Molecular characterization of ulcerative colitis-associated colorectal carcinomas

Abstract

Patients with ulcerative colitis (UC) are at increased risk for developing colorectal cancer (CRC). In contrast to sporadic colorectal tumorigenesis, TP53 mutations occur early in the progression from inflamed colonic epithelium to dysplasia to CRC, and are sometimes readily detectable in inflamed, (yet) non-dysplastic mucosa. Here, we analyzed formalin-fixed paraffin-embedded tissue samples from 19 patients with long-standing UC (median 18 years, range 3 to 34) who had developed CRC as a consequence of chronic inflammation of the large bowel. We performed microsatellite instability testing, copy number analysis by array-based comparative genomic hybridization, mutation analysis by targeted next generation sequencing (48-gene panel) and TP53 immunostaining. The results were compared to The Cancer Genome Atlas (TCGA) data on sporadic CRC. All UC-CRC lesions in our cohort were microsatellite stable. Overall, genomic imbalances of UC-CRCs showed patterns of chromosomal aneuploidies characteristic for sporadic CRC with the exception of gains of chromosome arm 5p (12 of 23 UC-CRC, 52%), which are rare in sporadic CRCs from TCGA (21 of 144, 15%; FDR adjusted P = 0.006). UC-CRCs showed a predilection for TP53 alterations, which was the most frequently mutated gene in our cohort (20 of 23, 87%). Interestingly, spatially separated tumor lesions from individual patients tended to harbor distinct TP53 mutations. Similar to CRCs arising in a background of Crohn’s colitis, the genetic landscape of UC-CRCs was characterized by TP53 mutations and chromosomal aneuploidies including gains of chromosome arm 5p. Both alterations harbor the potential for early detection in precursor lesions, thus complementing morphologic diagnosis.

Gene panel testing detects important genetic alterations in ulcerative colitis‑associated colorectal neoplasia

“…Almost all sporadic CRC have genetic alterations in APC, where it plays an important role in tumorigenesis (35). Conversely, previous reports have shown UCAN has fewer genetic alterations in APC compared with sporadic CRC (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), which is consistent with our findings (Table II). RNF43 is thought to negatively regulate the WNT pathway, and loss of RNF43 plays an important role in sporadic CRC through the enhancement of WNT signaling (36).…”

“…The genomic landscape of sporadic CRC has been fairly well studied using next-generation sequencing (NGS) technology. Despite previous analyses showing that UCAN harbors unique genetic alterations and mutational tendencies (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), chemotherapy regimens for UCAN continue to be extrapolated from those for sporadic CRC.…”

Exploring the Potential Mechanism of Xiaokui Jiedu Decoction for Ulcerative Colitis Based on Network Pharmacology and Molecular Docking

“…Variability and methylation patterns of ESR1 were associated with the development of Crohn's disease in patients [ 1 , 26 ]. The potential role of JUN and MAPK1 [ 27 , 28 ] and NR3C1 [ 29 ] on UC is well known, and our study systematically revealed these links between them. Finally, the expression of key mRNAs (FOS, TNF- α , and IL-1) in UC was also significantly downregulated after XJD administration.…”

Giant filiform polyposis with high-grade dysplasia: A case report and review of the literature

“…In this case, immunohistochemistry using anti-p53 antibodies revealed that the dysplastic lesion did not show p53 abnormal expression. As p53 mutations appear to be the initiating mutation in inflammatory carcinogenesis, these findings do not support the inflammatory carcinogenesis of filiform polyposis [ 31 , 32 ]. Furthermore, dysplasia was observed in some of the polyps in this case with no background of inflammation, so evidence was insufficient to support inflammatory carcinogenesis.…”