Dynamics of Genome Alterations in Crohn's Disease–Associated Colorectal Carcinogenesis
Autor: | Peter Kienle, Darawalee Wangsa, Daniel C. Edelman, Claudia Ott, Daniela Hirsch, Yue Hu, Karoline Horisberger, Christian Galata, Timo Gaiser, Kerstin Heselmeyer-Haddad, Thomas Ried, Yuelin J. Zhu, Paul S. Meltzer |
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Přispěvatelé: | University of Zurich, Gaiser, Timo |
Rok vydání: | 2018 |
Předmět: |
Adult
Male 0301 basic medicine Cancer Research Colorectal cancer 610 Medicine & health Disease medicine.disease_cause Genome Article Young Adult 03 medical and health sciences 0302 clinical medicine Crohn Disease medicine Humans 1306 Cancer Research Intestinal Mucosa neoplasms Gene In Situ Hybridization Fluorescence 10217 Clinic for Visceral and Transplantation Surgery Comparative Genomic Hybridization Crohn's disease business.industry Genetic Variation Genomics Middle Aged medicine.disease Immunohistochemistry Ulcerative colitis digestive system diseases Cell Transformation Neoplastic 030104 developmental biology Oncology 030220 oncology & carcinogenesis Disease Progression Cancer research 2730 Oncology Female KRAS Colorectal Neoplasms business Biomarkers Microsatellite Repeats Comparative genomic hybridization |
Zdroj: | Clin Cancer Res |
ISSN: | 1557-3265 1078-0432 |
Popis: | Purpose: Patients with inflammatory bowel diseases, that is, ulcerative colitis and Crohn's disease (CD), face an increased risk of developing colorectal cancer (CRC). Evidence, mainly from ulcerative colitis, suggests that TP53 mutations represent an initial step in the progression from inflamed colonic epithelium to CRC. However, the pathways involved in the evolution of CRC in patients with CD are poorly characterized. Experimental Design: Here, we analyzed 73 tissue samples from 28 patients with CD-CRC, including precursor lesions, by targeted next-generation sequencing of 563 cancer-related genes and array-based comparative genomic hybridization. The results were compared with 24 sporadic CRCs with similar histomorphology (i.e., mucinous adenocarcinomas), and to The Cancer Genome Atlas data (TCGA). Results: CD-CRCs showed somatic copy-number alterations (SCNAs) similar to sporadic CRCs with one notable exception: the gain of 5p was significantly more prevalent in CD-CRCs. CD-CRCs had a distinct mutation signature: TP53 (76% in CD-CRCs vs. 33% in sporadic mucinous CRCs), KRAS (24% vs. 50%), APC (17% vs. 75%), and SMAD3 (3% vs. 29%). TP53 mutations and SCNAs were early and frequent events in CD progression, while APC, KRAS, and SMAD2/4 mutations occurred later. In four patients with CD-CRC, at least one mutation and/or SCNAs were already present in non-dysplastic colonic mucosa, indicating occult tumor evolution. Conclusions: Molecular profiling of CD-CRCs and precursor lesions revealed an inflammation-associated landscape of genome alterations: 5p gains and TP53 mutations occurred early in tumor development. Detection of these aberrations in precursor lesions may help predicting disease progression and distinguishes CD-associated from sporadic colorectal neoplasia. Clin Cancer Res; 24(20); 4997–5011. ©2018 AACR. |
Databáze: | OpenAIRE |
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