Dynamics of Genome Alterations in Crohn's Disease-Associated Colorectal Carcinogenesis.

Abstract

<b>Purpose:</b> 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 <i>TP53</i> 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.<b>Experimental Design:</b> 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).<b>Results:</b> 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: <i>TP53</i> (76% in CD-CRCs vs. 33% in sporadic mucinous CRCs), <i>KRAS</i> (24% vs. 50%), <i>APC</i> (17% vs. 75%), and <i>SMAD3</i> (3% vs. 29%). <i>TP53</i> mutations and SCNAs were early and frequent events in CD progression, while <i>APC, KRAS</i>, and <i>SMAD2/4</i> 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.<b>Conclusions:</b> Molecular profiling of CD-CRCs and precursor lesions revealed an inflammation-associated landscape of genome alterations: 5p gains and <i>TP53</i> 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. <i>Clin Cancer Res; 24(20); 4997-5011. ©2018 AACR</i>.