{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:01:53Z","timestamp":1791298913916,"version":"4.1.0"},"reference-count":27,"publisher":"National Academy of Sciences","issue":"35","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,9,2]]},"abstract":"<jats:p>\n                    During the clonal expansion of cancer from an ancestral cell with an initiating oncogenic mutation to symptomatic neoplasm, the occurrence of somatic mutations (both driver and passenger) can be used to track the on-going evolution of the neoplasm. All subclones within a cancer are phylogenetically related, with the prevalence of each subclone determined by its evolutionary fitness and the timing of its origin relative to other subclones. Recently developed massively parallel sequencing platforms promise the ability to detect rare subclones of genetic variants without\n                    <jats:italic>a priori<\/jats:italic>\n                    knowledge of the mutations involved. We used ultra-deep pyrosequencing to investigate intraclonal diversification at the Ig heavy chain locus in 22 patients with B-cell chronic lymphocytic leukemia. Analysis of a non-polymorphic control locus revealed artifactual insertions and deletions resulting from sequencing errors and base substitutions caused by polymerase misincorporation during PCR amplification. We developed an algorithm to differentiate genuine haplotypes of somatic hypermutations from such artifacts. This proved capable of detecting multiple rare subclones with frequencies as low as 1 in 5000 copies and allowed the characterization of phylogenetic interrelationships among subclones within each patient. This study demonstrates the potential for ultra-deep resequencing to recapitulate the dynamics of clonal evolution in cancer cell populations.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0801523105","type":"journal-article","created":{"date-parts":[[2008,8,22]],"date-time":"2008-08-22T20:54:42Z","timestamp":1219438482000},"page":"13081-13086","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":307,"title":["Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing"],"prefix":"10.1073","volume":"105","author":[{"given":"Peter J.","family":"Campbell","sequence":"first","affiliation":[{"name":"*Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin D.","family":"Pleasance","sequence":"additional","affiliation":[{"name":"*Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J.","family":"Stephens","sequence":"additional","affiliation":[{"name":"*Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ed","family":"Dicks","sequence":"additional","affiliation":[{"name":"*Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Rance","sequence":"additional","affiliation":[{"name":"*Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Goodhead","sequence":"additional","affiliation":[{"name":"*Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George A.","family":"Follows","sequence":"additional","affiliation":[{"name":"Department of Haematology, University of Cambridge, Cambridge CB2 2XY, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony R.","family":"Green","sequence":"additional","affiliation":[{"name":"Department of Haematology, University of Cambridge, Cambridge CB2 2XY, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. Andy","family":"Futreal","sequence":"additional","affiliation":[{"name":"*Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Stratton","sequence":"additional","affiliation":[{"name":"*Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;"},{"name":"Institute of Cancer Research, Sutton, Surrey SW7 3RP, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,9,2]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05610"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1133427"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-1855"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V100.3.1014"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1164"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1150648"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1437"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.6468307"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm435"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-10-3407"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2006.01.009"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506654102"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050995"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-05-020644"},{"key":"e_1_3_3_15_2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/j.1365-2141.2005.05974.x","article-title":"IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemia","volume":"133","author":"Bagnara D","year":"2006","unstructured":"D Bagnara, et al., IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemia. Br J Haematol 133, 50\u201358 (2006).","journal-title":"Br J Haematol"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20011693"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403202"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1172"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-79-12-2921"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/16.21.10393"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.7.2833"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(05)09012-9"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.9.5122"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-03-066936"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa044238"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2006.10.009"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI23409"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0801523105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T07:46:38Z","timestamp":1709192798000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0801523105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,9,2]]},"references-count":27,"journal-issue":{"issue":"35","published-print":{"date-parts":[[2008,9,2]]}},"alternative-id":["10.1073\/pnas.0801523105"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0801523105","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,9,2]]},"assertion":[{"value":"2008-02-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-09-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}