{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T04:50:13Z","timestamp":1790484613115,"version":"4.1.0"},"reference-count":51,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,1,19]],"date-time":"2016-01-19T00:00:00Z","timestamp":1453161600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,1,19]],"date-time":"2016-01-19T00:00:00Z","timestamp":1453161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The precancerous lesion known as Barrett\u2019s oesophagus can evolve to oesophageal adenocarcinoma in decades-long processes of regenerative growth. Here we report the isolation and propagation of distinct, patient-matched stem cells of Barrett\u2019s, gastric and oesophageal epithelia that yield divergent tumour types following <jats:italic>in vitro<\/jats:italic> transformation and xenografting. Genomic analyses reveal a broad mutational spectrum unique to Barrett\u2019s stem cells that likely reflects their risk for oncogenesis. Remarkably, 25% of cases show no cancer-related genomic changes, suggesting that Barrett\u2019s initiates without driver mutations. Most cases, however, sustain patterns of deletions almost identical to adenocarcinoma though tumour-associated gene amplifications were absent. Notably, those suspected of low-grade dysplasia have p53 mutations or undergo amplifications of proto-oncogenes and receptor tyrosine kinases, implicating these events in lethal transitions. Our findings suggest paths for the initiation and progression of Barrett\u2019s and define a discrete stem cell underlying its regenerative growth whose eradication could prevent oesophageal adenocarcinoma.<\/jats:p>","DOI":"10.1038\/ncomms10380","type":"journal-article","created":{"date-parts":[[2016,1,19]],"date-time":"2016-01-19T12:13:00Z","timestamp":1453205580000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Mutational spectrum of Barrett\u2019s stem cells suggests paths to initiation of a precancerous lesion"],"prefix":"10.1038","volume":"7","author":[{"given":"Yusuke","family":"Yamamoto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Bertrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Kern","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"Duleba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supriya","family":"Srivastava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiea Chuen","family":"Khor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyu","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lane H.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagen","family":"Blaszyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniil","family":"Rolshud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Teh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke E.","family":"Howitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Vincent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P.","family":"Crum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niranjan","family":"Nagarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khek Yu","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"McKeon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wa","family":"Xian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,1,19]]},"reference":[{"key":"BFncomms10380_CR1","doi-asserted-by":"publisher","first-page":"2548","DOI":"10.1056\/NEJMcp0902173","volume":"361","author":"P Sharma","year":"2009","unstructured":"Sharma, P. Clinical practice. Barrett's esophagus. N. Engl. J. Med. 361, 2548\u20132556 (2009).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms10380_CR2","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/nrc2773","volume":"10","author":"BJ Reid","year":"2010","unstructured":"Reid, B. J., Li, X., Galipeau, P. C. & Vaughan, T. L. Barrett's oesophagus and oesophageal adenocarcinoma: time for a new synthesis. Nat. Rev. Cancer 10, 87\u2013101 (2010).","journal-title":"Nat. Rev. Cancer"},{"key":"BFncomms10380_CR3","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1136\/gutjnl-2012-302412","volume":"62","author":"G Edgren","year":"2013","unstructured":"Edgren, G., Adami, H. O., Weiderpass, E. & Nyr\u00e9n, O. A global assessment of the oesophageal adenocarcinoma epidemic. Gut 62, 1406\u20131414 (2013).","journal-title":"Gut"},{"key":"BFncomms10380_CR4","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1002\/bjs.18003815005","volume":"38","author":"NR Barrett","year":"1950","unstructured":"Barrett, N. R. Chronic peptic ulcer of the oesophagus and 'oesophagitis\u2019. Br. J. Surg. 38, 175\u2013182 (1950).","journal-title":"Br. J. Surg."},{"key":"BFncomms10380_CR5","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/S0022-5223(19)39666-7","volume":"70","author":"AP Naef","year":"1975","unstructured":"Naef, A. P., Savary, M. & Ozzello, L. Columnar-lined lower esophagus: an acquired lesion with malignant predisposition. Report on 140 cases of Barrett esophagus with 12 adenocarcinomas. J. Thorac. Cardiovasc. Surg. 70, 826\u2013835 (1975).","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"BFncomms10380_CR6","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1016\/0046-8177(94)90057-4","volume":"25","author":"RC Haggitt","year":"1994","unstructured":"Haggitt, R. C. Barrett\u2019s esophagus, dysplasia, and adenocarcinoma. Hum. Pathol. 25, 982\u2013993 (1994).","journal-title":"Hum. Pathol."},{"key":"BFncomms10380_CR7","doi-asserted-by":"publisher","first-page":"e1001780","DOI":"10.1371\/journal.pmed.1001780","volume":"12","author":"CS Ross-Innes","year":"2015","unstructured":"Ross-Innes, C. S. et al. Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett's esophagus: a multi-center case-control study. PLoS Med. 12, e1001780 (2015).","journal-title":"PLoS Med."},{"key":"BFncomms10380_CR8","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1016\/0092-8674(90)90186-I","volume":"61","author":"ER Fearon","year":"1990","unstructured":"Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759\u2013767 (1990).","journal-title":"Cell"},{"key":"BFncomms10380_CR9","first-page":"6735","volume":"52","author":"P Correa","year":"1992","unstructured":"Correa, P. Human gastric carcinogenesis: a multistep and multifactorial process. First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 52, 6735\u20136740 (1992).","journal-title":"Cancer Res."},{"key":"BFncomms10380_CR10","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1056\/NEJMoa1103042","volume":"365","author":"F Hvid-Jensen","year":"2011","unstructured":"Hvid-Jensen, F., Pedersen, L., Drewes, A. M., S\u00f8rensen, H. T. & Funch-Jensen, P. Incidence of adenocarcinoma among patients with Barrett's esophagus. N. Engl. J. Med. 365, 1375\u20131383 (2011).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms10380_CR11","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1056\/NEJMoa0808145","volume":"360","author":"NJ Shaheen","year":"2009","unstructured":"Shaheen, N. J. et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. N. Engl. J. Med. 360, 2277\u20132288 (2009).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms10380_CR12","doi-asserted-by":"publisher","first-page":"1996","DOI":"10.1007\/s10620-011-1680-4","volume":"56","author":"BJ Vaccaro","year":"2011","unstructured":"Vaccaro, B. J. et al. Detection of intestinal metaplasia after successful eradication of Barrett's Esophagus with radiofrequency ablation. Dig. Dis. Sci. 56, 1996\u20132000 (2011).","journal-title":"Dig. Dis. Sci."},{"key":"BFncomms10380_CR13","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1053\/j.gastro.2012.04.051","volume":"143","author":"M Titi","year":"2012","unstructured":"Titi, M. et al. Development of subsquamous high-grade dysplasia and adenocarcinoma after successful radiofrequency ablation of Barrett's esophagus. Gastroenterology 143, 564\u2013566 (2012).","journal-title":"Gastroenterology"},{"key":"BFncomms10380_CR14","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1097\/MOG.0000000000000190","volume":"31","author":"R Haidry","year":"2015","unstructured":"Haidry, R. & Lovat, L. Long-term durability of radiofrequency ablation for Barrett's-related neoplasia. Curr. Opin. Gastroenterol. 31, 316\u2013320 (2015).","journal-title":"Curr. Opin. Gastroenterol."},{"key":"BFncomms10380_CR15","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1126\/science.1234852","volume":"340","author":"T Sato","year":"2013","unstructured":"Sato, T. & Clevers, H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340, 1190\u20131194 (2013).","journal-title":"Science"},{"key":"BFncomms10380_CR16","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/nature14484","volume":"522","author":"X Wang","year":"2015","unstructured":"Wang, X. et al. Cloning and variation of ground state intestinal stem cells. Nature 522, 173\u2013178 (2015).","journal-title":"Nature"},{"key":"BFncomms10380_CR17","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/S0092-8674(75)80001-8","volume":"6","author":"JG Rheinwald","year":"1975","unstructured":"Rheinwald, J. G. & Green, H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 6, 331\u2013343 (1975).","journal-title":"Cell"},{"key":"BFncomms10380_CR18","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/j.cell.2011.10.001","volume":"147","author":"PA Kumar","year":"2011","unstructured":"Kumar, P. A. et al. Distal airway stem cells render alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell 147, 525\u2013538 (2011).","journal-title":"Cell"},{"key":"BFncomms10380_CR19","doi-asserted-by":"publisher","first-page":"e3534","DOI":"10.1371\/journal.pone.0003534","volume":"3","author":"DB Stairs","year":"2008","unstructured":"Stairs, D. B. et al. Cdx1 and c-Myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett's esophagus. PLoS ONE 3, e3534 (2008).","journal-title":"PLoS ONE"},{"key":"BFncomms10380_CR20","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1186\/1471-2407-13-137","volume":"13","author":"Q Wang","year":"2013","unstructured":"Wang, Q., Ma, C. & Kemmner, W. Wdr66 is a novel marker for risk stratification and involved in epithelial-mesenchymal transition of esophageal squamous cell carcinoma. BMC Cancer 13, 137 (2013).","journal-title":"BMC Cancer"},{"key":"BFncomms10380_CR21","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/S0166-2236(03)00031-6","volume":"26","author":"RM Seaberg","year":"2003","unstructured":"Seaberg, R. M. & van der Kooy, D. Stem and progenitor cells: the premature desertion of rigorous definitions. Trends Neurosci. 26, 125\u2013131 (2003).","journal-title":"Trends Neurosci."},{"key":"BFncomms10380_CR22","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1016\/j.cell.2011.05.026","volume":"145","author":"X Wang","year":"2011","unstructured":"Wang, X. et al. Residual embryonic cells as precursors of a Barrett's-like metaplasia. Cell 145, 1023\u20131035 (2011).","journal-title":"Cell"},{"key":"BFncomms10380_CR23","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.ccr.2011.12.004","volume":"21","author":"M Quante","year":"2012","unstructured":"Quante, M. et al. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell 21, 36\u201351 (2012).","journal-title":"Cancer Cell"},{"key":"BFncomms10380_CR24","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1136\/gutjnl-2011-301174","volume":"61","author":"AM Nicholson","year":"2012","unstructured":"Nicholson, A. M. et al. Barrett's metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor. Gut 61, 1380\u20131389 (2012).","journal-title":"Gut"},{"key":"BFncomms10380_CR25","doi-asserted-by":"publisher","first-page":"1854","DOI":"10.1136\/gutjnl-2013-306508","volume":"63","author":"DL Lavery","year":"2014","unstructured":"Lavery, D. L. et al. The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands. Gut 63, 1854\u20131863 (2014).","journal-title":"Gut"},{"key":"BFncomms10380_CR26","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1111\/j.1440-1746.2009.05824.x","volume":"24","author":"M Hongo","year":"2009","unstructured":"Hongo, M., Nagasaki, Y. & Shoji, T. Epidemiology of esophageal cancer: orient to occident. Effects of chronology, geography and ethnicity. J. Gastroenterol. Hepatol. 24, 729\u2013735 (2009).","journal-title":"J. Gastroenterol. Hepatol."},{"key":"BFncomms10380_CR27","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/22780","volume":"400","author":"WC Hahn","year":"1999","unstructured":"Hahn, W. C. et al. Creation of human tumour cells with defined genetic elements. Nature 400, 464\u2013468 (1999).","journal-title":"Nature"},{"key":"BFncomms10380_CR28","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1111\/j.1749-6632.2011.06310.x","volume":"1245","author":"LD Shultz","year":"2011","unstructured":"Shultz, L. D., Brehm, M. A., Bavari, S. & Greiner, D. L. Humanized mice as a preclinical tool for infectious disease and biomedical research. Ann. NY Acad. Sci. 1245, 50\u201354 (2011).","journal-title":"Ann. NY Acad. Sci."},{"key":"BFncomms10380_CR29","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1158\/2159-8290.CD-12-0189","volume":"2","author":"N Agrawal","year":"2012","unstructured":"Agrawal, N. et al. Comparative genomic analysis of esophageal adenocarcinoma and squamous cell carcinoma. Cancer Dis. 2, 899\u2013905 (2012).","journal-title":"Cancer Dis."},{"key":"BFncomms10380_CR30","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1038\/sj.onc.1201330","volume":"15","author":"D Michael","year":"1997","unstructured":"Michael, D., Beer, D. G., Wilke, C. W., Miller, D. E. & Glover, T. W. Frequent deletions of FHIT and FRA3B in Barrett's metaplasia and esophageal adenocarcinomas. Oncogene 15, 1653\u20131659 (1997).","journal-title":"Oncogene"},{"key":"BFncomms10380_CR31","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1097\/01.pas.0000170349.47680.e8","volume":"29","author":"EL Powell","year":"2005","unstructured":"Powell, E. L. et al. Concordant loss of MTAP and p16\/CDKN2A expression in gastroesophageal carcinogenesis: evidence of homozygous deletion in esophageal noninvasive precursor lesions and therapeutic implications. Am. J. Surg. Pathol. 29, 1497\u20131504 (2005).","journal-title":"Am. J. Surg. Pathol."},{"key":"BFncomms10380_CR32","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1158\/1541-7786.MCR-09-0529","volume":"8","author":"LA Lai","year":"2010","unstructured":"Lai, L. A. et al. Deletion at fragile sites is a common and early event in Barrett's esophagus. Mol. Cancer Res. 8, 1084\u20131094 (2010).","journal-title":"Mol. Cancer Res."},{"key":"BFncomms10380_CR33","doi-asserted-by":"publisher","first-page":"4138","DOI":"10.1038\/sj.onc.1208598","volume":"24","author":"K Schulmann","year":"2005","unstructured":"Schulmann, K. et al. Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk. Oncogene 24, 4138\u20134148 (2005).","journal-title":"Oncogene"},{"key":"BFncomms10380_CR34","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.tig.2012.02.006","volume":"28","author":"E Ozeri-Galai","year":"2012","unstructured":"Ozeri-Galai, E., Bester, A. C. & Kerem, B. The complex basis underlying common fragile site instability in cancer. Trends Genet. 28, 295\u2013302 (2012).","journal-title":"Trends Genet."},{"key":"BFncomms10380_CR35","doi-asserted-by":"publisher","first-page":"4383","DOI":"10.1158\/0008-5472.CAN-11-3893","volume":"72","author":"AM Dulak","year":"2012","unstructured":"Dulak, A. M. et al. Gastrointestinal adenocarcinomas of the esophagus, stomach, and colon exhibit distinct patterns of genome instability and oncogenesis. Cancer Res. 72, 4383\u20134393 (2012).","journal-title":"Cancer Res."},{"key":"BFncomms10380_CR36","doi-asserted-by":"publisher","first-page":"4163","DOI":"10.1158\/0008-5472.CAN-07-6710","volume":"68","author":"DJ Nancarrow","year":"2008","unstructured":"Nancarrow, D. J. et al. Genome-wide copy number analysis in esophageal adenocarcinoma using high-density single-nucleotide polymorphism arrays. Cancer Res. 68, 4163\u20134172 (2008).","journal-title":"Cancer Res."},{"key":"BFncomms10380_CR37","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1038\/ng.2591","volume":"45","author":"AM Dulak","year":"2013","unstructured":"Dulak, A. M. et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat. Genet. 45, 478\u2013486 (2013).","journal-title":"Nat. Genet."},{"key":"BFncomms10380_CR38","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1111\/j.1440-1746.2012.07079.x","volume":"27","author":"N Ishimura","year":"2012","unstructured":"Ishimura, N. et al. Endoscopic characteristics of short-segment Barrett's esophagus, focusing on squamous islands and mucosal folds. J. Gastroenterol. Hepatol. 27, (Suppl 3): 82\u201387 (2012).","journal-title":"J. Gastroenterol. Hepatol."},{"key":"BFncomms10380_CR39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/PAS.0b013e31822a5a2c","volume":"36","author":"P Chandrasoma","year":"2012","unstructured":"Chandrasoma, P. et al. Columnar-lined esophagus without intestinal metaplasia has no proven risk of adenocarcinoma. Am. J. Surg. Pathol. 36, 1\u20137 (2012).","journal-title":"Am. J. Surg. Pathol."},{"key":"BFncomms10380_CR40","doi-asserted-by":"publisher","first-page":"1762","DOI":"10.1053\/j.gastro.2011.07.050","volume":"141","author":"T Sato","year":"2011","unstructured":"Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 141, 1762\u20131772 (2011).","journal-title":"Gastroenterology"},{"key":"BFncomms10380_CR41","doi-asserted-by":"publisher","first-page":"3512","DOI":"10.1158\/1078-0432.CCR-09-2358","volume":"17","author":"BJ Reid","year":"2011","unstructured":"Reid, B. J., Kostadinov, R. & Maley, C. C. New strategies in Barrett's esophagus: integrating clonal evolutionary theory with clinical management. Clin. Cancer Res. 17, 3512\u20133519 (2011).","journal-title":"Clin. Cancer Res."},{"key":"BFncomms10380_CR42","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1126\/science.1145720","volume":"318","author":"LD Wood","year":"2007","unstructured":"Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108\u20131113 (2007).","journal-title":"Science"},{"key":"BFncomms10380_CR43","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","volume":"144","author":"D Hanahan","year":"2011","unstructured":"Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646\u2013674 (2011).","journal-title":"Cell"},{"key":"BFncomms10380_CR44","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545\u201315550 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms10380_CR45","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","volume":"25","author":"H Li","year":"2009","unstructured":"Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754\u20131760 (2009).","journal-title":"Bioinformatics"},{"key":"BFncomms10380_CR46","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","volume":"20","author":"A McKenna","year":"2010","unstructured":"McKenna, A. et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297\u20131303 (2010).","journal-title":"Genome Res."},{"key":"BFncomms10380_CR47","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","volume":"25","author":"H Li","year":"2009","unstructured":"Li, H. et al. The sequence alignment\/map format and SAMtools. Bioinformatics 25, 2078\u20132079 (2009).","journal-title":"Bioinformatics"},{"key":"BFncomms10380_CR48","doi-asserted-by":"publisher","first-page":"11189","DOI":"10.1093\/nar\/gks918","volume":"40","author":"A Wilm","year":"2012","unstructured":"Wilm, A. et al. LoFreq: a sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasets. Nucleic Acids Res. 40, 11189\u201311201 (2012).","journal-title":"Nucleic Acids Res."},{"key":"BFncomms10380_CR49","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1038\/ng.2246","volume":"44","author":"ZJ Zang","year":"2012","unstructured":"Zang, Z. J. et al. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat. Genet. 44, 570\u2013574 (2012).","journal-title":"Nat. Genet."},{"key":"BFncomms10380_CR50","doi-asserted-by":"publisher","first-page":"R115","DOI":"10.1186\/gb-2012-13-12-r115","volume":"13","author":"N Nagarajan","year":"2012","unstructured":"Nagarajan, N. et al. Whole-genome reconstruction and mutational signatures in gastric cancer. Genome Biol. 13, R115 (2012).","journal-title":"Genome Biol."},{"key":"BFncomms10380_CR51","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1038\/nprot.2009.86","volume":"4","author":"P Kumar","year":"2009","unstructured":"Kumar, P., Henikoff, S. & Ng, P. C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073\u20131081 (2009).","journal-title":"Nat. Protoc."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms10380.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms10380","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms10380.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T11:53:42Z","timestamp":1672833222000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms10380"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,19]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,4,22]]}},"alternative-id":["BFncomms10380"],"URL":"https:\/\/doi.org\/10.1038\/ncomms10380","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,1,19]]},"assertion":[{"value":"12 August 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 January 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10380"}}