eprintid: 26800 rev_number: 13 eprint_status: archive userid: 1589 dir: disk0/00/02/68/00 datestamp: 2019-08-13 09:00:40 lastmod: 2019-09-24 16:21:08 status_changed: 2019-08-13 09:00:40 type: article metadata_visibility: show creators_name: Alwers, Elizabeth creators_name: Bläker, Hendrik creators_name: Walter, Viola creators_name: Jansen, Lina creators_name: Kloor, Matthias creators_name: Arnold, Alexander creators_name: Sieber-Frank, Julia creators_name: Herpel, Esther creators_name: Tagscherer, Katrin E. creators_name: Roth, Wilfried creators_name: Chang-Claude, Jenny creators_name: Brenner, Hermann creators_name: Hoffmeister, Michael title: External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS subjects: ddc-610 divisions: i-850300 divisions: i-912000 keywords: Colorectal cancer, Molecular subtypes, Cancer-specific survival, External validation abstract: Background: Competing molecular classification systems have been proposed to complement the TNM staging system for a better prediction of survival in colorectal cancer (CRC). However, validation studies are so far lacking. The aim of this study was to validate and extend previously published molecular classifications of CRC in a large independent cohort of CRC patients. Methods: CRC patients were recruited into a population-based cohort study (DACHS). Molecular subtypes were categorized based on three previously published classifications. Cox-proportional hazard models, based on the same set of patients and using the same confounders as reported by the original studies, were used to determine overall, cancer-specific, or relapse-free survival for each subtype. Hazard ratios and confidence intervals, as well as Kaplan-Meier plots were compared to those reported by the original studies. Results: We observed similar patterns of worse survival for the microsatellite stable (MSS)/BRAF-mutated and MSS/KRAS-mutated subtypes in our validation analyses, which were included in two of the validated classifications. Of the two MSI subtypes, one defined by additional presence of CIMP-high and BRAF-mutation and the other by tumors negative for CIMP, BRAF and KRAS-mutations, we could not confirm associations with better prognosis as suggested by one of the classifications. For two of the published classifications, we were able to provide results for additional subgroups not included in the original studies (men, other disease stages, other locations). Conclusions: External validation of three previously proposed classifications confirmed findings of worse survival for CRC patients with MSS subtypes and BRAF or KRAS mutations. Regarding MSI subtypes, other patient characteristics such as stage of the tumor, may influence the potential survival benefit. Further integration of methylation, genetic, and immunological information is needed to develop and validate a comprehensive classification that will have relevance for use in clinical practice. date: 2019 publisher: BioMed Central ; Springer id_scheme: DOI ppn_swb: 1671874803 own_urn: urn:nbn:de:bsz:16-heidok-268008 language: eng bibsort: ALWERSELIZEXTERNALVA2019 full_text_status: public publication: BMC Cancer volume: 19 number: 681 place_of_pub: London ; Berlin, Heidelberg pagerange: 1-10 issn: 1471-2407 citation: Alwers, Elizabeth ; Bläker, Hendrik ; Walter, Viola ; Jansen, Lina ; Kloor, Matthias ; Arnold, Alexander ; Sieber-Frank, Julia ; Herpel, Esther ; Tagscherer, Katrin E. ; Roth, Wilfried ; Chang-Claude, Jenny ; Brenner, Hermann ; Hoffmeister, Michael (2019) External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS. BMC Cancer, 19 (681). pp. 1-10. ISSN 1471-2407 document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/26800/1/12885_2019_Article_5842.pdf