Molecular phenotype of inflammatory bowel disease-associated neoplasms with microsatellite instability

Karsten Schulmann, Yuriko Mori, Victoria Croog, Jing Yin, Andreea Olaru, Anca Sterian, Fumiaki Sato, Suna Wang, Yan Xu, Elena Deacu, Agnes T. Berki, James P. Hamilton, Takatsugu Kan, John M. Abraham, Wolff Schmiegel, Noam Harpaz, Stephen J. Meltzer

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


Background & Aims: Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). We sought to determine the frequency of high-level microsatellite instability (MSI-H) and the mutational and methylation profile of MSI-H IBD-related neoplasms (IBDNs). Methods: A total of 124 IBDNs (81 cancers, 43 dysplasias) from 78 patients were studied for the frequency of MSI-H and hypermethylation of 3 target genes: MLH1, HPP1, and RAB-32. Fifteen MSI-H IBDNs were characterized according to their profile of frameshift mutations in 28 mononucleotide repeats and compared with 46 sporadic MSI-H CRCs. Results: Nineteen of 124 IBDNs were MSI-H. The frequency of frameshift mutations in coding mononucleotide repeats was significantly lower in MSI-H IBDNs than in sporadic MSI-H CRCs for TGFBR2 (7 of 14 vs 34 of 43 samples; P = .047) and ACVR2 (3 of 14 vs 25 of 43 samples; P = .029). In contrast, ICA1 was mutated in 3 of 9 MSI-H IBDNs vs 2 of 54 sporadic MSI-H CRCs (P = .028). HPP1 and RAB32 methylation was independent of MSI status and was observed in 4 of 59 and 0 of 64 nondysplastic mucosae, 20 of 38 and 1 of 25 dysplasias, and 28 of 61 and 20 of 60 carcinomas, respectively. Conclusions: The profiles of coding microsatellite mutations (instabilotypes) differ significantly between MSI-H IBDNs and MSI-H sporadic CRCs. Specifically, TGFBR2 and ACVR2 mutations are significantly rarer in MSI-H IBDNs than in MSI-H sporadic CRCs. Furthermore, HPP1 methylation occurs early, in 7% of nondysplastic and approximately half of dysplastic mucosae, whereas RAB32 methylation occurs at the transition to invasive growth, being rarer in dysplasias.

Original languageEnglish
Pages (from-to)74-85
Number of pages12
Issue number1
StatePublished - Jul 2005


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