Dynamics of genome alterations in Crohn's disease associated colorectal carcinogenesis

Patients with Crohn''s disease (CD) involving the colon have an increased risk for developing colorectal cancer (CRC). However, the pathways involved in the evolution of CRC in CD patients are poorly characterized. To determine the landscape of somatic gene mutations that characterizes CD-CRCs, we performed targeted next generation sequencing (563 gene panel) of CD-CRCs. As control group, we used histomorphologically similar sporadic mucinous colorectal adenocarcinomas. Somatic mutations in CD-CRCs involved genes known to be significantly altered in CRC, however, mutation frequencies were different compared to sporadic mucinous CRC: TP53 (76% in CD-CRCs versus 33% in sporadic mucinous CRCs), KRAS (24% versus 50%), APC (17% versus 75%), and SMAD3 (3% versus 29%). To gain insight into the dynamics of genome alterations in CD associated colorectal tumor development, we additionally sequenced non-dysplastic, i.e., normal or inflamed, mucosa samples and dysplastic lesions from CD-CRC patients. This revealed that TP53 mutations were early and frequent events in CD progression while APC, KRAS and SMAD2/4 mutations occurred later.