two species. In an outdoor container experiment, seedlings inoculated with OY 2 weeks after sowing had a greater incidence of eyespot than those inoculated with OA, when assessed 7 weeks after inoculation. Seedlings inoculated with OA at 10 or 20 weeks after sowing developed more severe eyespot by maturity than those inoculated with OY. In an experiment at 15/10 degrees C with seedlings inoculated with OY + OA 2 weeks after sowing, more leaf sheaths were penetrated by OY (3.0 per plant) than OA (2.3 per plant) 6 weeks after inoculation. Field experiments with winter wheat consistently showed leaf sheath production, leaf sheath death, and number of leaf sheaths infected or penetrated by OA or OY were related linearly to thermal time (degrees C days) after sowing. Depending on cultivar, season and sample, a new leaf sheath was produced in 116-216 degrees C days; a leaf sheath died in 221-350 degrees C days; and infection of a new leaf sheath occurred in 129-389 degrees C days. The mean number of living leaf sheaths infected differed between samples, cultivars and seasons for both OY and OA. Regression analysis of the 1985/86 data suggested that OY progressed more rapidly than OA through the leaf sheaths, and that both the pathogens progressed more rapidly than the rate of leaf sheath death, but more slowly than the rate at which leaf sheaths were produced. It also suggested that OA progressed more slowly than the rate at which leaf sheaths died in 1987/88, but OY did not.Peer reviewe

Development of disease symptoms and fungal pathogens on shoot bases in continuous winter wheat, and effects of fungicides

Field plots in three consecutive crops of winter wheat were sampled at approximately 2-week intervals from April to July in 1989, 1990 and 1991. Culm and stem bases were examined for symptoms of eyespot, sharp eyespot and brown foot rot. The W-type and R-type of Pseudocercosporella herpotrichoides, P. anguioides, Fusarium culmorum, F. avenaceum and Microdochium nivale grown from this plant material on agar were identified. Eyespot was most severe in 1991, when plant development was least rapid following cool weather in late winter and the summer was relatively cool and wet. Sharp eyespot was most severe in 1990, which had a warm summer with moderate rainfall. The other warm summer, 1989, was drier and these conditions favoured late development of brown foot rot, associated mainly with F. culmorum which was scarce at other times. Sharp eyespot sometimes increased where prochloraz, which decreased eyespot, was applied. Distinct symptoms of more than one disease occurred less frequently on the same stem than expected from the individual total occurrences, but co-occurrences of different fungi were often more frequent than expected. In July 1990, Fusarium spp. co-occurred with R-type, but not W-type, P. herpotrichoides more frequently than expected, and in July 1990 and 1991 M. nivale and both W-type and R-type co-occurred more frequently than expected. Fusarium spp. and M. nivale were more frequent, especially in the earlier samples, on nodes than on internodes, whilst P. herpotrichoides normally infected at the internodes. The results suggest that stems weakened or altered by a primary colonizer are often a suitable substrate for a secondary colonizer, often a Fusarium sp., which may begin infection at a distance from the original lesion and often not cause distinct symptoms itself