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
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
Externí odkaz: