Somatic whole genome dynamics of precancer in Barrett’s Esophagus

Somatic whole genome dynamics of precancer in Barrett’s Esophagus | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Somatic whole genome dynamics of precancer in Barrett’s Esophagus Thomas Paulson, Patricia Galipeau, Kenji Oman, Carissa Sanchez, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-257949/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract 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 were 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 were 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. Oncology Medical Genetics Evolutionary Genetics Temporal-spatial Dynamics of Genomes Premalignant Tissues Esophageal Adenocarcinoma TP53-l-cell Populations Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Full Text Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the latest manuscript can be downloaded and accessed as a PDF. Additional Declarations There is NO Competing Interest. Supplementary Files PaulsonetalA03811ExtendedMethods.docx Extended Methods Paulson2021NatureCancerExtendedDataFigures.pdf Extended Data Figures Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-257949","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":13193967,"identity":"7fb7895e-4a76-4e0b-bad2-7c20506274e4","order_by":0,"name":"Thomas 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22:05:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-257949/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-257949/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":6544385,"identity":"c26a31aa-f4ac-4256-ab35-2b1061f8405b","added_by":"auto","created_at":"2021-03-02 23:20:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":318004,"visible":true,"origin":"","legend":"Longitudinal multi-sample study in cases with BE who progressed to an ESAD outcome compared to controls with BE who did not progress. \nSchematic of our study including 340 spatially mapped BE biopsies and 87 normal control samples across 80 patients with diagnosed BE, including 40 controls with BE who did not progress to ESAD and 40 cases who progressed to an endoscopically detected, incident ESAD. Unless otherwise noted, results combine T1 and T2 time points and do not include NCO T3 or the seven additional adjacent normal gastric control samples. \n","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-257949/v1/6825cf95a441131674335d88.png"},{"id":6544154,"identity":"9f63543a-2e23-4f6b-9069-514afcd4bbd5","added_by":"auto","created_at":"2021-03-02 23:17:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":273833,"visible":true,"origin":"","legend":"Highly mutated clones arise and expand prior to clinical detection of BE.\na, y-axis (log scale) shows unique SNV+indel mutations per megabase (2,800 Mb of sequence) per biopsy and per patient in NCO and CO. Per patient mutation burden was derived from the sum of unique SNV and indel mutations across four biopsies. Horizontal bar is median (3.56 vs. 5.21 by biopsy, and 11.62 vs. 15.35 by patient, in NCO and CO, respectively). Nine biopsies with exceptionally low mutation load were also included (Supplementary Table 5, See “Anomalous biopsies” in Extended Methods). b, Mutational diversity per biopsy using Shannon Diversity Index based on SNV+indel load and VAF in NCO patients (blue) and CO patients (orange). c, Count of unique SNV and indel mutations per patient classified as shared between biopsies (left) or private to a single biopsy (right), with “functional” (high or moderate) impact on protein function based on snpEFF 34 (top) vs. low or modifier (bottom) (comparison by t-test), (Supplementary Table 6). Box centerline indicates median, box edges 1st and 3rd quartiles and whiskers 1.5x interquartile range. d, Log2 ratio of private/shared SNV and indel mutations by patient. Patients with more mutations private to single biopsies than shared between two or more biopsies have values above zero; those with more shared mutations than private have values below zero. e, Percent of biopsies with mutation signatures (circle size) and median number of mutations per biopsy in each signature, including only biopsies in which that signature was detected (color scale). SBS3 not shown(only detected in a single CO biopsy). f, Signature cluster groups where each column is a single biopsy. Biopsies are grouped by patient and ordered by patient ID. N=count of NCO or CO patients in each signature cluster. Comparison by Fisher’s exact test. g, Signature probabilities were assigned to each mutation, mutations were binned as trunk (shared by all four biopsies per patient), branch (shared by 2 or 3), or leaf (private to a single biopsy), and the mean proportion of mutations in trunk, branch, or leaf for each signature per patient was calculated. SBS3 and SBS34 not shown (very low mutation counts), see Supplementary Table 10. ","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-257949/v1/cd3811c649f333f8cb845bcf.png"},{"id":6544150,"identity":"10584c01-3439-44e1-b884-6034910f6f5f","added_by":"auto","created_at":"2021-03-02 23:17:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":206171,"visible":true,"origin":"","legend":"Somatic alterations in ESAD genes and mutation selection before cancer. a, Top panels show cumulative functional alterations in 127 ESAD genes of interest per patient, with patient ID indicated below maximum SCA load and TP53 status per patient. Bottom panels show alteration types and frequency per gene in CO (orange) and NCO (blue) for genes with significantly different frequencies of alterations between CO and NCO (FDR\u003c=0.1) (Supplementary Table 8). b, Count of mutated ESAD genes per patient (comparison by t-test). Box centerline indicates median, box edges 1st and 3rd quartiles and whiskers 1.5x interquartile range. c, Nine genes had a significant dN/dS ratio \u003e1 in NCO and/or CO patients. dN/dS reflects the fraction of mutations observed in a gene that are likely to be under positive selection 38. A dN/dS of 10 indicates that there are 10 times more non-synonymous mutations in the gene than neutrally expected, suggesting that at least around 90% of mutations in that gene are selected. d-g, Parsimony tree phylogenies from typical BE patients having an average number of altered ESAD genes per patient, showing examples of heterogeneity of mutations in ESAD genes of interest mutations and convergent evolution in both NCO and CO. Only ESAD genes of interest are annotated, and Δ indicates the haplotype with the mutated allele identified in another sample was lost due to a copy loss event in this branch. Branch lengths are proportional to inferred mutation count for all SNVs. Mutations suffixed _a, _b, etc., indicate mutations at different sites in the same gene. Annotated phylogenies for all patients can be found in Source Data File 2. d, NCO patient with three MUC6 mutations (i.e. MUC6_a, b, c) and four ARID1A mutations. e, CO patient with two CHD18 mutations. f, NCO patient with two different ARID1A mutations and two CHD18 mutations. g, CO patient with two CDKN2A mutations, two TP53 mutations, and two SMARCA4 mutations.","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-257949/v1/b0747ec3ee3dd64b31e9c548.png"},{"id":6544387,"identity":"a279af0c-21d5-463c-a81e-ee247bc446f7","added_by":"auto","created_at":"2021-03-02 23:20:28","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":157659,"visible":true,"origin":"","legend":"Gene alterations within complex SV events selected in CO patients. a, CO ID 686 with complex SV in both T2 samples, which cluster together in the SNV-based parsimony tree. The phylogeny is annotated with ESAD genes of interest with functional 2+ caller mutations (multiple mutations in the same gene are appended with _a, _b), and Δ indicates chromosome copy loss of mutated allele. The complex structural rearrangement pattern of rigma 23 was detected in all four samples, whereas tyfonas (“typhoons” of high junction copy number junctions and fold back inversions 23) was only detected in the T2 sample, shown in the right panel. Within this region, CDK12 was disrupted by structural alterations and ERBB2 was within one of the highly amplified regions within this complex SV. b, CO ID 163 with expanded TP53 -/- and genome doubling in all four samples. The three samples on the lower clade in the SNV-based phylogeny share a common amplified region which includes increased copies of GATA6 and surrounding genes. Total Mb SCA are indicated for each sample. CN=copy number.","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-257949/v1/8b471297d7ea5a51a0211da6.png"},{"id":6544157,"identity":"b989efcf-1685-45d6-9783-65b5dfb001f2","added_by":"auto","created_at":"2021-03-02 23:17:28","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":269514,"visible":true,"origin":"","legend":"Expansion of TP53 -/- is a primary characteristic for progression to ESAD. a, TP53 mutations in four biopsies per patient collected over time (T1 and T2) and space (upper and lower esophagus) in CO and NCO. Each “lollipop” pie on the TP53 gene structure indicates a specific TP53 mutation with quadrants of the lollipop indicating the number of mutant copies in each of the patient’s four biopsies. The TP53 biopsy quadrants for two CO with homozygous deletions of TP53 (IDs 623 and 160) and one NCO (ID 88) with single copy deletion (ID 88) spanning TP53 are also plotted for completeness. (+) next to a pie corresponds to the amino acid change marked by (+) b, Proportions of patients and biopsies with wild-type TP53 +/+ (white), one-hit TP53 +/- (orange), and two-hit TP53 -/- (red) status. Of the six one-hit CO, five of the mutations were private and one was shared, and of the eight one-hit NCO, six were private and two shared. c, Somatic alterations stratified by TP53 zero-hit, one-hit, and two-hit. P-values between bars test for significant difference between TP53 categories, ns= P≥0.05, *=P\u003c0.05, **=P\u003c0.0001. SCA=somatic chromosomal alterations (gains, losses, cnLOH); SV=structural variants; BFB=bridge-fusion-break events.","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-257949/v1/010e91237e7bfaa047547f25.png"},{"id":6544155,"identity":"055ef99a-6075-4797-a38c-7f96720080f1","added_by":"auto","created_at":"2021-03-02 23:17:28","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":252354,"visible":true,"origin":"","legend":"Complex structural alterations in progression to ESAD. a, Top plot shows count of biopsies with SV features in T1 and T2 biopsies in NCO and CO. b, Proportion of SV events that are private to a single biopsy (grey) or shared between two or more biopsies (blue=NCO, orange=CO). (+) indicates significantly higher load of this SV feature is shared; (*) asterisk indicates a significantly higher load of SV feature is private, FDR 0.01 (Extended Data Fig. 9) c, Total SV burden of NCO, CO and ESAD patients, represented by the most rearranged sample per case. Statistical enrichment determined by Gamma-Poisson regression of SV burden as a function of group status, correcting for TP53 mutational status. d, Fraction of cases that harbor a complex amplification (BFB, double minute, and/or tyfonas), in NCO, CO, and ESAD (represented by the most rearranged sample). e, Left, UMAP clustering of NCO, CO, and ESAD patients using junction burden of most rearranged samples attributed to SV event types as input. Density contours determined on the basis of ESAD data only, with faded purple dots representing ESAD data points. Clusters determined by Gaussian mixture model regression. f, Each sample harboring the SV feature of interest is represented by black dots in the scatterplot, while others are colored transparent grey. g, Fraction of patients within each cluster containing complex amplification types. h, Fraction of NCO, CO, and ESAD cases within each cluster. Statistical enrichment determined by logistic regression of the fraction of cases as a function of cluster membership. Asterisks indicate significance level (**** P\u003c=0.0001; *** P\u003c=0.001).","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-257949/v1/bb1e843000db52821ac6f3e9.png"},{"id":13598982,"identity":"27c3c631-0a24-4811-bf39-9bd1f34270ff","added_by":"auto","created_at":"2021-09-17 05:37:52","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2007172,"visible":true,"origin":"","legend":"","description":"","filename":"PaulsonetalA03811Mainbodyandfigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-257949/v1_covered.pdf"},{"id":6544453,"identity":"571ed7c3-79c6-474c-845d-241e93f2633d","added_by":"auto","created_at":"2021-03-02 23:23:32","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2535968,"visible":true,"origin":"","legend":"","description":"","filename":"PaulsonetalA03811Mainbodyandfigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-257949/v1_stamped.pdf"},{"id":6544386,"identity":"be877037-ae42-4ba8-9106-d378af32f77e","added_by":"auto","created_at":"2021-03-02 23:20:28","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":65053,"visible":true,"origin":"","legend":"Extended Methods","description":"","filename":"PaulsonetalA03811ExtendedMethods.docx","url":"https://assets-eu.researchsquare.com/files/rs-257949/v1/c59288a186929cc9387c292d.docx"},{"id":6544388,"identity":"0304a2f8-b62b-4160-896f-eb116d4da86d","added_by":"auto","created_at":"2021-03-02 23:20:28","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":2267797,"visible":true,"origin":"","legend":"Extended Data Figures","description":"","filename":"Paulson2021NatureCancerExtendedDataFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-257949/v1/69f843e991a1087d145fc078.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Somatic whole genome dynamics of precancer in Barrett’s Esophagus","fulltext":[{"header":"Full Text","content":"Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the latest manuscript can be downloaded and \u003ca href='/article/rs-257949/latest.pdf' target='_blank'\u003e accessed as a PDF.\u003c/a\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Temporal-spatial Dynamics of Genomes, Premalignant Tissues, Esophageal Adenocarcinoma, TP53-l-cell Populations","lastPublishedDoi":"10.21203/rs.3.rs-257949/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-257949/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWhile 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\u0026rsquo;s esophagus compared to 40 Barrett\u0026rsquo;s patients who progressed to esophageal adenocarcinoma (ESAD). We show the same somatic mutational processes were active in Barrett\u0026rsquo;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\u0026rsquo;s versus those who progress to cancer is acquisition and expansion of \u003cem\u003eTP53\u003c/em\u003e-/- cell populations having complex structural variants and high-level amplifications, which were detectable up to six years prior to a cancer diagnosis. These findings reveal the timing of common somatic genome dynamics in stable Barrett\u0026rsquo;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.\u003c/p\u003e","manuscriptTitle":"Somatic whole genome dynamics of precancer in Barrett’s Esophagus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-03-02 23:17:26","doi":"10.21203/rs.3.rs-257949/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5dffa553-2901-4c38-8c6b-c7563f191c4a","owner":[],"postedDate":"March 2nd, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":2728559,"name":"Oncology"},{"id":2728560,"name":"Medical Genetics"},{"id":2728561,"name":"Evolutionary Genetics"}],"tags":[],"updatedAt":"2021-08-10T17:15:36+00:00","versionOfRecord":[],"versionCreatedAt":"2021-03-02 23:17:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-257949","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-257949","identity":"rs-257949","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}