deconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution

BACKGROUND: Analysis of somatic mutations provides insight into the mutational processes that have shaped the cancer genome, but such analysis currently requires large cohorts. We develop deconstructSigs, which allows the identification of mutational signatures within a single tumor sample. RESULTS: Application of deconstructSigs identifies samples with DNA repair deficiencies and reveals distinct and dynamic mutational processes molding the cancer genome in esophageal adenocarcinoma compared to squamous cell carcinomas. CONCLUSIONS: deconstructSigs confers the ability to define mutational processes driven by environmental exposures, DNA repair abnormalities, and mutagenic processes in individual tumors with implications for precision cancer medicine

Modelled mortality benefits of multi-cancer early detection screening in England

Background: Screening programmes utilising blood-based multi-cancer early detection (MCED) tests, which can detect a shared cancer signal from any site in the body with a single, low false-positive rate, could reduce cancer burden through early diagnosis. Methods: A natural history (‘interception’) model of cancer was previously used to characterise potential benefits of MCED screening (based on published performance of an MCED test). We built upon this using a two-population survival model to account for an increased risk of death from cfDNA-detectable cancers relative to cfDNA-non-detectable cancers. We developed another model allowing some cancers to metastasise directly from stage I, bypassing intermediate tumour stages. We used incidence and survival-by-stage data from the National Cancer Registration and Analysis Service in England to estimate longer-term benefits to a cohort screened between ages 50–79 years. Results: Estimated late-stage and mortality reductions were robust to a range of assumptions. With the least favourable dwell (sojourn) time and cfDNA status hazard ratio assumptions, we estimated, among 100,000 screened individuals, 67 (17%) fewer cancer deaths per year corresponding to 2029 fewer deaths in those screened between ages 50–79 years. Conclusion: Realising the potential benefits of MCED tests could substantially reduce late-stage cancer diagnoses and mortality

Modelled mortality benefits of multi-cancer early detection screening in England

Background Screening programmes utilising blood-based multi-cancer early detection (MCED) tests, which can detect a shared cancer signal from any site in the body with a single, low false-positive rate, could reduce cancer burden through early diagnosis. Methods A natural history (‘interception’) model of cancer was previously used to characterise potential benefits of MCED screening (based on published performance of an MCED test). We built upon this using a two-population survival model to account for an increased risk of death from cfDNA-detectable cancers relative to cfDNA-non-detectable cancers. We developed another model allowing some cancers to metastasise directly from stage I, bypassing intermediate tumour stages. We used incidence and survival-by-stage data from the National Cancer Registration and Analysis Service in England to estimate longer-term benefits to a cohort screened between ages 50–79 years. Results Estimated late-stage and mortality reductions were robust to a range of assumptions. With the least favourable dwell (sojourn) time and cfDNA status hazard ratio assumptions, we estimated, among 100,000 screened individuals, 67 (17%) fewer cancer deaths per year corresponding to 2029 fewer deaths in those screened between ages 50–79 years. Conclusion Realising the potential benefits of MCED tests could substantially reduce late-stage cancer diagnoses and mortality

APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution

The APOBEC mutational signature has only recently been detected in a multitude of cancers through next-generation sequencing. In contrast, APOBEC has been a focus of virology research for over a decade. Many lessons learnt regarding APOBEC within virology are likely to be applicable to cancer. In this review, we explore the parallels between the role of APOBEC enzymes in HIV and cancer evolution. We discuss data supporting the role of APOBEC mutagenesis in creating HIV genome heterogeneity, drug resistance, and immune escape variants. We hypothesize similar functions of APOBEC will also hold true in cancer

Deciphering Genetic Intratumor Heterogeneity and Its Impact on Cancer Evolution

Cancer is a disease reliant on the generation of mutations and the subsequent selection of those subpopulations endowed with the greatest fitness advantage. Beginning with a heterogeneous landscape of somatic alterations, various selective pressures acting on a tumor can shape the way it evolves. In this review, we first discuss the current bioinformatics tools available to tease apart the heterogeneous nature of a tumor and second consider the impact that evolutionary forces have on sculpting a tumor. Neighboring subclones may alter the microenvironment cultivating either cooperation or competition between clonal populations. Additionally, the harsh environment brought about by therapy and the immune system may force adaptation. Finally, we examine recent analyses focused on precancerous samples, which help to reveal clonal selection occurring during the earliest stages of tumor development, as well as work that has identified patterns of somatic evolution observed in normal tissues

Principles of Stakes Fairness in Sport

Fairness in sport is not just about assigning the top prizes to the worthiest competitors. It is also about the way the prize structure itself is organised. For many sporting competitions, although it may be acceptable for winners to receive more than losers, it can seem unfair for winners to take everything and for losers to get nothing. Yet this insight leaves unanswered some difficult questions about what stakes fairness requires and which principles of stakes fairness are appropriate for particular competitions. In this article I specify a range of different principles of stakes fairness (ten in total) that could regulate sporting competitions. I also put forward a theoretical method for pairing up appropriate principles of stakes fairness with given sporting competitions. Specifically, I argue that the underlying rationales for holding sporting competitions can provide useful guides for identifying appropriate principles of stakes fairness. I then seek to clarify and work through some of the implications of this method for a sample of real world controversies over sporting prize structures. I also attempt to refine the method in response to two possible objections from indeterminacy and relativism. Finally, I compare and contrast my conclusions with more general philosophical debates about justice

Targeted therapy for advanced salivary gland carcinoma based on molecular profiling: Results from MyPathway, a phase IIa multiple basket study

BACKGROUND: Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics. PATIENTS AND METHODS: MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR). RESULTS: As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease \u3e4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred. CONCLUSIONS: Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination

Grounding knowledge and normative valuation in agent-based action and scientific commitment

Philosophical investigation in synthetic biology has focused on the knowledge-seeking questions pursued, the kind of engineering techniques used, and on the ethical impact of the products produced. However, little work has been done to investigate the processes by which these epistemological, metaphysical, and ethical forms of inquiry arise in the course of synthetic biology research. An attempt at this work relying on a particular area of synthetic biology will be the aim of this chapter. I focus on the reengineering of metabolic pathways through the manipulation and construction of small DNA-based devices and systems synthetic biology. Rather than focusing on the engineered products or ethical principles that result, I will investigate the processes by which these arise. As such, the attention will be directed to the activities of practitioners, their manipulation of tools, and the use they make of techniques to construct new metabolic devices. Using a science-in-practice approach, I investigate problems at the intersection of science, philosophy of science, and sociology of science. I consider how practitioners within this area of synthetic biology reconfigure biological understanding and ethical categories through active modelling and manipulation of known functional parts, biological pathways for use in the design of microbial machines to solve problems in medicine, technology, and the environment. We might describe this kind of problem-solving as relying on what Helen Longino referred to as “social cognition” or the type of scientific work done within what Hasok Chang calls “systems of practice”. My aim in this chapter will be to investigate the relationship that holds between systems of practice within metabolic engineering research and social cognition. I will attempt to show how knowledge and normative valuation are generated from this particular network of practitioners. In doing so, I suggest that the social nature of scientific inquiry is ineliminable to both knowledge acquisition and ethical evaluations