In-depth analysis of the genomic landscape of 86 metastatic neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets

In-depth analysis of the genomic landscape of 86 metastatic neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets | 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 In-depth analysis of the genomic landscape of 86 metastatic neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets Bianca Mostert, Job van Riet, Harmen van de Werken, Edwin Cuppen, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-50333/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Jul, 2021 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Metastatic neuroendocrine neoplasms (mNEN) form clinically and genetically heterogeneous malignancies, characterized by distinct prognoses based upon primary tumor localization, functionality, grade, proliferation index and diverse outcomes to treatment. Here, we report the mutational landscape of 86 whole-genome sequenced mNEN. This landscape revealed distinct genomic subpopulations of mNEN based on primary localization and differentiation grade; we observed relatively high tumor mutational burdens (TMB) in neuroendocrine carcinoma (5.45 somatic mutations per megabase) with TP53 , KRAS , RB1 , MYC and APC as major drivers versus an overall low TMB in neuroendocrine tumors (1.08). Furthermore, we observed distinct drivers which were enriched with somatic aberrations in pancreatic ( MEN1 , ATRX , DAXX , PCNT and SETD2 ) and midgut-derived neuroendocrine tumors ( CDKN1B ). Finally, 49% of mNEN patients revealed extensions of their treatment-repertoire based upon actionable (and responsive) somatic aberrations; potentially directing improvements in mNEN treatment strategies. Cancer Biology Epigenetics & Genomics neuroendocrine neoplasm neuroendocrine tumors whole-genome sequencing CPCT02 metastasis therapy targets Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementalFigures.pdf Cite Share Download PDF Status: Published Journal Publication published 29 Jul, 2021 Read the published version in Nature Communications → 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. We do this by developing innovative software and high quality services for the global research community. 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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-50333","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":1615674,"identity":"2944a070-b545-4ea0-bb24-e6b174755cb8","order_by":0,"name":"Bianca Mostert","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYBACAziLvQFZvICQlgQGBh6eA9iNwqNFIoFILeYM3IkPf/6wybeXfHzsw48/2xLnTzv8gLkAjxbLBt7NxjwJaZY90mnJM3vbbiduuJ1mwDwDn8MO8G6TZkg4bMAjnWPMwNsA1CKdw8DMQ0CL5I+E/wY8kuc/M/75cztx/mwitEjwJBww4JHgYWbmYbud2HCbgBbLZpBf0pINeM6kGTPLtt02BvnlMD4t5uy9Gx/+sLEzYG8//JjxzZ/bsvNnJz98zFOBWwsDMzbBA3g0jIJRMApGwSggAgAAMhFLdhYHn1UAAAAASUVORK5CYII=","orcid":"","institution":"Erasmus MC Cancer Institute","correspondingAuthor":true,"prefix":"","firstName":"Bianca","middleName":"","lastName":"Mostert","suffix":""},{"id":1615675,"identity":"7f0c0ae5-36f9-49ea-926a-236867d155ca","order_by":1,"name":"Job van Riet","email":"","orcid":"https://orcid.org/0000-0001-7767-7923","institution":"Erasmus University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Job","middleName":"van","lastName":"Riet","suffix":""},{"id":1615676,"identity":"330b74eb-8c96-4195-9db5-c484e06bde69","order_by":2,"name":"Harmen van de Werken","email":"","orcid":"https://orcid.org/0000-0002-9794-1477","institution":"Erasmus MC","correspondingAuthor":false,"prefix":"","firstName":"Harmen","middleName":"van","lastName":"de Werken","suffix":""},{"id":1615677,"identity":"ee2fd9ea-dea5-42b0-a096-c1ca1cb7afc1","order_by":3,"name":"Edwin Cuppen","email":"","orcid":"","institution":"Hartwig Medical Foundation","correspondingAuthor":false,"prefix":"","firstName":"Edwin","middleName":"","lastName":"Cuppen","suffix":""},{"id":1615678,"identity":"55447bc8-69f8-4717-b992-b2dfa0837161","order_by":4,"name":"Ferry Eskens","email":"","orcid":"","institution":"Erasmus MC Cancer 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Centers","correspondingAuthor":false,"prefix":"","firstName":"Heinz-Josef","middleName":"","lastName":"Klümpen","suffix":""},{"id":1615682,"identity":"c2f850ab-9fd6-4baf-ab96-45e0fd8655da","order_by":8,"name":"Marcus Dercksen","email":"","orcid":"","institution":"Maxima Medisch Centrum","correspondingAuthor":false,"prefix":"","firstName":"Marcus","middleName":"","lastName":"Dercksen","suffix":""},{"id":1615683,"identity":"b005ec5a-7804-458d-8cb2-d97d836e3b85","order_by":9,"name":"Gerlof Valk","email":"","orcid":"","institution":"University Medical Center Utrecht","correspondingAuthor":false,"prefix":"","firstName":"Gerlof","middleName":"","lastName":"Valk","suffix":""},{"id":1615684,"identity":"de874a32-82d2-4ac9-9ead-64f3a92ff9a5","order_by":10,"name":"Martijn Lolkema","email":"","orcid":"https://orcid.org/0000-0003-0466-2928","institution":"Erasmus University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Martijn","middleName":"","lastName":"Lolkema","suffix":""},{"id":1615685,"identity":"393a2acc-fca5-41ca-9382-3c2af7d7262f","order_by":11,"name":"Stefan Sleijfer","email":"","orcid":"","institution":"Erasmus MC","correspondingAuthor":false,"prefix":"","firstName":"Stefan","middleName":"","lastName":"Sleijfer","suffix":""}],"badges":[],"createdAt":"2020-07-28 16:05:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-50333/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-50333/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-021-24812-3","type":"published","date":"2021-07-29T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":2076553,"identity":"a8880ab8-712b-4c09-a3ec-263a0e65bc4a","added_by":"auto","created_at":"2020-08-25 21:03:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":181711,"visible":true,"origin":"","legend":"Overview of patient inclusion and sub-classification of biopsies.\na) Flowchart of patient inclusion. From the CPCT-02 cohort, single biopsies from 86\ndistinct patients with metastatic neuroendocrine neoplasms (mNEN) were selected.\nFrom the total pool of available whole-genome sequenced mNET samples. If multiple\nderived mNET biopsies from the same patient were available, we selected the mNET\nbiopsy with the highest tumor cell purity.\nb) Subclassification of mNEN based on primary localization. The 86 mNEN were\nsubclassified, based on their primary localization, into six major categories; Foregut,\nHindgut, Lung, Pancreas and Midgut; whilst samples with indeterminable localization\nwere categorized as Unknown. The number of mNET (in blue) and mNEC (in red) are\nshown per category.","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-50333/v1/1.png"},{"id":2076554,"identity":"ea54ed4a-7a43-45e5-976d-ca8fd2febf5b","added_by":"auto","created_at":"2020-08-25 21:03:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":194126,"visible":true,"origin":"","legend":"Landscape of large-scale genomic alterations detected in mNEN, ordered by\ndifferentiation grade (NEC / NEC) and primary localization.\nOverview of genome-wide characteristics of the mNEN cohort ordered by mNEC / mNET and\nprimary localization on decreasing median tumor mutational burden. For each mNEN (n =\n86), the following tracks are shown:\na) Number of genomic mutations per megabase over the entire genome (TMB); SNV,\nInDel and MNV are depicted in blue, orange and salmon respectively. Threshold for\nhigh-TMB (≥10) is shown by a horizontal red dotted line. Y-axis is shown in log10-\nscale.\nb) Total number of structural variants including deletions, tandem duplications,\ntranslocations, inversions and insertions as detected by GRIDSS. Y-axis is shown in\nlog10-scale.\nc) Relative frequency of each of the structural variant categories; deletions in orange,\ntandem duplications in red, translocations in blue, inversions in light-blue and\ninsertions in yellow.\nd) Mean genome-wide ploidy, ranging from 0 (red) to 4 (green; tetraploid). Common\ndiploid status is shown in white.\ne) Relative contribution of the COSMIC single-base substitution mutational signatures\n(v3; n = 67). Signatures with less than 5 percent overall contribution within the entire mNEN cohort were categorized under the “Filtered (\u003c5%)” category. The proposed\netiology of the signatures is denoted below.\nf) Relative frequency of the pyrimidine mutations (SNV) in their six categories.\ng) Relative frequency of Doublet Base Substitution (DBS) categories.\nh) Presence of chromothripsis; mNEN with chromothripsis are shown in pink.\ni) Presence of kataegis; mNEN with kataegis are shown in red.\nj) Status of homologous recombination deficiency (HRD), as determined by CHORD;\nmNEN with BRCA1/2-associated HRD (p ≥ 0.5) are shown in pink., otherwise colored\nwhite.\nk) Differentiation grade of the mNEN; NEC in red, NET in blue.\nl) Primary localization of the mNEN.","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-50333/v1/2.png"},{"id":2076555,"identity":"7f2afccb-aba3-4872-bc0d-3fbf92bbd845","added_by":"auto","created_at":"2020-08-25 21:03:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":286217,"visible":true,"origin":"","legend":"Putative drivers and NEN-associated genes within the mNEN cohort as detected\nby unbiased discovery (dN/dS, GISTIC2) and literature.\nOverview of putative drivers harboring coding mutations within at least three mNEN. We\nshow putative drivers as detected by dN/dS and/or GISTIC2 and supplemented this list with\nadditional NEN-associated drivers. mNEN and genes are sorted based on mutuallyexclusivity\nof the depicted putative drivers. Only GISTIC2 focal peaks with deep\namplifications and deletions are shown.\na) Number of genomic mutations per megabase over the entire genome (TMB); SNV,\nInDel and MNV are depicted in blue, orange and salmon respectively. Threshold for\nhigh-TMB (≥10) is shown by a horizontal salmon dashed line. Y-axis is shown in log10-\nscale.\nb) Mean genome-wide ploidy, ranging from 0 (red) to 4 (green; tetraploid). Diploidy is\nshown in white.\nc) Relative contribution of the COSMIC single-base substitution mutational signatures\n(v3; n = 67). Signatures with less than 5 percent overall contribution within the entire\nmNEN cohort were categorized under the “Filtered (\u003c5%)” category. The proposed\netiology of the signatures is denoted below.\nd) Overview of coding mutation(s) per mNEN, (light-)green or (light-)red backgrounds\ndepict copy-number aberrations whilst the inner square depicts the type of (coding)\nmutation(s). The adjacent bar plots represent the relative proportions of mutational categories (coding mutations (SNV, InDels and MNV), splicing mutations, SV, deep\ngains (high-level amplifications resulting in many additional copies) and deep\ndeletions (high-level losses resulting in (near) homozygous losses) per gene. The\nmiddle-outer barplot depicts the percentage of mNEC (in red) and mNET in blue\nwhich harbored a mutation. In addition, dN/dS and/or GISTIC2 support are shown on\nthe outer-right bar plots for either the entire mNEN cohort or separate mNET/mNEC\nanalysis; GISTIC2 results are colored red if these genes were detected within a\nrecurrent focal deletion and green if detected within a recurrent focal gain.\ne) Presence of chromothripsis; mNEN with chromothripsis are shown in pink.\nf) Presence of kataegis; mNEN with kataegis are shown in red.\ng) Status of homologous recombination deficiency (HRD), as determined by CHORD;\nmNEN with BRCA1/2-associated HRD (p ≥ 0.5) are shown in pink., otherwise colored\nwhite.\nh) Differentiation grade of the mNEN; mNEC in red, mNET in blue.\ni) Primary localization of the mNEN.","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-50333/v1/3.png"},{"id":2076556,"identity":"fa7a6710-0649-41c4-a41a-16b7a4658b21","added_by":"auto","created_at":"2020-08-25 21:03:40","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":196141,"visible":true,"origin":"","legend":"Putative drivers and NEN-associated genes within the pancreas- and midgutderived\nmNET as detected by unbiased discovery (dN/dS, GISTIC2) and literature.\nOverview of putative drivers harboring coding mutations within at least two pancreasand/\nor midgut-derived mNET. We show putative drivers as detected by subgroup-specific\ndN/dS and/or GISTIC2 and supplemented this list with additional NEN-associated drivers.\nmNET and genes are sorted based on mutually-exclusivity of the depicted putative drivers.\nSame layout as figure 3, except the adjacent middle-outer bar (in d) depicts the percentage\nof pancreas-derived m(NET) in green and midgut-derived mNET in blue. In addition, e)\nrepresent chromosomal arm-aberrations on chr18p/q as detected by GISTIC2.","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-50333/v1/4.png"},{"id":2076557,"identity":"5e393710-8f43-4a4d-8c71-8697f0fb572f","added_by":"auto","created_at":"2020-08-25 21:03:40","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":115464,"visible":true,"origin":"","legend":"Clinically-actionable somatic alterations observed within mNEN.\na) Overview of distinct mNEN harboring current clinically-actionable alterations for onand\noff-label NEN therapies. The highest NEN-therapy option (ranked as on-label\nNEN subtype, on-label NEN, off-label for NEN, off-label for other cancer types but\ncurrently-available and drugs in development) per distinct mNEN is shown.\nb) mNEN harboring current clinically-actionable alterations, per gene. The highest NETtherapy\noption per mNEN and gene is shown. Bottom track represents the categorized primary localization of the mNEN whilst the right-hand side figure shown\nthe number of samples harboring a somatic alteration within the given gene and the\nproposed level of therapy.","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-50333/v1/5.png"},{"id":15780010,"identity":"11087096-3a7e-45c6-ae70-7b091bd93561","added_by":"auto","created_at":"2021-11-22 15:40:43","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":11410969,"visible":true,"origin":"","legend":"Article File","description":"","filename":"vanRietmNENNatComm.pdf","url":"https://assets-eu.researchsquare.com/files/rs-50333/v1_covered.pdf"},{"id":13526131,"identity":"eb8f02cc-bc40-4f69-af91-2e6ada70345b","added_by":"auto","created_at":"2021-09-17 00:51:09","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":11405923,"visible":true,"origin":"","legend":"Article File","description":"","filename":"vanRietmNENNatComm.pdf","url":"https://assets-eu.researchsquare.com/files/rs-50333/v1_covered.pdf"},{"id":2076596,"identity":"526e42ec-f130-4318-a119-c8e6532cf06c","added_by":"auto","created_at":"2020-08-25 21:04:45","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":11730640,"visible":true,"origin":"","legend":"Article File","description":"","filename":"vanRietmNENNatComm.pdf","url":"https://assets-eu.researchsquare.com/files/rs-50333/v1_stamped.pdf"},{"id":2076558,"identity":"9d783661-61cb-4b45-8613-8c9e23e0ca4a","added_by":"auto","created_at":"2020-08-25 21:03:40","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":11722181,"visible":true,"origin":"","legend":"Article File","description":"","filename":"vanRietmNENNatComm.pdf","url":"https://assets-eu.researchsquare.com/files/rs-50333/v1/vanRietmNENNatComm.pdf"},{"id":2076559,"identity":"5eb1c534-e09c-4c27-b212-e9d28dc8882b","added_by":"auto","created_at":"2020-08-25 21:03:41","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":7766590,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-50333/v1/SupplementalFigures.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"In-depth analysis of the genomic landscape of 86 metastatic neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets","fulltext":[{"header":"Full Text","content":"\u003cp\u003eThis preprint is available for \u003ca href='/article/rs-50333/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"neuroendocrine, neoplasm, neuroendocrine tumors, whole-genome sequencing, CPCT02, metastasis, therapy targets","lastPublishedDoi":"10.21203/rs.3.rs-50333/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-50333/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Metastatic neuroendocrine neoplasms (mNEN) form clinically and genetically heterogeneous malignancies, characterized by distinct prognoses based upon primary tumor localization, functionality, grade, proliferation index and diverse outcomes to treatment. Here, we report the mutational landscape of 86 whole-genome sequenced mNEN. This landscape revealed distinct genomic subpopulations of mNEN based on primary localization and differentiation grade; we observed relatively high tumor mutational burdens (TMB) in neuroendocrine carcinoma (5.45 somatic mutations per megabase) with \u003ci\u003eTP53\u003c/i\u003e, \u003ci\u003eKRAS\u003c/i\u003e, \u003ci\u003eRB1\u003c/i\u003e, \u003ci\u003eMYC\u003c/i\u003e and \u003ci\u003eAPC\u003c/i\u003e as major drivers versus an overall low TMB in neuroendocrine tumors (1.08). Furthermore, we observed distinct drivers which were enriched with somatic aberrations in pancreatic (\u003ci\u003eMEN1\u003c/i\u003e, \u003ci\u003eATRX\u003c/i\u003e, \u003ci\u003eDAXX\u003c/i\u003e, \u003ci\u003ePCNT\u003c/i\u003e and \u003ci\u003eSETD2\u003c/i\u003e) and midgut-derived neuroendocrine tumors (\u003ci\u003eCDKN1B\u003c/i\u003e). Finally, 49% of mNEN patients revealed extensions of their treatment-repertoire based upon actionable (and responsive) somatic aberrations; potentially directing improvements in mNEN treatment strategies.","manuscriptTitle":"In-depth analysis of the genomic landscape of 86 metastatic neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-08-25 21:03:39","doi":"10.21203/rs.3.rs-50333/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d8c82c4f-a55f-4f20-9c01-8b322f8cb713","owner":[],"postedDate":"August 25th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":362080,"name":"Cancer Biology"},{"id":362081,"name":"Epigenetics \u0026 Genomics"}],"tags":[],"updatedAt":"2021-11-22T15:36:49+00:00","versionOfRecord":{"articleIdentity":"rs-50333","link":"https://doi.org/10.1038/s41467-021-24812-3","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2021-07-29 04:00:00","publishedOnDateReadable":"July 29th, 2021"},"versionCreatedAt":"2020-08-25 21:03:39","video":"","vorDoi":"10.1038/s41467-021-24812-3","vorDoiUrl":"https://doi.org/10.1038/s41467-021-24812-3","workflowStages":[]},"version":"v1","identity":"rs-50333","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-50333","identity":"rs-50333","version":["v1"]},"buildId":"J0_U0BvcaRcwD8yVFaRlm","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}