D Hirsch1, T Gaiser2. 1. Institut für Pathologie, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Deutschland. daniela.hirsch@umm.de. 2. Institut für Pathologie, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim, Universität Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Deutschland. timo.gaiser@umm.de.
Abstract
BACKGROUND: Patients with inflammatory bowel diseases, i. e., 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. OBJECTIVES: In this study, we aimed to analyze the genetic events that define CD-CRCs, in particular the dynamics of their development from histologically undetectable precursor lesions to invasive disease. MATERIALS AND METHODS: We analyzed 73 tissue samples from 28 patients with CD-CRC, including precursor lesions by next generation sequencing (563 gene panel) and array-based comparative genomic hybridization. The results were compared with our own data and the Cancer Genome Atlas data on sporadic CRC. RESULTS: The gain of 5p was significantly more prevalent in CD-CRCs than in sporadic CRCs, despite an overall similar chromosomal aberration pattern. CD-CRCs had a distinct mutation signature with TP53 being the most frequently mutated gene in CD-CRCs. TP53 mutations and copy number alterations were early events in CD progression and could sometimes already be detected 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: gains of 5p and TP53 mutations occurred early in tumor development. Detection of these aberrations in precursor lesions may help predict disease progression and distinguishes CD-associated from sporadic colorectal neoplasia.
BACKGROUND:Patients with inflammatory bowel diseases, i. e., 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. OBJECTIVES: In this study, we aimed to analyze the genetic events that define CD-CRCs, in particular the dynamics of their development from histologically undetectable precursor lesions to invasive disease. MATERIALS AND METHODS: We analyzed 73 tissue samples from 28 patients with CD-CRC, including precursor lesions by next generation sequencing (563 gene panel) and array-based comparative genomic hybridization. The results were compared with our own data and the Cancer Genome Atlas data on sporadic CRC. RESULTS: The gain of 5p was significantly more prevalent in CD-CRCs than in sporadic CRCs, despite an overall similar chromosomal aberration pattern. CD-CRCs had a distinct mutation signature with TP53 being the most frequently mutated gene in CD-CRCs. TP53 mutations and copy number alterations were early events in CD progression and could sometimes already be detected 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: gains of 5p and TP53 mutations occurred early in tumor development. Detection of these aberrations in precursor lesions may help predict disease progression and distinguishes CD-associated from sporadic colorectal neoplasia.