Accuracy of mutational signature software on correlated signatures

Mutational signatures are characteristic patterns of mutations generated by exogenous mutagens or by endogenous mutational processes. Mutational signatures are important for research into DNA damage and repair, aging, cancer biology, genetic toxicology, and epidemiology. Unsupervised learning can infer mutational signatures from the somatic mutations in large numbers of tumors, and separating correlated signatures is a notable challenge for this task. To investigate which methods can best meet this challenge, we assessed 18 computational methods for inferring mutational signatures on 20 synthetic data sets that incorporated varying degrees of correlated activity of two common mutational signatures. Performance varied widely, and four methods noticeably outperformed the others: hdp (based on hierarchical Dirichlet processes), SigProExtractor (based on multiple non-negative matrix factorizations over resampled data), TCSM (based on an approach used in document topic analysis), and mutSpec.NMF (also based on non-negative matrix factorization). The results underscored the complexities of mutational signature extraction, including the importance and difficulty of determining the correct number of signatures and the importance of hyperparameters. Our findings indicate directions for improvement of the software and show a need for care when interpreting results from any of these methods, including the need for assessing sensitivity of the results to input parameters.

Boundary Work

The first chapter lays a foundation for the book by defining boundary discourse in crossdisciplinary and cross-sector work. It begins by distinguishing spatial and organic metaphors of boundaries, with initial emphasis on disciplines. It then combines the two metaphors in a composite concept of an ecology of spatializing practices, illustrated by the evolving nature of disciplines as well as trading zones and communities of practice. The chapter then describes structures for interdisciplinary work, followed by the concept of heterarchy, changing character of higher education, platforms for communication and collaboration, and role of the built environment. It turns next to boundary objects, illustrated by construction of a natural history museum, an academic reform initiative, a project on waste management, and the relationship of objects and their description in climate modeling, regulatory discourse, genetic toxicology, and human ecology. The chapter ends by examining boundary organizations and agents in two cross-sector case studies.

Healthy Volunteer Studies in the Development of Anticancer Drugs with Genotoxic Findings

Background Recent scientific advances in cancer research have led to the development of immunomodulatory and molecularly targeted drugs with better safety profiles than chemotherapeutics, which makes it possible to include healthy volunteers (HVs) in clinical trials. In this study, we aimed to identify the number of marketing authorization applications (MAAs) that enrolled HVs in a clinical trial and to identify the number of anticancer drugs that were given to HVs despite a positive genotoxic finding. In addition, we evaluated the dose of anticancer drugs administered to HVs and the justification for proceeding with HV studies despite a positive genotoxic finding. Methods Publicly available information from the European Medicines Agency (EMA) website was used for this study. Anticancer drugs were identified using the human medicines highlights published by EMA between January 2010 and December 2019. EPARs were used to collect general information of the anticancer drugs, details on genotoxicity studies, and the enrollment of HVs in clinical trials. Results We identified 71 MAAs for small molecule anticancer drugs with a positive or negative CHMP opinion in the EU. Forty-eight anticancer drugs were studied in HVs, of which 12 anticancer drugs were administered to HVs despite positive genotoxic findings in the standard battery. Systematic and extensive genetic toxicology screening demonstrated the absence of genotoxic risks to the cell system. Conclusion We showed that despite a positive genotoxic finding, comprehensive genetic toxicology testing demonstrated the absence of risks to the cell system at the human exposure dose. Therefore, these anticancer drugs posed no harm to HVs.

DNA Methylation—An Epigenetic Mark in Mutagen-Treated Brachypodium distachyon Cells

The chromatin structure is significantly influenced by some epigenetic modifications including DNA methylation. The nuclear organization plays an essential role in the cell response to external stresses including mutagens. We present an analysis of the correlation between epigenetic modifications and the instability of the Brachypodium distachyon genome, which are observed as micronuclei, following maleic hydrazide (MH) and nitroso-N-methylurea (MNU) treatments. We compared the level of DNA methylation in the control (untreated) and mutagen-treated B. distachyon nuclei. An immunostaining method using specific antibodies against modified DNA anti-5-methylcytosine was used for the evaluation of DNA methylation in a single nucleus and micronucleus. Interestingly, we showed an alteration of DNA methylation in cells after mutagenic treatments. The results indicate that DNA methylation might be involved in the response of the B. distachyon genome to mutagenic treatments. This demonstrates that analyses of the epigenetic modifications should be integrated into current plant genetic toxicology in order to explain the mechanisms of DNA damage and repair in plants.

How Family Histories Can Inform Research About Germ Cell Exposures: The Example of Autism

Throughout the scientific literature, heritable traits are routinely presumed to be genetic in origin. However, as emerging evidence from the realms of genetic toxicology and epigenomics demonstrate, heritability may be better understood as encompassing not only DNA sequence passed down through generations, but also disruptions to the parental germ cells causing de novo mutations or epigenetic alterations, with subsequent shifts in gene expression and functions in offspring. The Beyond Genes conference highlighted advances in understanding these aspects at molecular, experimental and epidemiological levels. In this commentary I suggest that future research on this topic could be inspired by collecting parents’ germ cell exposure histories, with particular attention to cases of families with multiple children suffering idiopathic disorders. In so doing I focus on the endpoint of autism spectrum disorders (ASD). Rates of this serious neurodevelopment disability have climbed around the world, a growing crisis that cannot be explained by diagnostic shifts. ASD’s strong heritability has prompted a research program largely focused on DNA sequencing to locate rare and common variants, but decades of this gene-focused research have revealed surprisingly little about the molecular origins of the disorder. Based on my experience as the mother of two children with idiopathic autism, and as a research philanthropist and autism advocate, I suggest ways researchers might probe parental germ cell exposure histories to develop new hypotheses that may ultimately reveal sources of non-genetic heritability in a subset of idiopathic heritable pathologies.