{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T22:22:16Z","timestamp":1773786136628,"version":"3.50.1"},"reference-count":84,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T00:00:00Z","timestamp":1636070400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Colorectal Disease"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>Colorectal carcinomas (CRCs) progress through heterogeneous pathways. The aim of this study was to analyse whether or not the cytogenetic evolution of CRC is linked to tumour site, level of chromosomal imbalance and metastasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>A set of therapy\u2010na\u00efve pT3 CRCs comprising 26 proximal and 49 distal pT3 CRCs was studied by combining immunohistochemistry of mismatch repair (MMR) proteins, microsatellite analyses and molecular karyotyping as well as clinical parameters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A MMR deficient\/microsatellite\u2010unstable (dMMR\/MSI\u2010H) status was associated with location of the primary tumour proximal to the splenic flexure, and dMMR\/MSI\u2010H tumours presented with significantly lower levels of chromosomal imbalances compared with MMR proficient\/microsatellite\u2010stable (pMMR\/MSS) tumours. Oncogenetic tree modelling suggested two evolutionary clusters characterized by dMMR\/MSI\u2010H and chromosomal instability (CIN), respectively, for both proximal and distal CRCs. In CIN cases, +13q, \u221218q and +20q were predicted as preferentially early events, and \u22121p, \u22124 \u2010and \u22125q as late events. Separate oncogenetic tree models of proximal and distal cases indicated similar early events independent of tumour site. However, in cases with high CIN defined by more than 10 copy number aberrations, loss of 17p occurred earlier in cytogenetic evolution than in cases showing low to moderate CIN. Differences in the oncogenetic trees were observed for CRCs with lymph node and distant metastasis. Loss of 8p was modelled as an early event in node\u2010positive CRC, while +7p and +8q comprised early events in CRC with distant metastasis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>CRCs characterized by CIN follow multiple, interconnected genetic pathways in line with the basic \u2018Vogelgram\u2019 concept proposed for the progression of CRC that places the accumulation of genetic changes at centre of tumour evolution. However, the timing of specific genetic events may favour metastatic potential.<\/jats:p><\/jats:sec>","DOI":"10.1111\/codi.15946","type":"journal-article","created":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T08:58:45Z","timestamp":1633769925000},"page":"157-176","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Evolutionary patterns of chromosomal instability and mismatch repair deficiency in proximal and distal colorectal cancer"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2477-9277","authenticated-orcid":false,"given":"Mariola Monika","family":"Golas","sequence":"first","affiliation":[{"name":"Department of Hematology and Medical Oncology Comprehensive Cancer Center Augsburg University Medical Center Augsburg  Augsburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bastian","family":"Gunawan","sequence":"additional","affiliation":[{"name":"Institute of Pathology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meliha","family":"Cakir","sequence":"additional","affiliation":[{"name":"Institute of Pathology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silke","family":"Cameron","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Gastrointestinal Oncology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Enders","sequence":"additional","affiliation":[{"name":"Institute of Pathology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Torsten","family":"Liersch","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Pediatric Surgery University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laszlo","family":"F\u00fczesi","sequence":"additional","affiliation":[{"name":"Institute of Pathology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"},{"name":"Institute of Pathology and Molecular Diagnostics University Medical Center Augsburg  Augsburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8495-2321","authenticated-orcid":false,"given":"Bjoern","family":"Sander","sequence":"additional","affiliation":[{"name":"Institute of Pathology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"},{"name":"Institute of Pathology Hannover Medical School  Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,11,5]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.2996"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21601"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-113-10-779"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/14737140.2018.1442217"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2017.0038"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2011-300865"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clcc.2018.10.005"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19092577"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3967"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910280407"},{"issue":"4","key":"e_1_2_12_12_1","first-page":"206","article-title":"Consistent deficiencies of chromosome 18 and of the short arm of chromosome 17 in eleven cases of human large bowel cancer: a possible recessive determinism","volume":"28","author":"Muleris M","year":"1985","journal-title":"Ann Genet"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergencyto.2009.12.006"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergen.2010.12.003"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11252"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-2264(199604)15:4<234::AID-GCC5>3.0.CO;2-2"},{"issue":"5","key":"e_1_2_12_17_1","first-page":"1808","article-title":"Gain of chromosome 8q23\u201024 is a predictive marker for lymph node positivity in colorectal cancer","volume":"9","author":"Ghadimi BM","year":"2003","journal-title":"Clin Cancer Res"},{"issue":"5","key":"e_1_2_12_18_1","first-page":"273","article-title":"Distinct chromosomal profiles in metastasizing and non\u2010metastasizing colorectal carcinomas","volume":"28","author":"Ghadimi BM","year":"2006","journal-title":"Cell Oncol"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.1380020505"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8484122"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0394-273"},{"issue":"24","key":"e_1_2_12_22_1","first-page":"6002","article-title":"Comparative genomic in situ hybridization of colon carcinomas with replication error","volume":"55","author":"Schlegel J","year":"1995","journal-title":"Cancer Res"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63500-6"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-018-5174-z"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-017-0434-0"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-1248"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0195-48"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.283"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90546-3"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90330-S"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/368258a0"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8128251"},{"issue":"5","key":"e_1_2_12_33_1","first-page":"808","article-title":"Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair\u2010defective human tumor cell lines","volume":"57","author":"Kane MF","year":"1997","journal-title":"Cancer Res"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.12.6870"},{"issue":"15","key":"e_1_2_12_35_1","first-page":"3455","article-title":"Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability","volume":"58","author":"Cunningham JM","year":"1998","journal-title":"Cancer Res"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.15.8681"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2012.241"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90186-I"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.20614"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1907-7"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/biostatistics\/kxh007"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0025-5564(02)00086-X"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1089\/cmb.1999.6.37"},{"key":"e_1_2_12_44_1","volume-title":"TNM Classification of Malignant Tumours","author":"Union for International Cancer Control","year":"2017"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040694"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.40.1836"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.2353\/jmoldx.2006.050092"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.21646"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.2870100403"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.03.007"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.2307\/1390807"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-4608(88)90174-4"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06132-1"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.51.12.901"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-4608(87)90239-1"},{"issue":"4","key":"e_1_2_12_56_1","first-page":"879","article-title":"Analysis of colorectal cancer by comparative genomic hybridization: evidence for induction of the metastatic phenotype by loss of tumor suppressor genes","volume":"4","author":"Paredes\u2010Zaglul A","year":"1998","journal-title":"Clin Cancer Res"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6690388"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/s003840000275"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgh134"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2018.289819"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergen.2016.11.001"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2010.0101"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.36051"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.2001.2095"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-61643-6"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.20261"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12926-8"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0423-x"},{"key":"e_1_2_12_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.20271"},{"key":"e_1_2_12_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.2180"},{"key":"e_1_2_12_71_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31869"},{"key":"e_1_2_12_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1672-7"},{"key":"e_1_2_12_73_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0091739"},{"key":"e_1_2_12_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.10.011"},{"key":"e_1_2_12_75_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf8399"},{"key":"e_1_2_12_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-32884-3"},{"key":"e_1_2_12_77_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20184652"},{"key":"e_1_2_12_78_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0796-343"},{"key":"e_1_2_12_79_1","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.5.8.1969-1976.1985"},{"key":"e_1_2_12_80_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1991.tb07929.x"},{"key":"e_1_2_12_81_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2005.07.053"},{"key":"e_1_2_12_82_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.4.12b.2353"},{"key":"e_1_2_12_83_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.5.2412"},{"key":"e_1_2_12_84_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-1514"},{"key":"e_1_2_12_85_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3173"}],"container-title":["Colorectal Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/codi.15946","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/codi.15946","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/codi.15946","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T01:35:32Z","timestamp":1692840932000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/codi.15946"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,5]]},"references-count":84,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["10.1111\/codi.15946"],"URL":"https:\/\/doi.org\/10.1111\/codi.15946","archive":["Portico"],"relation":{},"ISSN":["1462-8910","1463-1318"],"issn-type":[{"value":"1462-8910","type":"print"},{"value":"1463-1318","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,5]]},"assertion":[{"value":"2021-01-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}