Somatic mutation profiles as molecular classifiers of ulcerative colitis-associated colorectal cancer

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Mäki-Nevala , S , Ukwattage , S , Olkinuora , A , Almusa , H , Ahtiainen , M , Ristimäki , A , Seppälä , T , Lepistö , A , Mecklin , J-P & Peltomäki , P 2021 , ' Somatic mutation profiles as molecular classifiers of ulcerative colitis-associated colorectal cancer ' , International Journal of Cancer , vol. 148 , no. 12 , pp. 2997-3007 .

Title: Somatic mutation profiles as molecular classifiers of ulcerative colitis-associated colorectal cancer
Author: Mäki-Nevala, Satu; Ukwattage, Sanjeevi; Olkinuora, Alisa; Almusa, Henrikki; Ahtiainen, Maarit; Ristimäki, Ari; Seppälä, Toni; Lepistö, Anna; Mecklin, Jukka-Pekka; Peltomäki, Päivi
Contributor organization: Department of Medical and Clinical Genetics
University of Helsinki
Institute for Molecular Medicine Finland
Department of Pathology
Helsinki University Hospital Area
ATG - Applied Tumor Genomics
Research Programs Unit
HUS Abdominal Center
II kirurgian klinikka
Department of Surgery
University Management
Date: 2021-06-15
Language: eng
Number of pages: 11
Belongs to series: International Journal of Cancer
ISSN: 0020-7136
Abstract: Ulcerative colitis increases colorectal cancer risk by mechanisms that remain incompletely understood. We approached this question by determining the genetic and epigenetic profiles of colitis-associated colorectal carcinomas (CA-CRC). The findings were compared to Lynch syndrome (LS), a different form of cancer predisposition that shares the importance of immunological factors in tumorigenesis. CA-CRCs (n = 27) were investigated for microsatellite instability, CpG island methylator phenotype and somatic mutations of 999 cancer-relevant genes ("Pan-cancer" panel). A subpanel of "Pan-cancer" design (578 genes) was used for LS colorectal tumors (n = 28). Mutational loads and signatures stratified CA-CRCs into three subgroups: hypermutated microsatellite-unstable (Group 1, n = 1), hypermutated microsatellite-stable (Group 2, n = 9) and nonhypermutated microsatellite-stable (Group 3, n = 17). The Group 1 tumor was the only one with MLH1 promoter hypermethylation and exhibited the mismatch repair deficiency-associated Signatures 21 and 15. Signatures 30 and 32 characterized Group 2, whereas no prominent single signature existed in Group 3. TP53, the most common mutational target in CA-CRC (16/27, 59%), was similarly affected in Groups 2 and 3, but DNA repair genes and Wnt signaling genes were mutated significantly more often in Group 2. In LS tumors, the degree of hypermutability exceeded that of the hypermutated CA-CRC Groups 1 and 2, and somatic mutational profiles and signatures were different. In conclusion, Groups 1 (4%) and 3 (63%) comply with published studies, whereas Group 2 (33%) is novel. The existence of molecularly distinct subgroups within CA-CRC may guide clinical management, such as therapy options.
Subject: colorectal cancer
Lynch syndrome
microsatellite instability
somatic mutation
Ulcerative colitis
3122 Cancers
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: acceptedVersion

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