40 | THE DIRECT STUDY: A ROADMAP FOR ctDNA‐BASED RISK PREDICTION, MOLECULAR PROFILING AND MRD DETECTION IN DIFFUSE LARGE B CELL LYMPHOMA

Hematological Oncology · 2025-06-01

J. A. Krupka, I. Moutsopoulos, and N. J. Cutmore equally contributing authors. Introduction: Recent studies have engendered excitement over the potential for ctDNA to transform the management of DLBCL and to enable precision medicine trials where treatment is tailored by patient risk and biological subtype. However, current understanding of ctDNA remains at an early stage and existing studies are often limited by small cohort size, the predominant use of retrospective, archival material, and the use of assays and analytical pipelines whose availability is restricted to a single laboratory or single commercial provider. Methods: DIRECT was a prospective, multisite study assessing the feasibility and utility of circulating tumor DNA (ctDNA) in 188 patients with aggressive B-cell non-Hodgkin lymphoma. We developed a lymphoma-customized, targeted sequencing assay that captured 130 driver genes plus 250 Kb of hypermutated genomic space. This provided hundreds of trackable markers per patient including phased variants (PVs) to facilitate ultrasensitive assessment of minimal residual disease (MRD). We developed a customized, error suppressed analytical pipeline for low allele fraction, plasma-based genotyping and PV-supported response assessment. We explored the utility of this ctDNA assay in three applications: (1) Pre-treatment risk prediction. (2) Baseline genetic profiling. (3) MRD response assessment at end of treatment (EoT). Results: Pre-treatment risk prediction. We calculated ctDNA fraction and concentration using two approaches: single nucleotide (SNV) based or copy number (CNA) based. The latter has logistical advantages when applied across differing assays and analytical pipelines. CNA-based ctDNA fraction > 0.1 identified high-risk patients (2-year TTP 59% versus 90%; HR 5.7; p < 0.001) more effectively than SNV-based ctDNA concentration enhanced existing clinical risk stratification. Baseline genetic profiling. Plasma DNA was suitable for genetic profiling in 75% of cases and was especially valuable in the 14% of cases where available biopsy material was insufficient for molecular analysis. Across a total of 28,404 biopsy-defined variants, median plasma detection rate was 72%, increasing to 81% for driver variants and 95% for gene-level calls. Inadequate plasma genotyping was associated with very low tumor volume and could be accurately predicted from simple clinical factors. MRD assessment at EoT. We calculated limit of detection (LoD95) for every case. Median LoD95 was 4.6 × 10−6. LoD95 was more than an order of magnitude less when baseline biopsy material was unavailable. Patients achieving ctDNA clearance had extremely low risk 2-year progression (5%). Patients who remained MRD positive has a 61% 2-year progression. False positive MRD status was seen in 3 of the 4 patients with transformed follicular lymphoma, highlighting this as a potential caveat of PV-based MRD assessment. Conclusion: This study highlights both the value and limitations of ctDNA, providing a roadmap for its use in aggressive B-cell lymphoma. Research funding declaration: This study was financed by a grant from the Mark Foundation for Integrated Cancer Medicine to the CRUK Cancer Centre and by AstraZeneca. DJH was supported by a fellowship from Cancer Research UK (CRUK; RCCFEL\100072) Keywords: liquid biopsy; minimal residual disease; aggressive B-cell non-Hodgkin lymphoma Potential sources of conflict of interest: D. Hassane Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca V. Munugalavadla Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca D. J. Hodson Other remuneration: Research Funding AstraZeneca and GSK

The status of breeding Hen Harriers <i>Circus cyaneus</i> in the UK and Isle of Man in 2023

Bird Study · 2025-01-29

The History of the Panmictic Population Concept and Its Legacy in Contemporary Population Genetics

Annals of Human Genetics · 2025-07-28

The panmictic population concept is at the heart of population, evolutionary and conservation genetics. However, in nature, true panmictic populations are vanishingly rare. As an idea conceived for modelling evolutionary dynamics, it has been thought that the assumption of panmixia was formalised during the development of the Modern Synthesis. Here, we show that while the idea's longevity is almost certainly due to its mathematical convenience, it became embedded in evolutionary thought much earlier, initially as a way to reconcile long-standing essentialist ideas with the advent of Darwin's theories. Though the principles of essentialism and reversion have been largely rejected, these ideas persist in shaping assumptions made about populations in contemporary genetics research, including how they are conceptualised and sampled. This legacy has important implications for the interpretation of genomic findings in human evolution, conservation and medicine. From an evaluation of this history and its legacy, we contend that while the panmictic population concept has been, and continues to be useful, with the generation of terabytes of genomic data in the 21st century, its utility is likely to diminish as the need for continuous space models grows.

Historic Genomes Uncover Demographic Shifts and Kinship Structures in Post-Roman Central Europe

bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-06 · 1 citations

Summary Many European towns and villages trace their origins to Early Medieval foundations. In former Roman territories, their emergence has traditionally been linked to mass migrations from outside the Roman Empire. However, recent studies have emphasised local continuity with some individual-level mobility. We generated and analysed 248 historic genomes from Late Roman (3rd and 4th century CE) and Early Medieval (5th–8th century CE) burial sites in southern Germany, comparing them to over 2,500 contemporary and Iron Age genomes in addition to 1,344 modern-day genomes from Germany, Italy and Great-Britain. Despite small inferred Early Medieval period community sizes, genetic diversity exceeded that of modern German cities. In the Altheim graveyard, established in the 5th century by a group of Northern European descent, we inferred a demographic shift in the 6th century with the integration of newcomers with ancestry typical of a nearby Roman military camp, likely as a result of the collapse of Roman state structures. We reconstructed multigenerational pedigrees and, using a novel approach to infer ancestry of unsampled relatives, inferred immediate intermarriage between incoming and local groups, with a distinct tendency for men from former Roman background marrying women of northern descent. Burial proximity correlates strongly with kinship, in some cases spanning six generations. These communities were organized around small family units, exhibited loosely patrilineal or bilateral descent patterns, practiced reproductive monogamy, and avoided close-kin marriages. Such practices reflect broader transformations in family structures that began during the Late Roman period, were transferred to small agrarian societies in the Early Medieval period, and continued to shape European societies. By the 7th century, ongoing admixture had shaped genetic diversity patterns into those resembling Central Europe today.

Comparison of simulated and proxy-based climate reconstructions for mid-Holocene Europe reveals high uncertainty

2025-10-27

Gridded and time-continuous paleoclimate model outputs are increasingly used to inform high-resolution models in biogeography and other disciplines. However, few studies quantitatively evaluate such outputs for bias, uncertainty, and consistency with other climate reconstructions of similar scale and scope of interest. Here we evaluate downscaled and bias-corrected output from two paleoclimate models against proxy-based reconstructions from European sites in the mid-Holocene (9000–5000 years before present) by comparing absolute values of annual precipitation sum, and mean January and July air temperature. We paired proxy-based climate values with simulated ones from the same time and place. For pairs within each site we checked for correlation. Then we pooled pair-wise differences of all sites together to check for systematic over- or underestimation. Correlation analysis revealed that climate models reproduce a winter warming trend in the northern half of Europe. Pair-wise differences indicate that all gridded datasets show both over- and underestimation bias compared to proxies in different climate variables, but without one dataset performing consistently better. Distinguishing performance between these datasets is complicated by high uncertainties in proxy-based reconstructions. Our results indicate that, at least on the whole-European scale, time-continuous model outputs resolve relevant mid-Holocene climatic changes only to a very limited degree. In order to account for current uncertainties in reconstructing paleoclimate we advise users not to rely on only one gridded dataset and to evaluate reconstructions from models against proxy data from the area of interest. Author accepted manuscript, unformatted proof.

North Pontic crossroads: Mobility in Ukraine from the Bronze Age to the early modern period

Science Advances · 2025-01-08 · 8 citations

The North Pontic region, which encompasses present-day Ukraine, was a crossroads of migration, connecting the vast Eurasian Steppe with Central Europe. We generated shotgun-sequenced genomic data for 91 individuals dating from around 7000 BCE to 1800 CE to study migration and mobility history in the region, with a particular focus on historically attested migrating groups during the Iron Age and the medieval period. We infer a high degree of temporal heterogeneity in ancestry, with fluctuating genetic affinities to different present-day Eurasian groups. We also infer high heterogeneity in ancestry within geographically, culturally, and socially defined groups. Despite this, we find that ancestry components which are widespread in Eastern and Central Europe have been present in the Ukraine region since the Bronze Age. In short, our study reveals a diverse range of ancestries in the Ukraine region through time as a result of frequent movements, assimilation, and contacts.

Ancient DNA reveals the prehistory of the Uralic and Yeniseian peoples

Nature · 2025-07-02 · 8 citations

Occurrence of Twelve Haloacetic Acids and Health Risk Assessment in a Drinking Water System in Western France

SSRN Electronic Journal · 2025-01-01