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M\u00f8ller og Hustru Chastine Mc-Kinney M\u00f8llers Fond til almene Formaal","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005747","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:p>Patient\u2010derived <jats:italic>in\u00a0vitro<\/jats:italic> cultures of colorectal cancer (<jats:styled-content style=\"fixed-case\">CRC<\/jats:styled-content>) may help guide treatment strategies prior to patient treatment. However, most previous studies have been performed on a single biopsy per tumor. The purpose of this study was to analyze multiple spatially distinct biopsies from <jats:styled-content style=\"fixed-case\">CRC<\/jats:styled-content>s and see how well intratumor heterogeneity (<jats:styled-content style=\"fixed-case\">ITH<\/jats:styled-content>) was recapitulated in matching patient\u2010derived spheroids. Three to five biopsies were collected from six <jats:styled-content style=\"fixed-case\">CRC<\/jats:styled-content> tumors. Each biopsy was split in two; one half was used for spheroid culturing, while the other half was used for <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> purification. For two patients, lymph node metastases were analyzed. Somatic mutations were called from whole exome sequencing data. Each tumor contained mutations shared across all biopsies and spheroids, including major <jats:styled-content style=\"fixed-case\">CRC<\/jats:styled-content> drivers such as <jats:styled-content style=\"fixed-case\">APC<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> KRAS<\/jats:styled-content>, and <jats:styled-content style=\"fixed-case\">TP<\/jats:styled-content>53. At the same time, all tumors exhibited <jats:styled-content style=\"fixed-case\">ITH<\/jats:styled-content> on both mutation and copy number level. The concordance between biopsies and spheroids ranged between 40 and 70% for coding mutations. For three patients, the biopsy and spheroid from matching areas clustered together, meaning that the spheroid resembled the area of origin more than the other areas. However, all biopsies and spheroids contained private mutations. Therefore, multiple cultures from spatially distinct sites of the tumor increase the insight into the genetic profile of the entire tumor. Molecular subtypes were called from <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> sequencing data. When based on transcripts from both cancer and noncancerous cells, the subtypes were largely independent of sampling site. In contrast, subtyping based on cancer cell transcripts alone was dependent on sample site and genetic <jats:styled-content style=\"fixed-case\">ITH<\/jats:styled-content>. In conclusion, all examined <jats:styled-content style=\"fixed-case\">CRC<\/jats:styled-content> tumors showed genetic <jats:styled-content style=\"fixed-case\">ITH<\/jats:styled-content>. Spheroid cultures partly reflected this <jats:styled-content style=\"fixed-case\">ITH<\/jats:styled-content>, and having multiple cultures from distinct tumor sites improved the representation of the genetic tumor subclones. This should be taken into account when establishing patient\u2010derived models for drug screening.<\/jats:p>","DOI":"10.1002\/1878-0261.12156","type":"journal-article","created":{"date-parts":[[2017,11,11]],"date-time":"2017-11-11T14:42:34Z","timestamp":1510411354000},"page":"132-147","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Characterization of genetic intratumor heterogeneity in colorectal cancer and matching patient\u2010derived spheroid cultures"],"prefix":"10.1002","volume":"12","author":[{"given":"Sigrid S.","family":"\u00c1rnad\u00f3ttir","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine Aarhus University Hospital Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Jeppesen","sequence":"additional","affiliation":[{"name":"Digestive Disease Center Bispebjerg Hospital University of Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe","family":"Lamy","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Aarhus University Hospital Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesper B.","family":"Bramsen","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Aarhus University Hospital Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iver","family":"Nordentoft","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Aarhus University Hospital Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Knudsen","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Aarhus University Hospital Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00f8ren","family":"Vang","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Aarhus University Hospital Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mogens R.","family":"Madsen","sequence":"additional","affiliation":[{"name":"Surgical Research Unit Department of Surgery Herning Regional Hospital Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ole","family":"Thastrup","sequence":"additional","affiliation":[{"name":"2cureX Birker\u00f8d Denmark"},{"name":"Department of Drug Design and Pharmacology University of Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob","family":"Thastrup","sequence":"additional","affiliation":[{"name":"2cureX Birker\u00f8d Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claus","family":"L. 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