Extrachromosomal DNA in the cancerous transformation of Barrett's oesophagus.

Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer1-6. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett's oesophagus. These data included 206 biopsies in Barrett's oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case-control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett's-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.

Recycling paper to recarbonise soil.

Soil organic carbon can be increased through sympathetic land management and/or directly by incorporating carbon rich amendments. Herein, a field experiment amended paper crumble (PC) to soil at a normal deployment rate of 50 t ha-1, and at higher rates up to 200 t ha-1. The nominal 50 t ha-1 PC amendment resulted a mean increase in soil carbon of 12.5 g kg-1. Using a modified Roth-C carbon fate model, the long-term (50 years) carbon storage potential of a 50 t ha-1 PC amendment was determined to be 0.36 tOC ha-1. Modelling a rotational (4 yearly) 50 t ha-1 PC amendment indicated 6.65 tOC ha-1 uplift would accrue after 50 years. Contextualised for the average farm in the East of England (~120 ha, with 79 % as arable), PC derived increases in SOC would be equivalent to 2310 t CO2e. These results support the use of PC to deliver significant levels of soil recarbonisation. Beyond carbon, PC was observed to influence other soil properties. Benefits observed included, decreased bulk density, increased water holding capacity, and increased cation exchange capacity. While PC amendment did not significantly increase wheat (Triticum aestivum) crop yield, manifold benefits in terms of increased SOC, long-term carbon storage potential, and improved soil quality sustain PC as a beneficial soil conditioner.

Somatic whole genome dynamics of precancer in Barrett's esophagus reveals features associated with disease progression.

While the genomes of normal tissues undergo dynamic changes over time, little is understood about the temporal-spatial dynamics of genomes in premalignant tissues that progress to cancer compared to those that remain cancer-free. Here we use whole genome sequencing to contrast genomic alterations in 427 longitudinal samples from 40 patients with stable Barrett's esophagus compared to 40 Barrett's patients who progressed to esophageal adenocarcinoma (ESAD). We show the same somatic mutational processes are active in Barrett's tissue regardless of outcome, with high levels of mutation, ESAD gene and focal chromosomal alterations, and similar mutational signatures. The critical distinction between stable Barrett's versus those who progress to cancer is acquisition and expansion of TP53-/- cell populations having complex structural variants and high-level amplifications, which are detectable up to six years prior to a cancer diagnosis. These findings reveal the timing of common somatic genome dynamics in stable Barrett's esophagus and define key genomic features specific to progression to esophageal adenocarcinoma, both of which are critical for cancer prevention and early detection strategies.

The removal of arsenic from solution through biochar-enhanced precipitation of calcium-arsenic derivatives.

Arsenic (As) pollution remains a major threat to the quality of global soils and drinking water. The health effects of As pollution are often severe and have been largely reported across Asia and South America. This study investigated the possibility of using unmodified biochar derived from rice husk (RB) and aspen wood (WB) at 400 °C and 700 °C to enhance the precipitation of calcium/arsenic compounds for the removal of As(III) from solution. The approach was based on utilizing calcium to precipitate arsenic in solution and adding unmodified biochar to enhance the process. Using this approach, As(III) concentration in aqueous solution decreased by 58.1% when biochar was added, compared to 25.4% in the absence of biochar. Varying the pH from acidic to alkaline enabled an investigation into the pH dependent dynamics of the approach. Results indicated that significant precipitation was only possible at near neutral pH (i.e. pH = 6.5) where calcium arsenites (i.e. Ca(AsO2)2, and CaAsO2OH•½H2O) and arsenates (i.e. Ca5(AsO4)3OH) were precipitated and deposited as aggregates in the pores of biochars. Arsenite was only slightly precipitated under acidic conditions (pH = 4.5) while no arsenite was precipitated under alkaline conditions (pH = 9.5). Arsenite desorption from wood biochar was lowest at pH 6.5 indicating that wood biochar was able to retain a large quantity of the precipitates formed at pH 6.5 compared to pH 4.5 and pH 9.5. Given that the removal of As(III) from solution is often challenging and that biochar modification invites additional cost, the study demonstrated that low cost unmodified biochar can be effective in enhancing the removal of As(III) from the environment through Ca-As precipitation.

Trends in metaldehyde concentrations and fluxes in a lowland, semi-agricultural catchment in the UK (2008-2018).

Metaldehyde, a widely used molluscicide, is one of the most commonly detected pesticides in aquatic environments in the UK. In this study, metaldehyde concentrations and fluxes in stream water over a ten-year period (2008-2018) are reported for the River Colne catchment (Essex, southeast England), and the influence of hydrological conditions and application regimes are assessed. In general, peaks in metaldehyde concentration in river water occasionally exceeded 0.25 µg L-1, and concentrations did not typically exceed the European Union Drinking Water Directive (EU DWD) regulatory limit of 0.1 µg L-1. Metaldehyde concentration peaks displayed a seasonal pattern. Metaldehyde concentrations during periods when the molluscicide was not applied to agricultural land (January, July) and during the spring-summer application period (February to June) were generally low (0.01-0.03 µg L-1). Peaks in metaldehyde concentration mainly occurred during the autumn-winter application season (August to December), and were typically associated with high intensity hydrological regimes (daily rainfall ≥10 mm; stream flow up to 18 m3 s-1). Where metaldehyde concentrations exceeded the EU DWD regulatory limit, this was short-lived. The annual flux at the top of the Colne catchment (0.2-0.6 kg a-1) tended to be lower than in the middle of the catchment (0.3-1.4 kg a-1), with maximum flux values observed at the bottom of the catchment (0.5-25.8 kg a-1). Metaldehyde losses from point of application to surface water varied between 0.01 and 0.25%, with a maximum of 1.18% (2012). Annual flux was primarily controlled by the annual precipitation and stream flow (R2 = 0.9) rather than annual metaldehyde use (kg active applied). Precipitation explained 37% and 81% of variability in metaldehyde concentration and flux, respectively. Annual ranges in metaldehyde concentration were greater in the years 2012 and 2014 with an overall reduction in the range of metaldehyde concentrations evident over the period 2015-2018. It is the expectation that metaldehyde concentrations in stream water will continue to decrease following the withdrawal of metaldehyde for outdoor use in the UK from March 2022.

Systematic review of soil ecosystem services in tropical regions.

Soil ecosystem service (SES) approaches evidence the importance of soil for human well-being, contribute to improving dialogue between science and decision-making and encourage the translation of scientific results into public policies. Herein, through systematic review, we assess the state of the art of SES approaches in tropical regions. Through this review, 41 publications were identified; while most of these studies considered SES, a lack of a consistent framework to define SES was apparent. Most studies measured soil natural capital and processes, while only three studies undertook monetary valuation. Although the number of publications increased (from 1 to 41), between 2001 and 2019, the total number of publications for tropical regions is still small. Countries with the largest number of publications were Brazil (n = 8), Colombia (n = 6) and Mexico (n = 4). This observation emphasizes an important knowledge gap pertaining to SES approaches and their link to tropical regions. With global momentum behind SES approaches, there is an opportunity to integrate SES approaches into policy and practice in tropical regions. The use of SES evaluation tools in tropical regions could transform how land use decisions are informed, mitigating soil degradation and protecting the ecosystems that soil underpins.

Capturing a soil carbon economy.

Current carbon pricing and trading mechanisms, despite their efficacy in reducing GHG emissions from industry, will not be sufficient to achieve Net Zero targets. Current mechanisms that redress emissions are largely economic disincentives, in effect financial penalties for emitters. In order to attain Net Zero futures, financial incentives for activities that sequester carbon from the atmosphere are needed. Herein, we present the environmental and economic co-benefits of soil re-carbonization and justify support for soil carbon remuneration. With increasing momentum to develop green economies, and projected increases in carbon price, growth in the global carbon market is inevitable. The establishment of a soil-based carbon economy, within this emerging financial space, has the potential to deliver a paradigm shift that will accelerate climate change mitigation, and concurrently realize net gains for soil health and the delivery of soil ecosystem services. Pivotal to the emergence of a global soil carbon economy will be a consensus on certification instruments used for long-term soil carbon storage, and the development of robust institutional agreements and processes to facilitate soil carbon trading.

Within-patient phylogenetic reconstruction reveals early events in Barrett's Esophagus.

Barrett's Esophagus is a neoplastic condition which progresses to esophageal adenocarcinoma in 5% of cases. Key events affecting the outcome likely occur before diagnosis of Barrett's and cannot be directly observed; we use phylogenetic analysis to infer such past events. We performed whole-genome sequencing on 4-6 samples from 40 cancer outcome and 40 noncancer outcome patients with Barrett's Esophagus, and inferred within-patient phylogenies of deconvoluted clonal lineages. Spatially proximate lineages clustered in the phylogenies, but temporally proximate ones did not. Lineages with inferred loss-of-function mutations in both copies of TP53 and CDKN2A showed enhanced spatial spread, whereas lineages with loss-of-function mutations in other frequently mutated loci did not. We propose a two-phase model with expansions of TP53 and CKDN2A mutant lineages during initial growth of the segment, followed by relative stasis. Subsequent to initial expansion, mutations in these loci as well as ARID1A and SMARCA4 may show a local selective advantage but do not expand far: The spatial structure of the Barrett's segment remains stable during surveillance even in patients who go on to cancer. We conclude that the cancer/noncancer outcome is strongly affected by early steps in formation of the Barrett's segment.

Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs.

Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.g., chromothripsis) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,778 tumor whole-genome sequences, we uncovered three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early-replicating regions, superenhancers, and breast or ovarian cancers. Rigma comprise "chasms" of low-JCN deletions enriched in late-replicating fragile sites and gastrointestinal carcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold-back inversions associated with expressed protein-coding fusions, breakend hypermutation, and acral, but not cutaneous, melanomas. Clustering of tumors according to genome graph-derived features identified subgroups associated with DNA repair defects and poor prognosis.

Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma.

BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.

Remediation of cadmium and lead polluted soil using thiol-modified biochar.

Thiol-modified rice straw biochar (RS) was prepared by an esterification reaction with ß-mercaptoethanol and used for the remediation of Cd and Pb polluted soils. Modified biochar was characterized through elemental analysis, BET analysis, FE-SEM, FT-IR and XPS. These analytical results revealed that thiol groups were successfully grafted onto the surface of the biochar and were involved in metal ion complexation. Batch sorption experiments indicated that Cd2+ and Pb2+ sorption onto RS described well by a pseudo second order kinetic model and a Langmuir isotherm. The maximum adsorption capacities for Cd2+ and Pb2+, in the single-metal systems, were 45.1 and 61.4 mg g-1, respectively. In the binary-metal systems, RS selectively adsorbed Cd2+ over Pb2+. Cd2+ and Pb2+ were removed mainly through surface complexation. In the soil incubation experiments (28 days), RS reduced the available Cd by 34.8-39.2 %; while, RS reduced the available Pb by 8.6 %-11.1 %. This research demonstrates RS as a potentially effective amendment for the remediation of heavy metal polluted soils.

Ubiquity of microbial capacity to degrade metaldehyde in dissimilar agricultural, allotment and garden soils.

Metaldehyde is a molluscicide used to control slugs and snails. Despite its extensive use, very little is known about the capacity of soil microbial communities to degrade this chemical. This research provides a synopsis of the latent capacity of soil microbial communities, present in agricultural (n=14), allotment (n=4) and garden (n=10) soils, to degrade metaldehyde. Extents of 14C-metaldehyde mineralisation across all soils ranged from 17.7 to 60.0%. Pre-exposure (in situ, in the field) to metaldehyde was not observed to consistently increase extents of metaldehyde mineralisation. Where soils were augmented, (ex situ, in the laboratory) with metaldehyde (28 mg kg-1), the mineralisation capacity was increased in some, but not all, soils (uplift ranged from +0.10 to +16.9%). Results indicated that catabolic competence to degrade metaldehyde was evident in both surface (16.7-52.8%) and in sub-surface (30.0-66.4%) soil horizons. Collectively, the results suggest that catabolic competence to degrade metaldehyde was ubiquitous across a diverse range of soil environments; that varied in texture (from sand to silty clay loam), pH (6.15-8.20) and soil organic matter (SOM) content (1.2%-52.1%). Lighter texture soils, in general, were observed to have higher capacity to mineralise metaldehyde. Weak correlations between catabolic competence and soil pH and soil organic matter content were observed; it was noted that above a SOM threshold of 12% metaldehyde mineralisation was always >34%. It was concluded that the common occurrence of metaldehyde in EU waters is unlikely the consequence of low potential for this chemical to be degraded in soil. It is more likely that application regimes (quantities/timings) and meteorological drivers facilitate the transport of metaldehyde from point of application into water resources.

Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett's Esophagus.

BACKGROUND & AIMS: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones are associated with risk of EAC or Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization analysis using data from patients with EAC (n = 2488) or BE (n = 3247) and control participants (n = 2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single-nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. RESULTS: Higher genetically predicted levels of follicle-stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01-1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per SD increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulfate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. CONCLUSIONS: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle-stimulating and luteinizing hormones and risk of BE and EAC.

Correction to: NSAID use and somatic exomic mutations in Barrett's esophagus.

It was highlighted that in the original article [1] the Availability of data and materials section was incorrect.

No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study.

BACKGROUND & AIMS: Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS: We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS: Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS: In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC.

Organic Carbon Amendments Affect the Chemodiversity of Soil Dissolved Organic Matter and Its Associations with Soil Microbial Communities.

The "4 per mil" initiative recognizes the pivotal role of soil in carbon resequestration. The need for evidence to substantiate the influence of agricultural practices on chemical nature of soil carbon and microbial biodiversity has become a priority. However, owing to the molecular complexity of soil dissolved organic matter (DOM), specific linkages to microbial biodiversity have eluded researchers. Here, we characterized the chemodiversity of soil DOM, assessed the variation of soil bacterial community composition (BCC), and identified specific linkages between DOM traits and BCC. Sustained organic carbon amendment significantly ( P < 0.05) increased total organic matter reservoirs, resulted in higher chemodiversity of DOM and emergence of recalcitrant moieties (H/C < 1.5). In the meantime, sustained organic carbon amendment shaped the BCC to a more eutrophic state while long-term chemical fertilization directed the BCC toward an oligotrophic state. Meanwhile, higher connectivity and complexity were observed in organic carbon amendment by DOM-BCC network analysis, indicating that soil microbes tended to have more interaction with DOM molecules after organic matter inputs. These results highlight the potential for organic carbon amendments to not only build soil carbon stocks and increase their resilience but also mediate the functional state of soil bacterial communities.

Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett's Esophagus.

BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett's esophagus (BE). However, variants in these loci account for a small fraction of cases of EA and BE. Genetic factors might interact with environmental factors to affect risk of EA and BE. We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE. METHODS: We collected data on single BMI measurements, smoking status, and symptoms of GERD from 2284 patients with EA, 3104 patients with BE, and 2182 healthy individuals (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium GWAS, the UK Barrett's Esophagus Gene Study, and the UK Stomach and Oesophageal Cancer Study. We analyzed 993,501 SNPs in DNA samples of all study subjects. We used standard case-control logistic regression to test for gene-environment interactions. RESULTS: For EA, rs13429103 at chromosome 2p25.1, near the RNF144A-LOC339788 gene, showed a borderline significant interaction with smoking status (P = 2.18×10-7). Ever smoking was associated with an almost 12-fold increase in risk of EA among individuals with rs13429103-AA genotype (odds ratio=11.82; 95% CI, 4.03-34.67). Three SNPs (rs12465911, rs2341926, rs13396805) at chromosome 2q23.3, near the RND3-RBM43 gene, interacted with GERD symptoms (P = 1.70×10-7, P = 1.83×10-7, and P = 3.58×10-7, respectively) to affect risk of EA. For BE, rs491603 at chromosome 1p34.3, near the EIF2C3 gene, and rs11631094 at chromosome 15q14, at the SLC12A6 gene, interacted with BMI (P = 4.44×10-7) and pack-years of smoking history (P = 2.82×10-7), respectively. CONCLUSION: The associations of BMI, smoking, and GERD symptoms with risks of EA and BE appear to vary with SNPs at chromosomes 1, 2, and 15. Validation of these suggestive interactions is warranted.

NSAID use and somatic exomic mutations in Barrett's esophagus.

BACKGROUND: Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to protect against tetraploidy, aneuploidy, and chromosomal alterations in the metaplastic condition Barrett's esophagus (BE) and to lower the incidence and mortality of esophageal adenocarcinoma (EA). The esophagus is exposed to both intrinsic and extrinsic mutagens resulting from gastric reflux, chronic inflammation, and exposure to environmental carcinogens such as those found in cigarettes. Here we test the hypothesis that NSAID use inhibits accumulation of point mutations/indels during somatic genomic evolution in BE. METHODS: Whole exome sequences were generated from 82 purified epithelial biopsies and paired blood samples from a cross-sectional study of 41 NSAID users and 41 non-users matched by sex, age, smoking, and continuous time using or not using NSAIDs. RESULTS: NSAID use reduced overall frequency of point mutations across the spectrum of mutation types, lowered the frequency of mutations even when adjusted for both TP53 mutation and smoking status, and decreased the prevalence of clones with high variant allele frequency. Never smokers who consistently used NSAIDs had fewer point mutations in signature 17, which is commonly found in EA. NSAID users had, on average, a 50% reduction in functional gene mutations in nine cancer-associated pathways and also had less diversity in pathway mutational burden compared to non-users. CONCLUSIONS: These results indicate NSAID use functions to limit overall mutations on which selection can act and supports a model in which specific mutant cell populations survive or expand better in the absence of NSAIDs.

Evolution of Barrett's esophagus through space and time at single-crypt and whole-biopsy levels.

The low risk of progression of Barrett's esophagus (BE) to esophageal adenocarcinoma can lead to over-diagnosis and over-treatment of BE patients. This may be addressed through a better understanding of the dynamics surrounding BE malignant progression. Although genetic diversity has been characterized as a marker of malignant development, it is still unclear how BE arises and develops. Here we uncover the evolutionary dynamics of BE at crypt and biopsy levels in eight individuals, including four patients that experienced malignant progression. We assay eight individual crypts and the remaining epithelium by SNP array for each of 6-11 biopsies over 2 time points per patient (358 samples in total). Our results indicate that most Barrett's segments are clonal, with similar number and inferred rates of alterations observed for crypts and biopsies. Divergence correlates with geographical location, being higher near the gastro-esophageal junction. Relaxed clock analyses show that genomic instability precedes and is enhanced by genome doubling. These results shed light on the clinically relevant evolutionary dynamics of BE.

Determining Risk of Barrett's Esophagus and Esophageal Adenocarcinoma Based on Epidemiologic Factors and Genetic Variants.

BACKGROUND & AIMS: We developed comprehensive models to determine risk of Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC) based on genetic and non-genetic factors. METHODS: We used pooled data from 3288 patients with BE, 2511 patients with EAC, and 2177 individuals without either (controls) from participants in the international Barrett's and EAC consortium as well as the United Kingdom's BE gene study and stomach and esophageal cancer study. We collected data on 23 genetic variants associated with risk for BE or EAC, and constructed a polygenic risk score (PRS) for cases and controls by summing the risk allele counts for the variants weighted by their natural log-transformed effect estimates (odds ratios) extracted from genome-wide association studies. We also collected data on demographic and lifestyle factors (age, sex, smoking, body mass index, use of nonsteroidal anti-inflammatory drugs) and symptoms of gastroesophageal reflux disease (GERD). Risk models with various combinations of non-genetic factors and the PRS were compared for their accuracy in identifying patients with BE or EAC using the area under the receiver operating characteristic curve (AUC) analysis. RESULTS: Individuals in the highest quartile of risk, based on genetic factors (PRS), had a 2-fold higher risk of BE (odds ratio, 2.22; 95% confidence interval, 1.89-2.60) or EAC (odds ratio, 2.46; 95% confidence interval, 2.07-2.92) than individual in the lowest quartile of risk based on PRS. Risk models developed based on only demographic or lifestyle factors or GERD symptoms identified patients with BE or EAC with AUC values ranging from 0.637 to 0.667. Combining data on demographic or lifestyle factors with data on GERD symptoms identified patients with BE with an AUC of 0.793 and patients with EAC with an AUC of 0.745. Including PRSs with these data only minimally increased the AUC values for BE (to 0.799) and EAC (to 0.754). Including the PRSs in the model developed based on non-genetic factors resulted in a net reclassification improvement for BE of 3.0% and for EAC of 5.6%. CONCLUSIONS: We used data from 3 large databases of patients from studies of BE or EAC to develop a risk prediction model based on genetic, clinical, and demographic/lifestyle factors. We identified a PRS that increases discrimination and net reclassification of individuals with vs without BE and EAC. However, the absolute magnitude of improvement is not sufficient to justify its clinical use.