Ulcerative Colitis-Associated Colorectal Cancer is Frequently Associated with the Microsatellite Instability Pathway

Fujiwara, Ikuko; Yashiro, Masakazu; Kubo, Naoshi; Maeda, Kiyoshi; Hirakawa, Kosei

doi:10.1007/s10350-008-9212-9

Cited by 47 publications

(37 citation statements)

References 20 publications

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“…Previous studies have demonstrated that genetic instability occurs during IBD tumorigenesis and that the MSI phenomenon is identified in IBD, even in the regenerative nondysplastic mucosa of UC patients. [24][25][26] Our current study found that 9.6% of UC-associated adenocarcinomas and 9% of pouch adenocarcinomas had complete loss of at least 1 MMR protein, in line with previous reports that MSI-H is found in only a small proportion of IBD-associated adenocarcinomas. 10,[27][28][29] Collectively, existing evidence supports that loss of MMR protein(s) and MSI-H contributes to the tumorigenesis of about 15% of pouch and UC-associated adenocarcinomas.…”

Section: Discussionsupporting

confidence: 93%

Histomorphologic and Molecular Features of Pouch and Peripouch Adenocarcinoma

Jiang¹,

Shadrach²,

Carver³

et al. 2012

American Journal of Surgical Pathology

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The occurrence of adenocarcinoma after ileal pouch-anal anastomosis for ulcerative colitis (UC) is an infrequent but potentially lethal complication. Neither histomorphologic nor molecular features of pouch adenocarcinoma after ileal pouch-anal anastomosis have been fully investigated. We report the largest series of 12 pouch and peripouch adenocarcinomas and compared them with 58 randomly selected UC-associated adenocarcinomas. The mean age of patients with pouch/peripouch adenocarcinoma was 55.2 years (SD 14.8), which was not significantly different from that of controls (P=0.52). Pouch/peripouch adenocarcinoma and UC-associated adenocarcinoma had a comparable frequency of tumor-infiltrating lymphocytes, lack of dirty necrosis, mucin differentiation, signet ring cell differentiation, heterogeneity, and well differentiation (P>0.05 for all). Pouch/peripouch adenocarcinoma was more likely to show Crohn-like reaction compared with UC-associated adenocarcinoma (P=0.047). Loss of at least 1 mismatch repair protein was noted in 9% of pouch/peripouch adenocarcinomas and 9.6% of UC-related adenocarcinomas (P=1.0). There was no significant difference in the frequency of p53 overexpression (36.4% vs. 61.1%, P=0.184) or nuclear immunoreactivity for β-catenin (9% vs. 7.4%, P=0.99) in pouch/peripouch versus UC-associated adenocarcinomas, respectively. Pouch/peripouch and UC-associated adenocarcinoma had a comparable positive rate for CK7 (54.5% vs. 55.5%, P=0.99), CK20 (100% vs. 98.1%, P=0.99), and CDX2 (72.8% vs. 72.2%, P=0.99) by immunohistochemistry. In summary, pouch and peripouch adenocarcinoma can occur in patients without colorectal neoplasia and in those with idiopathic inflammatory bowel disease, can be potentially lethal, and has histomorphologic and molecular features similar to those of UC-associated adenocarcinoma.

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Section: Discussionsupporting

confidence: 93%

Histomorphologic and Molecular Features of Pouch and Peripouch Adenocarcinoma

Jiang¹,

Shadrach²,

Carver³

et al. 2012

American Journal of Surgical Pathology

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“…Microsatellite instability (MSI) and loss of heterozygosity (LOH) were analysed by PCR-LOH/MSI assay, as previously reported (Fujiwara et al, 2008). A 6 ml aliquot of reaction mixture was formulated using 0.4 ml of DNA extracted from normal epithelium, primary tumour, OCUM-12, and OCUM-12/Hypo cells.…”

Section: Pcr-loh/msi Assaymentioning

confidence: 99%

Establishment and characterization of a new hypoxia-resistant cancer cell line, OCUM-12/Hypo, derived from a scirrhous gastric carcinoma

et al. 2010

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BACKGROUND: Many kinds of solid tumour have heterogeneously a hypoxic environment. Tumour hypoxia reported to be associated with more aggressive tumour phenotypes such as high metastatic ability and resistance to various anti-cancer therapies which may lead to a poorer prognosis. However, the mechanisms by which hypoxia affects the aggressive phenotypes remain unclear. METHODS: We established a scirrhous gastric carcinoma cell line (OCUM-12) from ascites associated with scirrhous gastric carcinoma, and a hypoxia-resistant cancer cell line (OCUM-12/Hypo) was cloned from OCUM-12 cells by continuous exposure to 1% oxygen. RESULTS: Histologic findings from orthotopic tumours derived from parent OCUM-12 cells and daughter OCUM-12/Hypo cells revealed poorly differentiated adenocarcinoma with extensive fibrosis that resembled human scirrhous gastric cancer. Necrotic lesions were frequently detected in the OCUM-12 tumours but were rarely found in the OCUM-12/Hypo tumours, although both types had multiple hypoxic loci. Apoptosis rate of OCUM-12 cells was increased to 24.7% at 1% O 2 , whereas that of OCUM-12/ Hypo was 5.6%. The OCUM-12/Hypo orthotopic models developed multiple metastases to the peritoneum and lymph nodes, but the OCUM-12 models did not. OCUM-12/Hypo cells showed epithelial-to-mesenchymal transition and high migratory and invasive activities in comparison with OCUM-12 cells. The mRNA expression levels of both E-cadherin and zonula occludens ZO-1 and ZO-2 decreased in OCUM-12/Hypo cells, and that of vimentin, Snail-1, Slug/Snail-2, Twist, ZEB-1, ZEB-2, matrix metalloproteinase-1 (MMP-1), and MMP-2 were increased in OCUM-12/Hypo cells. CONCLUSION: OCUM-12 and OCUM-12/Hypo may be useful for the elucidation of disease progression associated with scirrhous gastric cancer in the setting of chronic hypoxia.

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“…Although the same pathogenetic and molecular features detected in patients with sporadic CRC such as microsatellite instability, chromosome instability, loss of heterozygosity, and DNA hypermethylation are also found in patients with colitis-associated cancers, the molecular pathway leading to CRC in IBD appears to differ significantly from the classical sporadic adenoma-to-CRC sequence, given the fact that these cancers appear to arise from either flat dysplastic tissue or dysplasia-associated lesions or masses (nonadenoma-like raised lesions or dysplasia-associated lesion or mass) [14,15,16,17,18]. IBD-associated carcinogenesis follows progression from an absence of dysplasia to indefinite dysplasia, then to LGD, on to HGD, and ultimately to invasive CRC.…”

Section: Molecular Mechanisms Of Ibd-associated Colon Carcinogenesismentioning

confidence: 99%

Colorectal Cancer in Patients with Inflammatory Bowel Disease: The True Impact of the Risk

Herszényi¹,

Barabás

Miheller³

et al. 2014

Dig Dis

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Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of colorectal cancer (CRC). The association between IBD and CRC is well supported, but reported risk estimates vary widely. Although recent evidence from population-based studies reports a decline in risk, CRC accounts for 10-15% of all deaths in IBD. The potential causes of recent epidemiological trends and the real magnitude of risk of CRC in IBD are subjects of debate. The molecular pathway leading to CRC differs from the classic adenoma-to-CRC sequence. Chronic inflammation contributes to the development of low- and high-grade dysplasia which may further convert into CRC. Patients with a young age at onset, long-standing and extensive colitis with severe inflammatory burden, a family history of sporadic CRC, and concomitant primary sclerosing cholangitis are at greatest risk. The CRC risk in patients with colonic Crohn's disease is similar to that of ulcerative colitis. IBD-associated CRC can frequently be detected at late stages and at a younger age. The long-term prognosis of CRC may be poorer in patients with IBD than in those with sporadic CRC. Regular surveillance colonoscopies may permit earlier detection of CRC, with a corresponding improved prognosis. The interval between surveillance colonoscopies is dependent on each patient's personal risk profile.

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Ulcerative Colitis-Associated Colorectal Cancer is Frequently Associated with the Microsatellite Instability Pathway

Abstract: The carcinogenesis process in ulcerative colitis-associated colorectal cancer was closely associated with the microsatellite instability pathway through TGFbetaRII mutation by a dysfunction of the mismatch repair system.

Cited by 47 publications

References 20 publications

Histomorphologic and Molecular Features of Pouch and Peripouch Adenocarcinoma

Histomorphologic and Molecular Features of Pouch and Peripouch Adenocarcinoma

Establishment and characterization of a new hypoxia-resistant cancer cell line, OCUM-12/Hypo, derived from a scirrhous gastric carcinoma

Colorectal Cancer in Patients with Inflammatory Bowel Disease: The True Impact of the Risk

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