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Yamamoto N, Urabe Y, Nakahara H, Nakamura T, Shimizu D, Konishi H, Ishibashi K, Ariyoshi M, Miyamoto R, Mizuno J, Takasago T, Ishikawa A, Tsuboi A, Tanaka H, Yamashita K, Hiyama Y, Kishida Y, Takigawa H, Kuwai T, Arihiro K, Shimamoto F, Oka S. Genetic Analysis of Biopsy Tissues from Colorectal Tumors in Patients with Ulcerative Colitis. Cancers (Basel) 2024; 16:3271. [PMID: 39409892 PMCID: PMC11475702 DOI: 10.3390/cancers16193271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND/OBJECTIVES Colorectal neoplasia developing from ulcerative colitis mucosa (CRNUC) can be divided into ulcerative colitis-associated neoplasia (UCAN) and non-UCAN; however, it is often difficult to distinguish UCAN from non-UCAN during a biopsy diagnosis. We investigated whether a genomic analysis could improve the diagnostic accuracy of UCAN using biopsy specimens. METHODS In step 1, 14 CRNUCs were used to examine whether the genomic landscape of biopsy and resection specimens matched. In step 2, we investigated the relationship between the genomic landscapes and the pathological diagnosis of 26 CRNUCs. The cancer genome was analyzed by deep sequencing using a custom panel of 27 genes found to be mutated in our previous CRNUC analysis. RESULTS In step 1, of the 27 candidate genes, 14 were mutated. The concordance rate of the pathogenic mutations in these 14 genes between the biopsy and resection specimens was 29% (4/14), while that of the pathogenic mutations in TP53 and KRAS was 79% (11/14). In step 2, the pathological diagnosis of biopsy specimens using only hematoxylin and eosin (HE) staining had a sensitivity of 33% and an accuracy of 38% for UCAN diagnosis. On the other hand, the combination of the HE pathology and p53 immunohistochemical staining had a sensitivity of 73% and an accuracy of 85% for UCAN diagnosis, while the combination of HE staining and a TP53 mutation had a sensitivity of 87% and an accuracy of 88% for UCAN diagnosis. CONCLUSIONS An evaluation of TP53 mutations in biopsy specimens may be useful for diagnosing UCAN. However, further studies with larger sample sizes are required before this can be applied in clinical practice.
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Affiliation(s)
- Noriko Yamamoto
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Yuji Urabe
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Hikaru Nakahara
- Department of Clinical and Molecular Genetics, Hiroshima University Hospital, Hiroshima 734-8551, Japan;
| | - Takeo Nakamura
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Daisuke Shimizu
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Hirona Konishi
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Kazuki Ishibashi
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Misa Ariyoshi
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Ryo Miyamoto
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Junichi Mizuno
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Takeshi Takasago
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Akira Ishikawa
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan;
| | - Akiyoshi Tsuboi
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Hidenori Tanaka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Ken Yamashita
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Yuichi Hiyama
- Clinical Research Center in Hiroshima, Hiroshima University Hospital, Hiroshima 734-8551, Japan;
| | - Yoshihiro Kishida
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Hidehiko Takigawa
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
| | - Toshio Kuwai
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
- Gastrointestinal Endoscopy and Medicine, Hiroshima University Hospital, Hiroshima 734-8551, Japan
| | - Koji Arihiro
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima 734-8551, Japan;
| | - Fumio Shimamoto
- Faculty of Health Sciences, Hiroshima Cosmopolitan University, Hiroshima 734-0014, Japan;
| | - Shiro Oka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (N.Y.); (T.N.); (D.S.); (H.K.); (K.I.); (M.A.); (R.M.); (J.M.); (T.T.); (A.T.); (H.T.); (K.Y.); (Y.K.); (H.T.); (T.K.); (S.O.)
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Osone K, Yokobori T, Katayama C, Takahashi R, Kato R, Tatsuski H, Takada T, Yajima R, Motegi Y, Ogawa H, Fujii T, Ojima H, Nakamura J, Yao T, Shirabe K, Kuwano H. STMN1 accumulation is associated with dysplastic and neoplastic lesions in patients with ulcerative colitis. Oncol Lett 2019; 18:4712-4718. [PMID: 31611980 PMCID: PMC6781569 DOI: 10.3892/ol.2019.10814] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 04/23/2019] [Indexed: 01/29/2023] Open
Abstract
Ulcerative colitis (UC) is thought to be associated with precancerous lesions that can ultimately lead to colon cancer. Therefore, diagnostic markers for colorectal dysplasia and cancer are urgently needed for patients with UC. Stathmin 1 (STMN1) is a novel cancer biomarker that is also a novel target for treatment in several cancers, including colon cancer. However, few studies have investigated the relationship between STMN1 expression and clinical features in colorectal dysplasia and cancer in patients with UC. The present study examined the clinical significance of STMN1 expression in colorectal dysplasia and cancer with UC. The present study performed an immunohistochemical analysis of 31 clinical colorectal samples from eight patients with colorectal dysplasia and/or cancer to assess the relationships between STMN1 expression and clinicopathological features including mismatch repair protein expression, rate of Ki-67 positivity, differentiation level, TNM stage, and UC duration. STNM1 expression was detected in 95.7% of dysplastic and cancerous lesions, whereas p53, the current diagnostic marker, was not expressed in 39.1% of dysplastic and cancerous lesions. Furthermore, STMN1 expression was associated with a high rate of positivity for Ki-67, a proliferation marker. Our data suggest that STMN1 in the colonic mucosa of UC patients may be useful as an early diagnostic marker of dysplasia and colitic cancer.
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Affiliation(s)
- Katsuya Osone
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Takehiko Yokobori
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.,Department of Innovative Cancer Immunotherapy, Gunma University, Maebashi, Gunma 371-8511, Japan.,Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma 371-8511, Japan
| | - Chika Katayama
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Ryo Takahashi
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Ryuji Kato
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Hironori Tatsuski
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Takahiro Takada
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Reina Yajima
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Yoko Motegi
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Hiroomi Ogawa
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Takaaki Fujii
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Hitoshi Ojima
- Department of Gastroenterological Surgery, Gunma Prefectural Cancer Center, Ohta, Gunma 373-8550, Japan
| | - Junichi Nakamura
- Department of Gastroenterological Surgery, Saitama Red Cross Hospital, Ohmiya, Saitama 330-8553, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Bunkyouku, Tokyo 113-8421, Japan
| | - Ken Shirabe
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.,Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
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Lu X, Yu Y, Tan S. p53 expression in patients with ulcerative colitis - associated with dysplasia and carcinoma: a systematic meta-analysis. BMC Gastroenterol 2017; 17:111. [PMID: 29070013 PMCID: PMC5655860 DOI: 10.1186/s12876-017-0665-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 10/03/2017] [Indexed: 02/08/2023] Open
Abstract
Background Tumor suppressor gene p53 expression has been reported in patients with ulcerative colitis (UC). However, the correlation between p53 expression and UC remains controversial. The aim of this meta-analysis was to investigate the association between p53 expression and different pathological types of UC. Methods Publications were searched in the PubMed, Embase, EBSCO, Wangfang, and CNKI databases. The overall odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were summarized in this study. Results Final 19 papers were identified in this meta-analysis, including 1068 patients with UC and 130 normal tissue samples. Immunohistochemical p53 expression was significantly higher in UC without dysplasia and carcinoma (UC group) compared to normal tissue samples (OR = 3.14, P = 0.001), higher in UC with dysplasia than in UC group (OR = 10.76, P < 0.001), and higher in UC with colorectal cancer (CRC) than in UC with dysplasia (OR = 1.69, P = 0.035). Subgroup analysis of ethnicity (UC group vs. normal tissues) showed that p53 expression was correlated with UC in Asians, but not in Caucasians. When UC with dysplasia was compared to UC group, p53 expression was linked to UC with dysplasia among both Asians and Caucasians. When UC-CRC was compared to UC with dysplasia, p53 expression was not associated with UC-CRC in both Caucasians and Asians. Conclusions p53 expression was closely associated with UC-CRC development. p53 expression showed different ethnic characteristics among different pathological types of UC. Electronic supplementary material The online version of this article (10.1186/s12876-017-0665-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaohong Lu
- Departmemt of gastroenterology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China.
| | - Yuanjie Yu
- Departmemt of gastroenterology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Shiyun Tan
- Departmemt of gastroenterology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
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Shivakumar BM, Chakrabarty S, Rotti H, Seenappa V, Rao L, Geetha V, Tantry BV, Kini H, Dharamsi R, Pai CG, Satyamoorthy K. Comparative analysis of copy number variations in ulcerative colitis associated and sporadic colorectal neoplasia. BMC Cancer 2016; 16:271. [PMID: 27080994 PMCID: PMC4831153 DOI: 10.1186/s12885-016-2303-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Accepted: 04/07/2016] [Indexed: 12/12/2022] Open
Abstract
Background The incidence of and mortality from colorectal cancers (CRC) can be reduced by early detection. Currently there is a lack of established markers to detect early neoplastic changes. We aimed to identify the copy number variations (CNVs) and the associated genes which could be potential markers for the detection of neoplasia in both ulcerative colitis-associated neoplasia (UC-CRN) and sporadic colorectal neoplasia (S-CRN). Methods We employed array comparative genome hybridization (aCGH) to identify CNVs in tissue samples of UC nonprogressor, progressor and sporadic CRC. Select genes within these CNV regions as a panel of markers were validated using quantitative real time PCR (qRT-PCR) method along with the microsatellite instability (MSI) in an independent cohort of samples. Immunohistochemistry (IHC) analysis was also performed. Results Integrated analysis showed 10 overlapping CNV regions between UC-Progressor and S-CRN, with the 8q and 12p regions showing greater overlap. The qRT-PCR based panel of MYC, MYCN, CCND1, CCND2, EGFR and FNDC3A was successful in detecting neoplasia with an overall accuracy of 54 % in S-CRN compared to that of 29 % in UC neoplastic samples. IHC study showed that p53 and CCND1 were significantly overexpressed with an increasing frequency from pre-neoplastic to neoplastic stages. EGFR and AMACR were expressed only in the neoplastic conditions. Conclusion CNVs that are common and unique to both UC-associated and sporadic colorectal neoplasm could be the key players driving carcinogenesis. Comparative analysis of CNVs provides testable driver aberrations but needs further evaluation in larger cohorts of samples. These markers may help in developing more effective neoplasia-detection strategies during screening and surveillance programs. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2303-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- B M Shivakumar
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal University, Manipal, India.,School of Life Sciences, Manipal University, Manipal, Karnataka, 576104, India
| | | | - Harish Rotti
- School of Life Sciences, Manipal University, Manipal, Karnataka, 576104, India
| | - Venu Seenappa
- School of Life Sciences, Manipal University, Manipal, Karnataka, 576104, India
| | - Lakshmi Rao
- Department of Pathology, Kasturba Medical College, Manipal University, Manipal, India
| | - Vasudevan Geetha
- Department of Pathology, Kasturba Medical College, Manipal University, Manipal, India
| | - B V Tantry
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal University, Mangalore, India
| | - Hema Kini
- Department of Pathology, Kasturba Medical College, Manipal University, Mangalore, India
| | - Rajesh Dharamsi
- Dharamsi Hospital, Chandni Chowk, Sangli, Maharashtra, India
| | - C Ganesh Pai
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal University, Manipal, India
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Wohl P, Hucl T, Drastich P, Kamenar D, Spicak J, Honsova E, Sticova E, Lodererova A, Matous J, Hill M, Wohl P, Kucera M. Epithelial markers of colorectal carcinogenesis in ulcerative colitis and primary sclerosing cholangitis. World J Gastroenterol 2013; 19:2234-2241. [PMID: 23599650 PMCID: PMC3627888 DOI: 10.3748/wjg.v19.i14.2234] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Revised: 01/09/2013] [Accepted: 02/06/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the expression of epithelial markers of colorectal carcinogenesis in patients with long-term ulcerative colitis (UC) and primary sclerosing cholangitis (PSC) before and after transplantation.
METHODS: Eight patients with UC and PSC prior to liver transplantation (PSC-UC), 22 patients with UC after liver transplantation for PSC (OLT), 9 patients with active ulcerative colitis without PSC (UCA), 7 patients with UC in remission (UCR) and 10 controls (N) underwent colonoscopy with multiple biopsies. Specimens were analysed histologically and semi-quantitatively immunohistochemically for p53, Bcl-2 and cyclooxygenase-2 (COX-2) markers. Statistical analysis was performed by Kruskal-Wallis and Fisher’s exact tests.
RESULTS: PSC-UC had a statistically significantly higher expression of p53 in the nondysplastic mucosa as compared to OLT, UCA, UCR and N (P < 0.05). We also found a statistically significant positive correlation between the incidence of PSC and the expression of p53 (P < 0.001). UCA had a higher p53 expression as compared to UCR. OLT had a significantly lower expression of p53 as compared with PSC-UC (P < 0.001). Bcl-2 had a significant higher bcl-2 expression as compared with controls. No difference in COX-2 expression between PSC-UC, UCR and UCA was found. UCA had higher COX-2 expression as compared to UCR. We also found a statistically significant positive correlation between the expression of COX-2 and p53. Patients after liver transplantation for PSC had a statistically significantly lower expression of the p53 compared with PSC-UC (P < 0.001). PSC-UC had the same inflammatory endoscopic activity as OLT and UCR when evaluated with the Mayo score.
CONCLUSION: Our study shows that the nondysplatic mucosa of UC patients with PSC is characterised by a higher expression of the tumour suppressor gene p53, suggesting a higher susceptibility of cancer. This p53 overexpression correlates with the presence of PSC whilst it is not present in patients with UC after liver transplantation for PSC.
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Kanaan Z, Rai SN, Eichenberger MR, Barnes C, Dworkin AM, Weller C, Cohen E, Roberts H, Keskey B, Petras RE, Crawford NPS, Galandiuk S. Differential microRNA expression tracks neoplastic progression in inflammatory bowel disease-associated colorectal cancer. Hum Mutat 2012; 33:551-60. [PMID: 22241525 DOI: 10.1002/humu.22021] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
One of the most serious complications faced by patients with inflammatory bowel disease (IBD) is the potential development of colorectal cancer (CRC). There is a compelling need to enhance the accuracy of cancer screening of IBD patients. MicroRNAs (miRNAs) are small nonprotein-coding RNAs that play important roles in CRC oncogenesis. In this study, we report differential miRNA expression in IBD patients with associated CRC from non-neoplastic tissue to dysplasia and eventually cancer. In addition, we identify and examine the role of dysregulated miRNAs in the TP53 pathway. In our CD patients, six miRNAs were upregulated from non-neoplastic tissue to dysplasia, but downregulated from dysplasia to cancer (miR-122, miR-181a, miR-146b-5p, let-7e, miR-17, miR-143) (P < 0.001). Six differentially expressed miRNAs affected the TP53 pathway (miR-122, miR-214, miR-372, miR-15b, let-7e, miR-17) (P < 0.001). Using two human colon cancer cell lines (HT-29 and HCT-116), E2F1, an upstream regulator of TP53, was downregulated in both cell lines transfected with let-7e (P < 0.05) as well as in HCT-116 cells transfected with miR-17 (P < 0.05). Additionally, cyclin G, a cell-cycle regulator miR-122 target was downregulated in both cell lines (P < 0.05). Unique differentially expressed miRNAs were observed in CD-associated CRC progression. Six of these miRNAs had a tumorigenic effect on the TP53 pathway; the effect of three of which was studied using cell lines.
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Affiliation(s)
- Ziad Kanaan
- Department of Surgery, Price Institute of Surgical Research and the Section of Colorectal Surgery, University of Louisville School of Medicine, Louisville, Kentucky, USA
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Abstract
Patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Risk factors are extent and severity of colonic inflammation, concurrent primary sclerosing cholangitis, and a positive family history of sporadic CRC. The chromosomal instability, microsatellite instability and hypermethylation pathways form the molecular background of IBD-related carcinogenesis, which is not different from sporadic CRC. The dysplasia-carcinoma sequence of IBD-related colorectal carcinogenesis makes patients suitable for endoscopic surveillance. In the future, new molecular biomarkers and endoscopic techniques may improve early detection of precursor lesions of IBD-related CRC. The potential of aminosalicylates and ursodeoxycholic acid as chemopreventive agents needs to be studied in randomized clinical trials. Patients with IBD who are being treated with thiopurines have a slightly increased risk of developing lymphoproliferative disorders, whereas patients with small bowel Crohn's disease have a high relative risk and a small absolute risk of developing small bowel adenocarcinoma.
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Affiliation(s)
- M M H Claessen
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
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Sameshima S, Tomozawa S, Koketsu S, Okada T, Miyato H, Iijima M, Kojima M, Kaji T. Intramucosal adenocarcinoma of the ileum originated 40 years after ileosigmoidostomy. World J Surg Oncol 2009; 7:41. [PMID: 19379525 PMCID: PMC2676285 DOI: 10.1186/1477-7819-7-41] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2009] [Accepted: 04/21/2009] [Indexed: 01/13/2023] Open
Abstract
Background Small bowel adenocarcinomas (SBAs) are rare carcinomas. They are asymptomatic and usually neither endoscopy nor contrast studies are performed for screening Case presentation A 72-year-old Japanese male had a positive fecal occult blood test at a regular check-up in 2006. He suffered appendicitis and received an ileosigmoidostomy in 1966. A colonoscopy revealed an irregular mucosal lesion with an unclear margin at the ileum side of the anastomosis. A mucosal biopsy specimen showed adenocarcinoma histopathologically. Excision of the anastomosis was performed for this patient. The resected specimen showed a flat mucosal lesion with a slight depression at the ileum adjacent to the anastomosis. Histological examination revealed a well differentiated intramucosal adenocarcinoma (adenocarcinoma in situ). Immunohistological staining demonstrated the overexpression of p53 protein in the adenocarcinoma. Conclusion Adenocarcinoma of the ileum at such an early stage is a very rare event. In this case, there is a possibility that the ileosigmoidostomy resulted in a back flow of colonic stool to the ileum that caused the carcinogenesis of the small intestine.
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Affiliation(s)
- Shinichi Sameshima
- Department of Surgery, Hitachi Yokohama Hospital, 550 Totsuka-cho, Totsuka-ku, Yokohama, Kanagawa 244-0003, Japan.
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Marx A, Wandrey T, Simon P, Wewer A, Grob T, Reichelt U, Minner S, Simon R, Spehlmann M, Tigges W, Soehendra N, Seitz U, Seewald S, Izbicki JR, Yekebas E, Kaifi JT, Mirlacher M, Terracciano L, Fleischmann A, Raedler A, Sauter G. Combined α-methylacyl coenzyme A racemase/p53 analysis to identify dysplasia in inflammatory bowel disease. Hum Pathol 2009; 40:166-73. [DOI: 10.1016/j.humpath.2008.06.027] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2007] [Revised: 05/15/2008] [Accepted: 06/13/2008] [Indexed: 10/21/2022]
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10
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Tao Y, Hart J, Lichtenstein L, Joseph LJ, Ciancio MJ, Hu S, Chang EB, Bissonnette M. Inducible heat shock protein 70 prevents multifocal flat dysplastic lesions and invasive tumors in an inflammatory model of colon cancer. Carcinogenesis 2008; 30:175-82. [PMID: 19005184 DOI: 10.1093/carcin/bgn256] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Heat shock protein 70 (Hsp70) regulates protein biosynthesis and refolding of denatured proteins. Since Hsp70 participates in recovery from stress injury, we examined the effect of Hsp70 genetic deletion in the azoxymethane (AOM)/dextran sulfate sodium (DSS) model of inflammation and colon cancer. METHODS Hsp70 mutant mice (Hsp70.1(-/-)/70.3(-/-)) and wild-type (WT) littermates received AOM and three cycles of DSS and were killed 24 weeks later. Tumors were graded for histology and immunostained for p53, adenomatous polyposis coli, beta-catenin, cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNOS) and sequenced for p53 mutations. RESULTS Elevated adenomas developed in 4/10 WT mice with no dysplasia in adjacent mucosa. In contrast, 7/8 Hsp70 knock out (KO) mice developed chronic mucosal inflammation and multifocal areas of flat dysplasia and 4/8 progressed to invasive carcinomas arising in a background of flat dysplastic mucosa. These differences in the incidence of flat dysplasia and invasive cancers were significant (P < 0.05). Nuclear p53 was stronger in Hsp70 KO tumors compared with WT tumors, and sequencing confirmed p53 mutations in 2/5 tumors from Hsp70(-/-) versus 0/5 in WT mice. In Hsp70 WT tumors, beta-catenin was predominantly nuclear, compared with membranous beta-catenin in Hsp70(-/-) tumors, suggesting that Hsp70 regulates beta-catenin in colonic tumorigenesis. Cox-2 and iNOS levels were increased in tumors from Hsp70(-/-) mice compared with Hsp70 WT tumors. CONCLUSIONS Hsp70-deleted mice treated with AOM/DSS develop flat invasive colonic tumors that mimic many histological and molecular features of ulcerative colitis colon cancer. This model will be useful to dissect the role of Hsp70 in inflammatory bowel disease colon cancer.
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Affiliation(s)
- Yun Tao
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
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11
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Kojima Y, Mogaki M, Takagawa R, Ota I, Sugita M, Natori S, Hamaguchi Y, Kurosawa H, Fukushima T, Masui H, Fukazawa S, Yamanaka S, Tsuura Y, Nagahori K. A case of lymphoepithelioma-like carcinoma of the colon with ulcerative colitis. J Gastroenterol 2007; 42:181-5. [PMID: 17351809 DOI: 10.1007/s00535-006-1981-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2006] [Accepted: 11/21/2006] [Indexed: 02/04/2023]
Abstract
Follow-up colonoscopy of a 25-year-old Japanese man with ulcerative colitis (UC) who had undergone endoscopic mucosal resection twice for early colon cancers revealed the presence of a new 1.5-cm-diameter tumor in the sigmoid colon. It was diagnosed by preoperative biopsy as a poorly differentiated adenocarcinoma. Sigmoidectomy was performed, and the pathological findings revealed lymphoepithelioma-like carcinoma (LEC). In situ hybridization to detect Epstein-Barr virus (EBV)-encoded small RNAs showed positive signals in stromal lymphocytes, but weak signals in the tumor cells. The association between EBV and LEC was obscure in this case. Unlike typical UC-mediated colon cancers, the lesion was poorly differentiated, and negative for p53 signals immunohistochemically. These findings may hint at a novel mechanism of carcinogenesis in UC-mediated colorectal cancer.
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Affiliation(s)
- Yasuyuki Kojima
- Department of Surgery, Yokosuka Kyosai Hospital, 1-16 Yonegahama, Yokosuka, Kanagawa, Japan
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12
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Risques RA, Rabinovitch PS, Brentnall TA. Cancer surveillance in inflammatory bowel disease: new molecular approaches. Curr Opin Gastroenterol 2006; 22:382-90. [PMID: 16760754 DOI: 10.1097/01.mog.0000231812.95525.a7] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW Patients with chronic inflammatory bowel disease, such as ulcerative colitis and Crohn's disease, have an increased risk of colorectal cancer. Life-long colonoscopy surveillance is performed to detect the presence of dysplasia, but this approach is expensive and time-consuming. Thus, there is intensive research to identify molecular factors with prognostic value. This review summarizes recent research, with a special emphasis on the mechanisms underlying these molecular alterations. RECENT FINDINGS The role of chromosomal instability in the progression to inflammatory bowel disease-associated colorectal cancer is clear and likely relates to chronic cycles of injury, inflammation, repair and telomere shortening. The role of microsatellite instability has been a subject of discussion, and data suggest that microsatellite instability in inflammatory bowel disease might be different from microsatellite instability in sporadic colorectal cancer. Methylation, as a mechanism of gene silencing, also plays a role in ulcerative colitis tumorigenesis. Chronic inflammation has been linked to p53 activation and oxidative stress, contributing to the extensive genomic DNA damage observed in ulcerative colitis. SUMMARY Improved understanding of the molecular biology of cancer progression in inflammatory bowel disease will hopefully lead to the identification of useful prognostic biomarkers. Efforts are needed to prove the clinical utility of the most promising markers now identified.
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Colliver DW, Crawford NPS, Eichenberger MR, Zacharius W, Petras RE, Stromberg AJ, Galandiuk S. Molecular profiling of ulcerative colitis-associated neoplastic progression. Exp Mol Pathol 2005; 80:1-10. [PMID: 16277983 DOI: 10.1016/j.yexmp.2005.09.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2005] [Accepted: 09/14/2005] [Indexed: 12/13/2022]
Abstract
Fundamental differences exist between ulcerative colitis (UC)-associated and sporadic forms of colorectal cancer, including preexisting inflammation, type of dysplasia, and timing of molecular events in carcinogenesis. Transcriptional alterations that occur in UC-associated neoplasia in the progression from normal mucosa through dysplastic epithelium to invasive cancer have not been described. We used Affymetrix U95Av2 microarrays to assess differential gene expression in the neoplastic progression of UC tissue from the colonic mucosa of individuals with benign UC, UC-dysplasia-associated lesions or masses, and UC adenocarcinoma. By correlating transcript alterations across tissue types using a mixed statistical model, we identified 699 genes exhibiting altered expression with dysplasia development. A different expression profile was observed in progression to adenocarcinoma with 392 transcripts exhibiting differential expression. There were 224 transcripts common to both dysplasia and adenocarcinoma. Most of the differentially expressed genes described herein were not previously known to play a role in neoplastic progression in UC, including transcripts affecting cell proliferation and apoptosis, signal transduction and signaling, and DNA repair. The altered expression of five transcripts was confirmed by quantitative real-time reverse-transcription polymerase chain reaction. Based on comparisons with previous studies on sporadic colorectal carcinoma, several similarities were found. There were, however, important differences that suggest that different molecular events may occur in the development of UC-associated neoplasia. Several of these genes demonstrated similar changes in dysplastic and cancerous tissue and may be involved in early cancer formation. Identification of these genes as potential clinical biomarkers may lead to improved early disease diagnosis.
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Affiliation(s)
- Daniel W Colliver
- Digestive Surgery Research Laboratory, Price Institute for Surgical Research, Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40292, USA.
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Wong NACS, Mayer NJ, Anderson CE, McKenzie HC, Morris RG, Diebold J, Mayr D, Brock IW, Royds JA, Gilmour HM, Harrison DJ. Cyclin D1 and p21 in ulcerative colitis-related inflammation and epithelial neoplasia: a study of aberrant expression and underlying mechanisms. Hum Pathol 2003; 34:580-8. [PMID: 12827612 DOI: 10.1016/s0046-8177(03)00125-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
It is unclear whether and how cyclin D1 and/or p21(WAF1/CIP1) dysregulation contribute to ulcerative colitis (UC)-related inflammation and colorectal carcinogenesis. Cases of quiescent UC (QUC; n = 15), active UC (AUC; n = 23), UC-related dysplasia (n = 35) and UC-related colorectal adenocarcinomas (CRCs; n = 11) were studied with cyclin D1 and p21(WAF1/CIP1) immunohistochemistry. The CRCs were also studied with beta-catenin, bcl2, and p53 immunohistochemistry, p53 and k-ras mutation analyses, and cyclin D1 gene fluorescence in situ hybridization. QUC showed cyclin D1 (negative/weak staining) and p21(WAF1/CIP1) (surface epithelial and upper-third crypt staining) expression similar to that of normal colorectum. Moderate or strong cyclin D1 immunostaining was seen in 9% of AUC cases, 40% of dysplasia cases, and 36% of UC-related CRCs. Although these carcinomas showed neither cyclin D1 gene amplification nor any association between k-ras mutation and cyclin D1 overexpression, the latter was closely related to nuclear beta-catenin expression. Increased lower-third crypt p21(WAF1/CIP1) staining was seen in 57% of AUC cases; decreased upper-third crypt p21(WAF1/CIP1) staining, in 23% of dysplasia cases; and absent or weak p21(WAF1/CIP1) staining, in 55% of UC-related CRCs. The latter change was always associated with p53 mutation but could not be related to p53 or bcl2 expression. In conclusion, AUC shows up-regulated cyclin D1 and p21(WAF1/CIP1) expression. Cyclin D1 up-regulation and p21(WAF1/CIP1) down-regulation occur early in UC-related carcinogenesis. Cyclin D1 up-regulation is less common in UC-related CRCs than in sporadic CRCs, and is related to beta-catenin nuclear signaling. p21(WAF1/CIP1) down-regulation is seen at an equal or higher frequency among UC-related CRCs compared with sporadic CRCs and is attributable to p53 mutation.
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Affiliation(s)
- Newton A C S Wong
- Sir Alastair Currie CRC Laboratories, Department of Pathology, University of Edinburgh Medical School, UK
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Bruewer M, Schmid KW, Krieglstein CF, Senninger N, Schuermann G. Metallothionein: early marker in the carcinogenesis of ulcerative colitis-associated colorectal carcinoma. World J Surg 2002; 26:726-31. [PMID: 12053227 DOI: 10.1007/s00268-002-6266-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Metallothioneins (MTs) are zinc-binding proteins whose overexpression may lead to sequestration of zinc ions and consequently to functional inactivation of the p53 tumor suppressor gene. The aim of the study was to investigate the potential role of MTs in the carcinogenesis of ulcerative colitis (UC) as well as possible effects on p53 function. The monoclonal antibodies E9 (anti-MT), DO-7, and 1801 (anti-p53) and the polyclonal antibody CM-1 (anti-p53) were used to stain formalin-fixed, paraffin-embedded colon specimens obtained from 14 patients with UC-associated colorectal carcinoma (CAC), 13 with high-grade dysplasia (HGD), 10 with low-grade dysplasia (LGD), and 30 with UC without dysplasia or carcinoma. Statistical significance (p <0.05) was assessed using Fisher's exact test. Positive MT staining (> 20% of tumor, dysplastic, or epithelial cells) was found in most UC and LGD but in only a small percentage of HGD and CAC (p <0.01 for CAC vs. UC and LGD vs. HGD). Positive p53 immunoreactivity was observed predominantly in HGD and CAC but not in LGD and UC (p <0.01 for CAC vs. UC and HGD vs. LGD). In histologically normal tissue neighboring CAC, significant MT expression was found in six of seven specimens with simultaneous lack of p53 expression. MT overexpression may represent an important early step in the development of CAC independent of p53 expression and should be investigated in the long term as an independent cancer risk factor in UC.
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Affiliation(s)
- Matthias Bruewer
- Department of General Surgery, University of Muenster, Waldeyerstrasse 1, D-48149 Muenster, Germany.
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